Plant food-derived antioxidant nutrients in neuroprotection against chemotherapy-induced neurotoxicity: from molecular mechanisms to clinical applications

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most challenging dose-limiting toxicities in contemporary oncology, affecting 19–85% of patients receiving neurotoxic chemotherapy agents. The pathophysiological mechanisms of CIPN are complex, involving multiple interconnected processes including oxidative stress, neuroinflammation, neurotrophic factor depletion, and mitochondrial dysfunction. Plant-derived antioxidant nutrients have emerged as promising candidates for CIPN prevention due to their unique multi-target neuroprotective capabilities. This comprehensive review systematically analyzes the molecular protective mechanisms of plant-derived nutrients, evaluates existing clinical evidence, and discusses practical application strategies. The focus is on the neuroprotective effects of curcumin, green tea catechins, vitamin E, and other plant compounds. Evidence indicates that these compounds exert protective effects through activation of endogenous antioxidant systems, modulation of inflammatory pathways, enhancement of neurotrophic factors, and protection of mitochondrial function. While clinical evidence is still accumulating, preliminary studies show encouraging results, providing a scientific basis for developing plant food-based CIPN prevention strategies.

1 Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating dose-limiting toxicity, affecting 19–85% of patients treated with neurotoxic agents (1–3). Its sensorimotor symptoms—including numbness, tingling, and burning pain—often force dose reductions or discontinuation, compromising cancer outcomes (4, 5). Current therapies offer only modest symptom relief and fail to address the underlying mechanisms (6, 7) (Table 1).

The pathogenesis of CIPN is multifactorial, involving oxidative stress, neuroinflammation, neurotrophic factor depletion, and mitochondrial dysfunction (6–10). These convergent processes overwhelm the limited regenerative capacity of the peripheral nervous system, indicating that effective interventions must target multiple pathways simultaneously rather than isolated mechanisms (11).

Plant-derived foods have emerged as promising candidates for CIPN prevention due to their unique multi-target antioxidant properties. Their bioactive compounds can alleviate oxidative stress, modulate inflammatory cascades, preserve mitochondrial integrity, and enhance neurotrophic signaling, while offering safety, accessibility, and broad patient acceptance (12, 13). Advances in precision nutrition and nutrigenomics further expand their potential by enabling personalized interventions tailored to genetic and metabolic profiles (14–16).

This comprehensive review examines the current state of knowledge regarding plant food-derived nutrients in CIPN prevention and management. We analyze molecular mechanisms, evaluate clinical evidence, and discuss practical applications while identifying key research priorities for clinical translation.

2 Pathophysiological foundations of chemotherapy-induced neurotoxicity

The development of CIPN involves multiple convergent mechanisms that fundamentally alter the neurobiological landscape of peripheral nervous system function. These mechanisms arise from direct chemotherapy-induced cellular damage but subsequently evolve into self-perpetuating cycles of dysfunction and impaired repair (6–8, 17). Understanding these interconnected pathways provides essential context for evaluating how plant food-derived nutrients can effectively intervene in disease progression and support neural recovery (11, 18, 19).

2.1 Oxidative stress and cellular antioxidant depletion

The peripheral nervous system demonstrates exceptional vulnerability to chemotherapy-induced oxidative damage due to its unique structural and metabolic characteristics, including long axonal transport distances, high polyunsaturated fatty acid content in neural membranes as major targets for lipid peroxidation, and weaker blood–nerve barrier protection compared with central structures (9, 20–23). Chemotherapy agents initiate oxidative stress through diverse pathways that collectively overwhelm cellular antioxidant defenses, with platinum-based compounds generating excessive reactive oxygen species through direct DNA interaction and mitochondrial dysfunction while rapidly depleting glutathione stores that serve as the primary intracellular antioxidant defense system (6, 24) (Figure 1).

Figure 1

Taxane agents contribute through distinct mechanisms involving microtubule disruption and impaired axonal transport of antioxidant enzymes and protective molecules. This creates localized oxidative stress hotspots in distal nerve regions, explaining the characteristic length-dependent pattern of taxane-induced neuropathy (9, 25). Anthracycline compounds directly target mitochondrial electron transport chains, generating superoxide radicals and hydrogen peroxide while simultaneously compromising ATP-dependent antioxidant regeneration systems. This creates vicious cycles where mitochondrial damage produces more oxidants that further impair cellular function and perpetuate neuronal dysfunction (24, 26).

The temporal dynamics of chemotherapy-induced oxidative stress involve both acute phases occurring during and immediately after treatment administration, characterized by rapid antioxidant depletion and damage marker accumulation, and chronic phases persisting long after treatment completion, driven by sustained mitochondrial dysfunction, impaired antioxidant enzyme expression, and ongoing inflammatory processes (6, 27). This persistent oxidative imbalance contributes significantly to the chronic nature of CIPN and its resistance to conventional therapeutic approaches (7).

2.2 Neuroinflammatory networks and immune system activation

Neuroinflammation represents a critical pathophysiological mechanism that amplifies and perpetuates neural damage beyond the direct cytotoxic effects of chemotherapy treatment through complex interactions between immune cells, neural tissue, and inflammatory mediators that create self-reinforcing cycles of damage and impaired repair (10, 28). The inflammatory cascade begins with chemotherapy-induced tissue damage that releases damage-associated molecular patterns, including high mobility group box 1, ATP, and DNA fragments, which activate pattern recognition receptors on resident macrophages and Schwann cells that respond by producing pro-inflammatory cytokines including tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 (28–30).

These inflammatory mediators recruit additional immune cells and disrupt the blood-nerve barrier, allowing systemic inflammatory mediators to enter peripheral nerve tissue and further exacerbate local inflammation while creating a permissive environment for ongoing neural damage (29, 31–33). Nuclear factor-kappa B serves as a central mediator of chemotherapy-induced neuroinflammation, coordinating the expression of multiple pro-inflammatory genes in response to cellular stress and damage through multiple activation pathways including oxidative stress, DNA damage responses, and cytokine signaling cascades (28, 34).

Once activated, nuclear factor-kappa B translocates to the nucleus and initiates transcription of genes encoding inflammatory cytokines, chemokines, and enzymes such as cyclooxygenase-2 and inducible nitric oxide synthase that perpetuate inflammatory processes and directly damage neurons while impairing neurotrophic factor signaling and axonal regeneration (28, 34). Critically, chemotherapy-induced neuroinflammation often persists long after treatment completion, contributing to the chronic nature of CIPN and representing a potential therapeutic target for interventions aimed at breaking the cycle of ongoing inflammation and neural dysfunction.

2.3 Neurotrophic factor dysregulation and regenerative capacity impairment

The depletion of neurotrophic factors represents a crucial mechanism contributing to CIPN development and progression, as these essential proteins for neural survival, growth, differentiation, and synaptic plasticity demonstrate marked reductions during chemotherapy treatment through both direct suppression of gene expression by chemotherapy agents and indirect consequences of inflammation and oxidative stress that create a hostile environment for neurotrophic factor synthesis and signaling (6, 8, 35–38). Brain-derived neurotrophic factor and nerve growth factor, which are particularly important for maintaining sensory neurons predominantly affected in CIPN, show dramatic decreases that not only impair neuronal survival and increase susceptibility to chemotherapy-induced damage but also compromise the regenerative capacity of peripheral nerves, contributing to the persistent nature of CIPN and limiting recovery potential even after treatment completion (17, 39–43).

This neurotrophic factor deficiency creates a cascade of dysfunction that extends from direct effects on neuronal survival and growth to broader impacts on synaptic plasticity, pain processing, and neural adaptation mechanisms that are essential for maintaining normal sensory function (44–47). The spatial and temporal patterns of neurotrophic factor depletion correlate closely with the characteristic distal-to-proximal progression of neuropathy symptoms, suggesting that restoration of neurotrophic support represents a critical therapeutic target for both prevention and treatment of CIPN (48–50).

2.4 Mitochondrial bioenergetic crisis and cellular energy metabolism

Mitochondrial dysfunction emerges as a fundamental mechanism underlying chemotherapy-induced neurotoxicity, as these organelles serve as both primary targets of chemotherapy-induced damage and critical determinants of neuronal survival and function, with the peripheral nervous system’s exceptionally high energy demands making it particularly vulnerable to mitochondrial impairment since neurons rely heavily on oxidative phosphorylation for ATP generation and lack the glycolytic capacity to compensate for mitochondrial dysfunction (39, 51–54). Chemotherapy agents affect mitochondrial function through multiple interconnected mechanisms, including direct accumulation in mitochondria with formation of DNA crosslinks that impair replication and transcription, disruption of mitochondrial dynamics and transport processes, and direct inhibition of electron transport complexes, leading to ATP depletion and enhanced reactive oxygen species production that triggers apoptotic pathways and neuronal death (55–61) (Figure 2).

Figure 2

The bioenergetic crisis particularly affects distal nerve segments where energy demands are highest and mitochondrial transport distances are greatest, explaining the characteristic length-dependent pattern of chemotherapy-induced neuropathy and its predilection for sensory neurons that have particularly long axons and high metabolic demands (62–64) (Figure 3). Mitochondrial dysfunction also impairs the cell’s ability to maintain calcium homeostasis, support axonal transport, and synthesize essential proteins and lipids needed for membrane maintenance and repair, creating a cascade of cellular dysfunction that extends far beyond simple energy depletion to encompass fundamental aspects of neuronal structure and function (65–68).

Figure 3

3 Plant food Neuroprotective mechanisms: molecular targets and pathways

3.1 Endogenous antioxidant system activation

Plant polyphenolic compounds provide neuroprotection primarily through activation of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway (69, 70) (Table 2). This pathway serves as the master regulator of cellular antioxidant defenses (71). Under normal conditions, Nrf2 remains sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1) (72). Keap1 facilitates rapid Nrf2 degradation through the ubiquitin-proteasome system (73).

Plant polyphenolic compounds disrupt this regulatory interaction through multiple mechanisms. They form direct covalent modifications of Keap1 cysteine residues (70, 74). They also promote phosphorylation of Nrf2 by upstream kinases and create competitive inhibition of protein–protein binding interactions (75, 76). Once released from Keap1-mediated repression, Nrf2 translocates to the nucleus (70, 74). There it forms heterodimers with small Maf proteins and binds to antioxidant response element sequences (77, 78).

This transcriptional activation upregulates numerous cytoprotective enzymes. These collectively enhance cellular resistance to oxidative stress and toxic insults (79, 80). Key enzymes include heme oxygenase-1, which catalyzes heme degradation to produce powerful antioxidant and anti-inflammatory products (81, 82). NAD(P)H: quinone oxidoreductase 1 functions as a two-electron reductase preventing quinone participation in redox cycling reactions (83, 84). Glutathione S-transferases facilitate glutathione conjugation to electrophilic compounds for detoxification and elimination (85, 86).

Curcumin exemplifies the potent Nrf2-activating potential of plant polyphenols. Its diferuloylmethane structure contains multiple electrophilic sites that form covalent adducts with Keap1 cysteine residues (87, 88). This leads to conformational changes that disrupt Nrf2 binding. Curcumin simultaneously activates upstream kinases including protein kinase C and mitogen-activated protein kinases. These phosphorylate Nrf2 and promote its nuclear translocation (89–91). This mechanism is particularly relevant in CIPN, as Nrf2-driven upregulation of glutathione and phase II detoxification enzymes directly counteracts platinum-induced glutathione depletion, while enhancement of antioxidant enzymes such as SOD and catalase mitigates the distal oxidative stress hotspots characteristic of taxane-induced neuropathy.

3.2 Anti-inflammatory pathway modulation

Plant polyphenols demonstrate potent anti-inflammatory activity through inhibition of nuclear factor-kappa B signaling (92). This represents the key transcriptional pathway coordinating inflammatory gene expression in response to cellular stress (93). Curcumin functions as a particularly effective nuclear factor-kappa B inhibitor. It directly binds to nuclear factor-kappa B subunits, preventing their nuclear translocation and DNA binding (94). It also inhibits IκB kinase activity, preventing phosphorylation and degradation of IκB proteins (95).

The dual action of curcumin creates synergistic protective effects particularly relevant to chemotherapy-induced neuroinflammation prevention. It simultaneously activates anti-inflammatory Nrf2 pathways while inhibiting pro-inflammatory nuclear factor-kappa B signaling (96–98). This mechanistic duality explains curcumin’s demonstrated efficacy in reducing inflammatory cytokine expression and preserving nerve function in experimental neuropathy models (99–101).

Resveratrol from grapes and berries demonstrates anti-inflammatory effects through sirtuin 1 pathway activation (102). This deacetylates and inactivates nuclear factor-kappa B subunits while promoting cellular stress resistance (103, 104). Enhanced DNA repair and metabolic optimization provide sustained anti-inflammatory effects that promote cellular adaptation to stress (105–109).

Green tea catechins provide complementary anti-inflammatory activity through multiple pathways. These include direct inhibition of inflammatory enzymes such as cyclooxygenase-2 and lipoxygenase (110, 111). They also suppress inflammatory cytokine production and modulate immune cell activation patterns (112, 113). These compounds enhance the production of anti-inflammatory mediators and promote active resolution of inflammatory processes. This anti-inflammatory action directly suppresses the NF-κB–mediated cytokine cascades that drive persistent neuroinflammation and amplify chemotherapy-induced neural damage.

3.3 Neurotrophic factor enhancement systems

Plant foods contain numerous compounds that specifically support neurotrophic factor synthesis and signaling. These provide essential nutritional support for neural survival, growth, and repair processes (114–117). Flavonoid compounds from various plant sources demonstrate the ability to cross the blood–brain barrier (116). They directly stimulate brain-derived neurotrophic factor synthesis in neural tissue through activation of cAMP response element-binding protein pathways (115, 116, 118, 119). This transcriptional activation drives brain-derived neurotrophic factor gene transcription via phosphorylation-dependent mechanisms. The result is increased brain-derived neurotrophic factor expression that enhances neuronal survival. It also promotes axonal growth and supports synaptic plasticity essential for neural adaptation and recovery (120–123).

Soy isoflavones, particularly genistein and daidzein, demonstrate unique neurotrophic properties (124–126). These occur through their selective estrogen receptor modulator activities (127–129). They bind preferentially to estrogen receptor beta, which is highly expressed in neural tissue (130, 131). This promotes brain-derived neurotrophic factor gene transcription via estrogen response elements (132–135). The result is increased brain-derived neurotrophic factor protein synthesis and release (133, 135–137).

The neurotrophic effects of soy isoflavones extend beyond brain-derived neurotrophic factor modulation. They enhance nerve growth factor synthesis in Schwann cells, the primary supportive cells of peripheral nerves (138–140). They also promote expression of neurotrophin-3 and neurotrophin-4 that support different populations of sensory neurons (141). This makes these compounds particularly valuable for preventing and treating peripheral neuropathy. This neurotrophic support directly addresses the depletion of BDNF and NGF that limits peripheral nerve survival and regenerative capacity during chemotherapy.

3.4 Mitochondrial protection and bioenergetic enhancement

Plant foods provide mitochondrial protective nutrients that deliver essential bioenergetic support (142–145). These can prevent chemotherapy-induced mitochondrial damage and promote neural recovery through enhanced cellular energy production and reduced oxidative stress. α-Lipoic acid, found naturally in spinach, broccoli, and other green vegetables, functions as a unique mitochondrial antioxidant (146, 147).

This compound possesses both lipophilic and hydrophilic properties that allow comprehensive protection in both aqueous and lipid phases (148). It serves as an essential cofactor for mitochondrial enzyme complexes including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (149). These catalyze crucial steps in cellular energy production. α-Lipoic acid also functions as a potent antioxidant that directly scavenges reactive oxygen species while regenerating other antioxidants (150, 151).

The protective effects extend to activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). This serves as the master regulator of mitochondrial biogenesis (152, 153). PGC-1α activation promotes transcription of nuclear genes encoding mitochondrial proteins while enhancing mitochondrial DNA replication and protein synthesis (154, 155).

Coenzyme Q10, obtained from plant foods including spinach, cauliflower, and whole grains, serves as an essential component of the mitochondrial electron transport chain (156). It shuttles electrons between Complex I/II and Complex III while playing a crucial role in oxidative phosphorylation and ATP synthesis (157, 158). Coenzyme Q10 also functions as a powerful lipid-phase antioxidant that protects mitochondrial membranes from oxidative damage (158, 159).

Pyrroloquinoline quinone (PQQ), found in fermented soy products, green tea, and various fruits and vegetables, demonstrates unique mitochondrial protective properties (160). It functions as a redox cofactor for various enzymes while demonstrating potent antioxidant activity and mitochondrial biogenesis-promoting effects (161). PQQ can directly activate PGC-1α through cAMP/cAMP response element-binding protein signaling pathways. This leads to enhanced mitochondrial biogenesis and improved cellular bioenergetic capacity (162). These protective effects directly oppose the mitochondrial bioenergetic failure caused by platinum- and taxane-induced impairment of oxidative phosphorylation, calcium homeostasis, and axonal energy supply.

4 Clinical evidence landscape for plant food interventions

The translation of preclinical neuroprotective mechanisms into clinical applications has generated substantial research interest and a growing body of evidence. However, direct clinical evidence for plant food interventions in chemotherapy-induced peripheral neuropathy prevention remains limited compared to the extensive and consistently positive preclinical foundation (163–165). This highlights the critical need for well-designed clinical trials that can bridge the gap between mechanistic understanding and therapeutic application while addressing the unique challenges associated with studying complex, multi-component dietary interventions in cancer patient populations.

4.1 Turmeric and curcumin: evidence chain validation

Curcumin is the plant-derived compound with the most comprehensive validation for CIPN prevention, anchored by a landmark Level I pediatric randomized trial and further supported by cross-disease and mechanistic studies (166). This double-blind study enrolled 141 children aged 5–15 years with acute lymphoblastic leukemia receiving vincristine-based chemotherapy protocols. Patients randomized to oral curcumin supplementation at 3 mg/kg twice daily for 3 months demonstrated significant reduction in vincristine-induced peripheral neuropathy incidence from 70.0% in the placebo group to 39.4% in the treatment group (Table 3). Beyond incidence reduction, curcumin treatment resulted in significantly improved Total Neuropathy Score-Pediatric Vincristine (TNS-PV) evaluations and reduced motor nerve electrophysiological abnormalities, providing objective validation of genuine neuroprotective effects.

Cross-disease validation arises from neuropathies that share convergent mechanisms. In patients with type 2 diabetes-associated sensorimotor polyneuropathy, nano-curcumin 80 mg once daily for 8 weeks significantly reduced HbA1c and fasting plasma glucose while improving the total neuropathy score, reflexes and skin temperature (167). Although median nerve conduction velocity was not assessed, the concordant amelioration of clinical signs and symptoms provides indirect yet compelling support for curcumin’s capacity to counter peripheral nerve dysfunction via antioxidant and anti-inflammatory pathways. Such cross-condition efficacy strengthens the translational case for curcumin as a broad neuroprotective agent against disorders that share common pathophysiological drivers (168–170).

Extensive animal data establish curcumin’s pharmacological foundation across multiple chemotherapy-induced neuropathy models. In paclitaxel-induced peripheral neuropathy mice, dietary supplementation with 1.5% curcumin-phospholipid complex (Meriva®) completely blocked both mechanical and cold pain hypersensitivity (171). Mechanistic investigations revealed that this protection operates through the α7 nicotinic acetylcholine receptor (α7 nAChR) signaling axis, which suppresses spinal cord inflammatory responses. The specificity of this mechanism was definitively established through α7 nAChR gene knockout mice studies, where curcumin’s protective effects were completely eliminated. Administration of α7 nAChR receptor antagonists similarly abolished the neuroprotective benefits, confirming α7 nAChR as the critical molecular target.

Validation across different chemotherapy agents is robustly demonstrated in models of cisplatin-, vincristine-, and oxaliplatin-induced neuropathy. In oxaliplatin models, curcumin dose-dependently alleviates mechanical and cold hypersensitivity, improves both motor (MNCV) and sensory (SNCV) nerve conduction velocities, and repairs damaged spinal neurons. This protection is mechanistically linked to its ability to enhance endogenous antioxidant enzymes (SOD, GSH-Px, CAT) while reducing lipid peroxidation (MDA), and critically, to suppress neuroinflammation by inhibiting the activation of the NF-κB pathway and its downstream inflammatory cytokines (TNF-α, IL-1β, IL-6) (98). Similarly, in vincristine-induced neuropathy, advanced formulations like curcumin nano-emulsions significantly reduce cold and thermal hyperalgesia by boosting antioxidant (SOD, CAT) and anti-inflammatory (IL-10) markers, while downregulating NF-κB expression in the sciatic nerve (172). In cisplatin models, curcumin nanoparticles effectively counteract neurotoxicity by normalizing levels of lipid peroxidation, TNF-α, and caspase-3, and restoring depleted glutathione and Na+, K + -ATPase activity (173, 174). Collectively, these studies confirm that curcumin’s efficacy stems from its multi-target ability to mitigate oxidative stress, suppress the NF-κB-driven neuroinflammatory cascade, and preserve both the structure and function of peripheral nerves.

The curcumin evidence represents the most comprehensive clinical validation among plant-derived neuroprotective compounds, with the pediatric randomized controlled trial providing Level I evidence for efficacy, cross-condition validation demonstrating broader therapeutic potential, and robust preclinical data elucidating specific molecular mechanisms through α7 nAChR-Nrf2 dual pathway targeting. This evidence integration demonstrates completion of a comprehensive “clinical-preclinical-mechanistic” validation loop that positions curcumin as having achieved the most complete validation profile among plant-derived neuroprotective compounds.

4.2 Green tea: epidemiological and intervention evidence

Green tea catechins represent an emerging intervention with promising evidence from related neuropathies and ongoing clinical trials. Green tea is a widely consumed polyphenolic beverage with substantial neuroprotective potential (175–177). Green tea contains a complex mixture of bioactive compounds with catechins representing the predominant polyphenolic constituents. Epigallocatechin gallate (EGCG) comprises 30–60% of total catechins and demonstrates the most potent neuroprotective activities through its ability to cross the blood–brain barrier and accumulate in neural tissue (175, 178).

Robust epidemiological evidence provides a strong population-level basis for green tea’s neuroprotective effects. Large-scale, long-term observational studies consistently link green tea consumption with superior nervous system health, showing an inverse association with the risk of cognitive decline and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease (179–182). These real-world data offer a compelling rationale for investigating green tea as a targeted intervention.

Preclinical research provides clear mechanistic support for EGCG’s protective role against CIPN and related chemotherapy-induced toxicities. In mouse models of cisplatin-induced nephrotoxicity, a condition sharing oxidative stress pathways with CIPN, EGCG was shown to significantly mitigate tissue damage by protecting mitochondrial function, restoring electron transport chain activity, enhancing mitochondrial antioxidant enzymes (e.g., GPX and MnSOD), and suppressing inflammation via the NF-κB pathway (183–185). Similar protective effects against cisplatin-induced hepatotoxicity have also been observed when EGCG is combined with Coenzyme Q10 (186). Furthermore, demonstrating a direct neuro-regenerative potential, green tea polyphenols, particularly EGCG, have been shown to enhance nerve growth factor (NGF)-induced neurite outgrowth in cell culture models (187, 188).

While large-scale clinical trials for CIPN are still emerging, compelling evidence comes from studies on related neuropathies. A randomized controlled trial in patients with mild-to-moderate diabetic peripheral neuropathy (DPN), a condition with similar pathological mechanisms to CIPN, found that 16 weeks of green tea extract supplementation resulted in significant improvements compared to placebo (189). Specifically, patients experienced reductions in pain (Visual Analogue Scale, VAS), total symptoms (Total Symptom Score, TCSS), and vibration perception thresholds (VPT), with benefits becoming apparent as early as 8 weeks into treatment.

In the context of oncology, the evidence is moving from indirect support to direct validation. A preliminary clinical study in liver cancer patients undergoing chemotherapy found that daily supplementation with green tea polyphenol tablets (equivalent to ~474 mg of polyphenols) significantly reduced treatment-induced oxidative stress (190). More significantly, a frontier of clinical research has been opened with the initiation of a Phase 1/2 clinical trial (NCT06524609) specifically designed to evaluate a topical EGCG solution for the prevention and treatment of taxane-induced peripheral neuropathy (TIPN). The launch of this trial marks a critical step in translating EGCG’s potential into a viable clinical intervention for CIPN.

A particularly compelling aspect of EGCG is its dual functionality in cancer therapy: it not only protects normal tissues from chemotherapy-induced damage but can also enhance the cytotoxic effects of chemotherapy on cancer cells (191, 192). This chemosensitizing effect is achieved through multiple mechanisms. For instance, EGCG has been shown to enhance the efficacy of platinum-based drugs like cisplatin and oxaliplatin by inducing autophagy in colorectal cancer cells (193). Other studies have demonstrated that EGCG can increase cancer cell sensitivity to cisplatin by inhibiting the DNA repair enzyme ERCC1/XPF, or by upregulating the platinum drug transporter CTR1, thereby increasing intracellular drug accumulation in lung and ovarian cancer cells (194). This unique ability to both protect nerves and potentiate anti-cancer treatment makes EGCG a highly attractive candidate for adjuvant therapy.

4.3 Nuts and seeds: vitamin E clinical trial lessons

Despite promising mechanistic rationale, the clinical evidence for Vitamin E presents a more complex and sometimes contradictory picture. Evidence for vitamin E’s neuroprotective potential comes from multiple randomized trials with mixed results but important methodological insights (195–204). These studies highlight important considerations regarding supplement forms, dosing strategies, patient populations, and study methodologies that have significant implications for future research and clinical application.

The landmark positive study by Pace et al. randomized 108 patients receiving cisplatin-based chemotherapy to vitamin E supplementation at 400 mg daily or placebo. The study demonstrated significantly lower incidence of peripheral neuropathy in the vitamin E group compared to placebo with better preserved nerve conduction parameters and reduced symptom severity scores (197). However, larger subsequent trials have produced conflicting results that highlight the complexity of translating promising preliminary findings into consistent clinical benefits (200). These contradictory results highlight several important methodological considerations including the use of different vitamin E forms (synthetic α-tocopherol versus natural mixed tocopherols), varying dosing regimens, diverse patient populations with different baseline nutritional status, different chemotherapy agents with distinct mechanisms of neurotoxicity, and heterogeneous neuropathy assessment methods (195, 196, 205). Synthetic α-tocopherol supplementation may deplete or competitively inhibit γ-tocopherol and tocotrienols, thereby diminishing overall antioxidant defense, whereas whole-food sources provide these compounds in physiologic ratios with additional polyphenols, minerals, and unsaturated fatty acids that act synergistically to stabilize neuronal membranes and modulate inflammation (206–210).

The contradictory clinical evidence strongly emphasizes the importance of obtaining vitamin E from whole food sources rather than isolated synthetic supplements. Nuts and seeds provide vitamin E in natural ratios with other tocopherols and tocotrienols along with complementary antioxidants, minerals, and bioactive compounds that may enhance protective effects through synergistic interactions (211, 212). Natural vitamin E from food sources also provides more sustained tissue levels through gradual absorption compared to rapid absorption and clearance associated with high-dose supplement administration (213–216).

Plant-based omega-3 sources from walnuts, flaxseeds, and chia seeds contribute to anti-inflammatory neuroprotection through α-linolenic acid that serves as a precursor for longer-chain omega-3 fatty acids (217, 218). A double-blind RCT (NCT01049295) showed that 640 mg omega-3 TID during paclitaxel therapy kept 70% of breast-cancer patients neuropathy-free versus 40.7% with placebo, underscoring the protective potential of essential n-3 fatty acids (219).

4.4 Fruits and vegetables: carotenoid and anthocyanin evidence

For carotenoids and anthocyanins, clinical data remain limited, but preclinical and cognitive studies provide supportive evidence. Colorful fruits and vegetables provide carotenoids and anthocyanins with specialized neuroprotective properties that demonstrate significant promise in preclinical studies. Direct clinical evidence in chemotherapy-induced peripheral neuropathy remains limited, but supportive evidence from neurodegeneration studies suggests broader protective potential (220–222). Dark leafy greens provide lutein and zeaxanthin, xanthophyll carotenoids that cross the blood–brain barrier and accumulate in neural tissue (223–225).

A meta-analysis of 4,402 older adults demonstrated that carotenoid supplementation significantly improved global cognition (226); large cross-sectional datasets such as NHANES likewise associate higher intakes of α- and β-carotene, lutein and zeaxanthin with better performance in memory, processing speed and attention tests (227, 228). The mechanistic foundation for carotenoid neuroprotection stems from their unique molecular structure and tissue distribution patterns (229–231). These compounds demonstrate preferential accumulation in neural tissue regions with high metabolic activity and oxidative stress vulnerability. The conjugated double-bond systems characteristic of carotenoids provide exceptional capacity for singlet oxygen quenching and free radical neutralization, while their lipophilic nature enables integration into neural membrane phospholipids where they stabilize membrane architecture and protect against lipid peroxidation (230–233). This mechanism is particularly relevant to chemotherapy-induced neurotoxicity, where oxidative membrane damage represents a primary pathological process.

Berry anthocyanins represent another compelling class of neuroprotective compounds with emerging evidence for peripheral nerve protection (234). These deeply pigmented flavonoid compounds demonstrate sophisticated abilities to modulate neuroinflammatory cascades while simultaneously enhancing neurotrophic factor expression and supporting cellular repair mechanisms (234, 235). Preclinical studies have shown that anthocyanin-rich extracts from blueberries, blackberries, and other dark berries can reduce oxidative stress markers and inflammatory cytokine expression in neural tissue while promoting nerve growth factor synthesis (236, 237). The protective mechanisms of anthocyanins operate through multiple convergent pathways including potent nuclear factor-κB pathway inhibition, enhancement of brain-derived neurotrophic factor expression in neural tissue, and direct antioxidant effects that complement carotenoid protection through different molecular targets (236, 237).

5 Practical application of plant food neuroprotection

The convergence of mechanistic understanding and clinical evidence detailed in the preceding sections provides a compelling rationale for the clinical application of plant-based neuroprotective strategies. However, translating these research findings into effective, safe, and feasible dietary protocols for patients undergoing chemotherapy requires careful consideration. This section, therefore, aims to delineate evidence-based principles for the selection, preparation, and combination of neuroprotective plant foods, thereby bridging the gap between scientific knowledge and practical implementation in patient care.

5.1 Evidence-based food selection and prioritization

Given the varying levels of clinical validation across different plant foods, a tiered approach to food selection provides the most rational foundation for practical implementation.

Tier 1 foods include those with direct clinical evidence in neuropathy prevention, primarily turmeric-containing foods and green tea, which should form the foundation of any plant food neuroprotection strategy (163, 179, 238, 239) (Table 4). Daily consumption of turmeric-spiced foods prepared with fat and black pepper, along with 2–3 cups of green tea, provides clinically relevant doses of curcumin and EGCG with established safety profiles (239–241). An illustrative example of nutrient synergy is the combination of curcumin with piperine, a bioactive alkaloid from black pepper (242). Piperine inhibits hepatic and intestinal glucuronidation, thereby slowing curcumin metabolism and increasing its systemic exposure (243). This interaction provides a mechanistic rationale for pairing turmeric with black pepper in culinary and clinical contexts, underscoring that the form and combination of bioactive compounds can be as critical as their individual properties for achieving therapeutic efficacy.

Tier 2 foods encompass those with strong preclinical evidence and supportive clinical data from related conditions, including nuts and seeds rich in vitamin E and omega-3 fatty acids, colorful berries high in anthocyanins, and dark leafy greens providing multiple complementary compounds (244–249). These foods should be consumed regularly as part of a diverse dietary pattern that maximizes synergistic interactions while ensuring nutritional adequacy (246, 249–251).

Tier 3 foods include those with primarily mechanistic evidence but limited clinical validation, such as specific vegetables high in individual antioxidants or specialized fermented products (249, 252–254). While these foods may provide additional benefits, they should supplement rather than replace the evidence-based Tier 1 and 2 selections.

5.2 Addressing treatment-related dietary challenges

Chemotherapy treatment creates unique dietary challenges that require adaptive strategies to maintain neuroprotective food intake while accommodating treatment-related side effects and safety considerations (255). Nausea and altered taste perception, common with many chemotherapy regimens, can be addressed through strategic use of ginger-containing warm preparations and mild, room-temperature foods that minimize aversive sensory experiences (256, 257). Well-cooked vegetable soups combining leafy greens, root vegetables, and gentle spices provide concentrated nutrition in easily tolerated liquid forms that accommodate swallowing difficulties and reduced appetite.

Immunocompromised status during chemotherapy necessitates careful attention to food safety, requiring thorough cooking of all plant foods to eliminate potential pathogens (258, 259). Raw fruits and vegetables should be avoided, with emphasis on cooked preparations including steamed vegetables, baked fruits, and thoroughly heated plant-based soups and stews. Frozen vegetables and fruits can provide year-round access to neuroprotective compounds while offering convenience and safety advantages through processing that reduces microbial contamination risk.

Reduced appetite and early satiety require emphasis on nutrient-dense foods in smaller portions, with frequent consumption of small amounts of high-quality plant foods rather than attempting to maintain normal portion sizes (260–262). Concentrated sources such as cooked nut butters, well-cooked dried fruits, and warm herbal teas can provide meaningful neuroprotective compounds without requiring large food volumes. The incorporation of neuroprotective spices into familiar comfort foods can maintain nutritional goals while supporting psychological well-being during treatment.

Oral mucositis and swallowing difficulties, common with certain chemotherapy regimens, require modifications toward softer textures and neutral temperatures (263). Pureed vegetable soups, well-cooked mashed vegetables with olive oil, and lukewarm herbal teas provide gentle nutrition delivery that minimizes oral discomfort while maintaining neuroprotective compound intake. Room-temperature foods often provide better tolerance than hot or cold preparations during periods of oral sensitivity.

5.3 Long-term sustainability and patient-centered implementation

Successful long-term implementation requires integration of neuroprotective foods into sustainable dietary patterns that account for individual preferences, cultural backgrounds, and economic constraints (264, 265). Rather than prescriptive dietary protocols, flexible frameworks that allow for personal adaptation while maintaining core neuroprotective principles demonstrate superior adherence and long-term sustainability.

Cultural adaptation involves identifying traditional foods and preparation methods that naturally provide neuroprotective compounds, such as curry dishes in South Asian cuisines, tea ceremonies in East Asian cultures, and Mediterranean dietary patterns that emphasize olive oil, nuts, and vegetables. This approach respects cultural preferences while achieving therapeutic objectives through familiar and acceptable foods.

Economic considerations require emphasis on affordable, accessible plant foods that provide optimal neuroprotective value per unit cost. Dried legumes, seasonal vegetables, frozen berries, and basic spices often provide superior nutritional value compared to expensive supplements or exotic foods, while also being more widely available and culturally acceptable across diverse populations.

Patient education should focus on practical skills including food selection, preparation techniques, and meal planning that empowers individuals to make informed choices rather than relying on complex dietary protocols. Simple guidelines such as “eat colorful vegetables daily,” “include nuts or seeds with meals,” and “drink green tea regularly” provide actionable direction without overwhelming complexity.

6 Research limitations and future priorities

A critical limitation for the clinical translation of plant-derived polyphenols is their inherently low oral bioavailability (266). Compounds such as curcumin undergo rapid metabolism and systemic clearance, which significantly reduces their effective plasma and tissue concentrations (267). This pharmacokinetic barrier explains why the consistently positive results observed in preclinical models often fail to translate into equivalent efficacy in human trials using simple extracts (268). Advanced formulation strategies—including phospholipid complexes, nanoparticle encapsulation, and co-administration with piperine from black pepper—are therefore not merely technical details but essential requirements for achieving therapeutic exposure (243, 268). These delivery approaches enhance intestinal absorption, inhibit rapid metabolism, and prolong systemic circulation, thereby providing a mechanistic basis for the observed improvements in clinical outcomes (267, 268). Consequently, the form of the intervention must be considered as critically important as the compound itself when evaluating translational potential.

Another limitation relates to safety nuances that require careful consideration. While plant-derived antioxidants are generally regarded as safe in dietary amounts, some polyphenols may exert pro-oxidant effects under specific conditions, such as high doses in the presence of free transition metal ions (269–271). Moreover, these compounds have the potential to interact with chemotherapy drugs by modulating cytochrome P450 enzymes and drug transporters such as P-glycoprotein (272). Although such risks remain largely theoretical at nutritional doses, they highlight the importance of systematic pharmacokinetic and interaction studies to ensure patient safety in clinical applications.

Despite promising mechanistic foundations and preliminary clinical evidence, significant limitations constrain the clinical application of plant food neuroprotection strategies. The most critical limitation is the scarcity of large-scale, well-controlled clinical trials specifically designed for chemotherapy-induced peripheral neuropathy prevention (2, 163, 164, 273). Current evidence relies primarily on single studies, cross-condition extrapolation, and preclinical models that cannot provide the definitive evidence required for clinical practice guidelines. Methodological challenges include the difficulty of standardizing complex plant food interventions and the natural variability in bioactive compound content across different sources, seasons, and preparation methods. The lack of validated biomarkers for early neuroprotective effects and the reliance on subjective symptom reporting further complicate intervention assessment and optimization.

Future research priorities center on three critical areas. First, large-scale multicenter randomized controlled trials are urgently needed to evaluate plant food interventions in diverse patient populations receiving different chemotherapy regimens. These studies should utilize standardized outcome measures and incorporate biomarker assessments to provide objective evidence of neuroprotective efficacy. Second, mechanistic research should focus on individual variability in plant food metabolism and response, including genetic polymorphisms affecting compound absorption and effectiveness. This research can inform personalized nutrition approaches that optimize interventions based on individual characteristics and treatment protocols. Third, standardization efforts must address intervention reproducibility through development of quality control methods for plant food characterization, establishment of preparation protocols, and creation of practical implementation guidelines that translate research findings into clinical recommendations while maintaining safety standards. The integration of these research priorities with systematic safety evaluations and long-term outcome studies will provide the evidence base necessary for widespread clinical adoption of plant food neuroprotection strategies.

7 Conclusion

The Level I evidence for curcumin in pediatric patients is particularly compelling, providing definitive proof-of-concept for plant-based neuroprotection. This comprehensive review demonstrates that plant food-derived antioxidant nutrients represent a promising approach to neuroprotection against chemotherapy-induced neurotoxicity. The mechanistic foundations are well-established, with plant foods providing multi-target protection through antioxidant system activation, anti-inflammatory effects, neurotrophic factor support, and mitochondrial preservation. The clinical evidence, while requiring further validation, provides encouraging proof-of-concept, with curcumin demonstrating the strongest validation and other plant foods showing supportive evidence from related conditions.

The practical advantages of plant food approaches include established safety profiles, widespread accessibility, and cost-effectiveness compared to pharmaceutical alternatives. However, significant limitations constrain clinical implementation, particularly the scarcity of large-scale clinical trials specifically designed for chemotherapy-induced peripheral neuropathy prevention. Future research priorities include large-scale multicenter randomized controlled trials and development of standardized intervention protocols. Plant food-derived antioxidant nutrients are a safe, accessible, and evidence-based strategy that warrants continued investigation as a complement to conventional cancer therapy, with the potential to transform supportive oncology care.

References

• 1.

  BaeEHGreenwaldMKSchwartzAG. Chemotherapy-induced peripheral neuropathy: mechanisms and therapeutic avenues. Neurotherapeutics. (2021) 18:2384–96. doi: 10.1007/s13311-021-01142-2

  • CrossRef
  • Google Scholar

• 2.

  SzklenerKSzklenerSMichalskiAŻakKKuryłoWRejdakKet al. Dietary supplements in chemotherapy-induced peripheral neuropathy: a new Hope?Nutrients. (2022) 14:625. doi: 10.3390/nu14030625

  • CrossRef
  • Google Scholar

• 3.

  ZajączkowskaRKocot-KępskaMLeppertWWrzosekAMikaJWordliczekJ. Mechanisms of chemotherapy-induced peripheral neuropathy. Int J Mol Sci. (2019):20. doi: 10.3390/ijms20061451

  • CrossRef
  • Google Scholar

• 4.

  KlafkeNBossertJKrögerBNeubergerPHeyderULayerMet al. Prevention and treatment of chemotherapy-induced peripheral neuropathy (Cipn) with non-pharmacological interventions: clinical recommendations from a systematic scoping review and an expert consensus process. Med Sci. (2023) 11. doi: 10.3390/medsci11010015

  • CrossRef
  • Google Scholar

• 5.

  PretiKDavisME. Chemotherapy-induced peripheral neuropathy: assessment and treatment strategies for advanced practice providers. Clin J Oncol Nurs. (2024) 28:351–7. doi: 10.1188/24.Cjon.351-357

  • CrossRef
  • Google Scholar

• 6.

  FlattersSJLDoughertyPMColvinLA. Clinical and preclinical perspectives on chemotherapy-induced peripheral neuropathy (Cipn): a narrative review. Br J Anaesth. (2017) 119:737–49. doi: 10.1093/bja/aex229

  • CrossRef
  • Google Scholar

• 7.

  StarobovaHVetterI. Pathophysiology of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci. (2017) 10:174. doi: 10.3389/fnmol.2017.00174

  • CrossRef
  • Google Scholar

• 8.

  Boyette-DavisJACataJPDriverLCNovyDMBruelBMMooringDLet al. Persistent Chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine. Cancer Chemother Pharmacol. (2013) 71:619–26. doi: 10.1007/s00280-012-2047-z

  • CrossRef
  • Google Scholar

• 9.

  FlattersSJBennettGJ. Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain. (2006) 122:245–57. doi: 10.1016/j.pain.2006.01.037

  • CrossRef
  • Google Scholar

• 10.

  ZhangHYoonSYZhangHDoughertyPM. Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of paclitaxel-induced painful neuropathy. J Pain. (2012) 13:293–303. doi: 10.1016/j.jpain.2011.12.002

  • CrossRef
  • Google Scholar

• 11.

  Mohd SairaziNSSirajudeenKNS. Natural products and their bioactive compounds: Neuroprotective potentials against neurodegenerative diseases. Evid Based Complement Alternat Med. (2020) 2020:6565396. doi: 10.1155/2020/6565396

  • CrossRef
  • Google Scholar

• 12.

  TrushinaEMcMurrayCT. Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience. (2007) 145:1233–48. doi: 10.1016/j.neuroscience.2006.10.056

  • CrossRef
  • Google Scholar

• 13.

  MedawarEHuhnSVillringerAVeronicaWA. The effects of plant-based diets on the body and the brain: a systematic review. Transl Psychiatry. (2019) 9:226. doi: 10.1038/s41398-019-0552-0

  • CrossRef
  • Google Scholar

• 14.

  OrdovasJMFergusonLRTaiESMathersJC. Personalised nutrition and health. BMJ (2018) 361:bmj.k2173. doi:10.1136/bmj.k2173

  • CrossRef
  • Google Scholar

• 15.

  FergusonLR. Nutrigenomics approaches to functional foods. J Am Diet Assoc. (2009) 109:452–8. doi: 10.1016/j.jada.2008.11.024

  • CrossRef
  • Google Scholar

• 16.

  CorellaDOrdovasJM. Nutrigenomics in cardiovascular medicine. Circ Cardiovasc Genet. (2009) 2:637–51. doi: 10.1161/circgenetics.109.891366

  • CrossRef
  • Google Scholar

• 17.

  CavalettiGMarmiroliP. Chemotherapy-induced peripheral neurotoxicity. Nat Rev Neurol. (2010) 6:657–66. doi: 10.1038/nrneurol.2010.160

  • CrossRef
  • Google Scholar

• 18.

  ShoaibSAnsariMAFateaseAASafhiAYHaniUJahanRet al. Plant-derived bioactive compounds in the Management of Neurodegenerative Disorders: challenges, future directions and molecular mechanisms involved in Neuroprotection. Pharmaceutics. (2023) 15. doi: 10.3390/pharmaceutics15030749

  • CrossRef
  • Google Scholar

• 19.

  PachmanDRBartonDLWatsonJCLoprinziCL. Chemotherapy-induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther. (2011) 90:377–87. doi: 10.1038/clpt.2011.115

  • CrossRef
  • Google Scholar

• 20.

  JessenKMirskyR. The repair Schwann cell and its function in regenerating nerves. J Physiol. (2016) 594:3521–31. doi: 10.1113/JP270874

  • CrossRef
  • Google Scholar

• 21.

  MillecampsSJulienJP. Axonal transport deficits and neurodegenerative diseases. Nat Rev Neurosci. (2013) 14:161–76. doi: 10.1038/nrn3380

  • CrossRef
  • Google Scholar

• 22.

  LinMTBealMF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. (2006) 443:787–95. doi: 10.1038/nature05292

  • CrossRef
  • Google Scholar

• 23.

  AbbottNJRönnbäckLHanssonE. Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci. (2006) 7:41–53. doi: 10.1038/nrn1824

  • CrossRef
  • Google Scholar

• 24.

  PodratzJLKnightAMTaLEStaffNPGassJMGenelinKet al. Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis. (2011) 41:661–8. doi: 10.1016/j.nbd.2010.11.017

  • CrossRef
  • Google Scholar

• 25.

  ZhengHXiaoWBennettG. Mitotoxicity and Bortezomib-induced chronic painful peripheral neuropathy. Exp Neurol. (2012) 238:225–34. doi: 10.1016/j.expneurol.2012.08.023

  • CrossRef
  • Google Scholar

• 26.

  XiaoWZhengHBennettG. Characterization of Oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel. Neuroscience. (2012) 203:194–206. doi: 10.1016/j.neuroscience.2011.12.023

  • CrossRef
  • Google Scholar

• 27.

  AretiAYerraVGNaiduVKumarA. Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biol. (2014) 2:289–95. doi: 10.1016/j.redox.2014.01.006

  • CrossRef
  • Google Scholar

• 28.

  JiRRXuZZGaoYJ. Emerging targets in Neuroinflammation-driven chronic pain. Nat Rev Drug Discov. (2014) 13:533–48. doi: 10.1038/nrd4334

  • CrossRef
  • Google Scholar

• 29.

  GracePMHutchinsonMRMaierSFWatkinsLR. Pathological pain and the Neuroimmune Interface. Nat Rev Immunol. (2014) 14:217–31. doi: 10.1038/nri3621

  • CrossRef
  • Google Scholar

• 30.

  WangHBloomOZhangMVishnubhakatJMOmbrellinoMCheJet al. Hmg-1 as a late mediator of endotoxin lethality in mice. Science. (1999) 285:248–51. doi: 10.1126/science.285.5425.248

  • CrossRef
  • Google Scholar

• 31.

  Gutiérrez-IbarluzeaIArana-ArriE. Nutrition, a health technology that deserves increasing interest among Hta doers. A systematic review. Front Pharmacol (2015) Volume 6–2015. doi:10.3389/fphar.2015.00156

  • CrossRef
  • Google Scholar

• 32.

  PacificoPCoy-DibleyJSMillerRJMenichellaDM. Peripheral mechanisms of peripheral neuropathic pain. Front Mol Neurosci. (2023) 16:1252442. doi: 10.3389/fnmol.2023.1252442

  • CrossRef
  • Google Scholar

• 33.

  HavelinJImbertICormierJAllenJPorrecaFKingT. Central sensitization and neuropathic features of Ongoing pain in a rat model of advanced osteoarthritis. J Pain. (2016) 17:374–82. doi: 10.1016/j.jpain.2015.12.001

  • CrossRef
  • Google Scholar

• 34.

  LawrenceT. The nuclear factor Nf-Κb pathway in inflammation. Cold Spring Harb Perspect Biol. (2009) 1:a001651. doi: 10.1101/cshperspect.a001651

  • CrossRef
  • Google Scholar

• 35.

  SekiguchiFKawabataA. Role of Hmgb1 in chemotherapy-induced peripheral neuropathy. Int J Mol Sci. (2020) 22. doi: 10.3390/ijms22010367

  • CrossRef
  • Google Scholar

• 36.

  QuasthoffSHartungHP. Chemotherapy-induced peripheral neuropathy. J Neurol. (2002) 249:9–17. doi: 10.1007/pl00007853

  • CrossRef
  • Google Scholar

• 37.

  Staff NPGrisoldAGrisoldWWindebankAJ. Chemotherapy-induced peripheral neuropathy: a current review. Ann Neurol. (2017) 81:772–81. doi: 10.1002/ana.24951

  • CrossRef
  • Google Scholar

• 38.

  García-DomínguezM. Ngf in neuropathic pain: understanding its role and therapeutic opportunities. Curr Issues Mol Biol. (2025) 47. doi: 10.3390/cimb47020093

  • CrossRef
  • Google Scholar

• 39.

  DoyleTMSalveminiD. Mini-review: mitochondrial dysfunction and chemotherapy-induced neuropathic pain. Neurosci Lett. (2021) 760:136087. doi: 10.1016/j.neulet.2021.136087

  • CrossRef
  • Google Scholar

• 40.

  GeremiaNMPetterssonLMHasmataliJCHryciwTDanielsenNSchreyerDJet al. Endogenous Bdnf regulates induction of intrinsic neuronal growth programs in injured sensory neurons. Exp Neurol. (2010) 223:128–42. doi: 10.1016/j.expneurol.2009.07.022

  • CrossRef
  • Google Scholar

• 41.

  SamaddarSRedhwanMAMEraiahMMKoneriR. Neurotrophins in peripheral neuropathy: exploring pathophysiological mechanisms and emerging therapeutic opportunities. CNS Neurol Disord Drug Targets. (2025) 24:91–101. doi: 10.2174/0118715273327121240820074049

  • CrossRef
  • Google Scholar

• 42.

  AromolaranKAGoldsteinPA. Ion channels and neuronal Hyperexcitability in chemotherapy-induced peripheral neuropathy; cause and effect?Mol Pain. (2017) 13:1744806917714693. doi: 10.1177/1744806917714693

  • CrossRef
  • Google Scholar

• 43.

  ApfelSC. Neurotrophic factors and diabetic peripheral neuropathy. Eur Neurol. (1999) 41:27–34. doi: 10.1159/000052077

  • CrossRef
  • Google Scholar

• 44.

  KotliarovaASidorovaYA. Glial cell line-derived Neurotrophic factor family ligands, players at the Interface of Neuroinflammation and Neuroprotection: focus onto the glia. Front Cell Neurosci. (2021) 15:679034. doi: 10.3389/fncel.2021.679034

  • CrossRef
  • Google Scholar

• 45.

  SikandarSMinettMSMilletQSantana-VarelaSLauJWoodJNet al. Brain-derived Neurotrophic factor derived from sensory neurons plays a critical role in chronic pain. Brain. (2018) 141:1028–39. doi: 10.1093/brain/awy009

  • CrossRef
  • Google Scholar

• 46.

  NumakawaTKajiharaR. The role of brain-derived Neurotrophic factor as an essential mediator in neuronal functions and the therapeutic potential of its Mimetics for Neuroprotection in neurologic and psychiatric disorders. Molecules. (2025) 30. doi: 10.3390/molecules30040848

  • CrossRef
  • Google Scholar

• 47.

  MitroshinaEVMishchenkoTAShishkinaTVVedunovaMV. Role of Neurotrophic factors Bdnf and Gdnf in nervous system adaptation to the influence of ischemic factors. Bull Exp Biol Med. (2019) 167:574–9. doi: 10.1007/s10517-019-04574-1

  • CrossRef
  • Google Scholar

• 48.

  YoukJKimYSLimJAShinDYKohYLeeSTet al. Depletion of nerve growth factor in chemotherapy-induced peripheral neuropathy associated with hematologic malignancies. PLoS One. (2017) 12:e0183491. doi: 10.1371/journal.pone.0183491

  • CrossRef
  • Google Scholar

• 49.

  SiniscalcoDGiordanoCRossiFMaioneSde NovellisV. Role of Neurotrophins in neuropathic pain. Curr Neuropharmacol. (2011) 9:523–9. doi: 10.2174/157015911798376208

  • CrossRef
  • Google Scholar

• 50.

  GaurAVaratharajanSBalanYTaranikantiMJohnNAUmeshMet al. Brain-derived Neurotrophic factor (Bdnf) and other Neurotrophic factors in type 2 diabetes mellitus and their association with neuropathy. Ir J Med Sci. (2024) 193:2287–92. doi: 10.1007/s11845-024-03716-3

  • CrossRef
  • Google Scholar

• 51.

  CantaAPozziECarozziVA. Mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy (Cipn). Toxics. (2015) 3:198–223. doi: 10.3390/toxics3020198

  • CrossRef
  • Google Scholar

• 52.

  RoviniA. Tubulin-Vdac interaction: molecular basis for mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy. Front Physiol. (2019) 10:671. doi: 10.3389/fphys.2019.00671

  • CrossRef
  • Google Scholar

• 53.

  Cabezas-OpazoFAVergara-PulgarKPérezMJJaraCOsorio-FuentealbaCQuintanillaRA. Mitochondrial dysfunction contributes to the pathogenesis of Alzheimer's disease. Oxidative Med Cell Longev. (2015) 2015:509654. doi: 10.1155/2015/509654

  • CrossRef
  • Google Scholar

• 54.

  StangaSCarettoABoidoMVercelliA. Mitochondrial dysfunctions: a red thread across neurodegenerative diseases. Int J Mol Sci. (2020) 21. doi: 10.3390/ijms21103719

  • CrossRef
  • Google Scholar

• 55.

  GriffithsLAFlattersSJ. Pharmacological modulation of the mitochondrial electron transport chain in paclitaxel-induced painful peripheral neuropathy. J Pain. (2015) 16:981–94. doi: 10.1016/j.jpain.2015.06.008

  • CrossRef
  • Google Scholar

• 56.

  LuB. Mitochondrial dynamics and Neurodegeneration. Curr Neurol Neurosci Rep. (2009) 9:212–9. doi: 10.1007/s11910-009-0032-7

  • CrossRef
  • Google Scholar

• 57.

  BabuAUrulangodiM. Chemotherapy-induced neuronal DNA damage: An intriguing toolbox to elucidate DNA repair mechanisms in the brain. Genome Instab Dis. (2023) 4:315–32. doi: 10.1007/s42764-023-00110-8

  • CrossRef
  • Google Scholar

• 58.

  GoriniSDe AngelisABerrinoLMalaraNRosanoGFerraroE. Chemotherapeutic drugs and mitochondrial dysfunction: focus on doxorubicin, Trastuzumab, and Sunitinib. Oxidative Med Cell Longev. (2018) 2018:7582730. doi: 10.1155/2018/7582730

  • CrossRef
  • Google Scholar

• 59.

  BaekMLLeeJPendletonKEBernerMJGoffEBTanLet al. Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment. Oncogene. (2023) 42:1117–31. doi: 10.1038/s41388-023-02596-8

  • CrossRef
  • Google Scholar

• 60.

  MarulloRWernerEDegtyarevaNMooreBAltavillaGRamalingamSSet al. Cisplatin induces a mitochondrial-Ros response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One. (2013) 8:e81162. doi: 10.1371/journal.pone.0081162

  • CrossRef
  • Google Scholar

• 61.

  GuerraFArbiniAAMoroL. Mitochondria and cancer Chemoresistance. Biochim Biophys Acta Bioenerg. (2017) 1858:686–99. doi: 10.1016/j.bbabio.2017.01.012

  • CrossRef
  • Google Scholar

• 62.

  ChengX-THuangNShengZ-H. Programming axonal mitochondrial maintenance and bioenergetics in Neurodegeneration and regeneration. Neuron. (2022) 110:1899–923. doi: 10.1016/j.neuron.2022.03.015

  • CrossRef
  • Google Scholar

• 63.

  WangBHuangMShangDYanXZhaoBZhangX. Mitochondrial behavior in axon degeneration and regeneration. Front Aging Neurosci. (2021) 13:650038. doi: 10.3389/fnagi.2021.650038

  • CrossRef
  • Google Scholar

• 64.

  LimTKRoneMBLeeSAntelJPZhangJ. Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy. Mol Pain (2015) 11:s12990-015-0057-7. doi:10.1186/s12990-015-0057-7

  • CrossRef
  • Google Scholar

• 65.

  SharmaYGuptaJKBabuMASinghSSindhuRK. Signaling pathways concerning mitochondrial dysfunction: implications in Neurodegeneration and possible molecular targets. J Mol Neurosci. (2024) 74:101. doi: 10.1007/s12031-024-02269-5

  • CrossRef
  • Google Scholar

• 66.

  BathinaSDasUN. Role of mitochondrial dysfunction in cellular lipid homeostasis and disease. Discov Med. (2023) 35:653–63. doi: 10.24976/Discov.Med.202335178.64

  • CrossRef
  • Google Scholar

• 67.

  SuomalainenANunnariJ. Mitochondria at the crossroads of health and disease. Cell. (2024) 187:2601–27. doi: 10.1016/j.cell.2024.04.037

  • CrossRef
  • Google Scholar

• 68.

  MoroL. Mitochondria at the crossroads of physiology and pathology. J Clin Med. (2020) 9. doi: 10.3390/jcm9061971

  • CrossRef
  • Google Scholar

• 69.

  TkachevVOMenshchikovaEBZenkovNK. Mechanism of the Nrf2/Keap1/are Signaling system. Biochemistry (Mosc). (2011) 76:407–22. doi: 10.1134/s0006297911040031

  • CrossRef
  • Google Scholar

• 70.

  SykiotisGP. Keap1/Nrf2 Signaling pathway. Antioxidants. (2021) 10. doi: 10.3390/antiox10060828

  • CrossRef
  • Google Scholar

• 71.

  Dinkova-KostovaATKostovRVCanningP. Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants. Arch Biochem Biophys. (2017) 617:84–93. doi: 10.1016/j.abb.2016.08.005

  • CrossRef
  • Google Scholar

• 72.

  StewartJDHengstlerJGBoltHM. Control of oxidative stress by the Keap1-Nrf2 pathway. Arch Toxicol. (2011) 85:239. doi: 10.1007/s00204-011-0694-1

  • CrossRef
  • Google Scholar

• 73.

  TaguchiKMotohashiHYamamotoM. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells. (2011) 16:123–40. doi: 10.1111/j.1365-2443.2010.01473.x

  • CrossRef
  • Google Scholar

• 74.

  EgglerALSavinovSN. Chemical and biological mechanisms of phytochemical activation of Nrf2 and importance in disease prevention. Recent Adv Phytochem. (2013) 43:121–55. doi: 10.1007/978-3-319-00581-2_7

  • CrossRef
  • Google Scholar

• 75.

  LiMHuangWJieFWangMZhongYChenQet al. Discovery of Keap1-Nrf2 small-molecule inhibitors from phytochemicals based on molecular docking. Food Chem Toxicol. (2019) 133:110758. doi: 10.1016/j.fct.2019.110758

  • CrossRef
  • Google Scholar

• 76.

  AlzainAAMukhtarRMAbdelmoniemNShoaibTHOsmanWAlsulaimanyMet al. Modulation of Nrf2/Keap1-mediated oxidative stress for cancer treatment by natural products using Pharmacophore-based screening, molecular docking, and molecular dynamics studies. Molecules. (2023) 28. doi: 10.3390/molecules28166003

  • CrossRef
  • Google Scholar

• 77.

  HayesJDMcMahonMChowdhrySDinkova-KostovaAT. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal. (2010) 13:1713–48. doi: 10.1089/ars.2010.3221

  • CrossRef
  • Google Scholar

• 78.

  SunZWuTZhaoFLauABirchCMZhangDD. Kpna6 (Importin {alpha}7)-mediated nuclear import of Keap1 represses the Nrf2-dependent antioxidant response. Mol Cell Biol. (2011) 31:1800–11. doi: 10.1128/mcb.05036-11

  • CrossRef
  • Google Scholar

• 79.

  BiswasCShahNMuthuMLaPFernandoAPSenguptaSet al. Nuclear Heme Oxygenase-1 (Ho-1) modulates subcellular distribution and activation of Nrf2, impacting metabolic and anti-oxidant Defenses. J Biol Chem. (2014) 289:26882–94. doi: 10.1074/jbc.M114.567685

  • CrossRef
  • Google Scholar

• 80.

  CollinsonEJWimmer-KleikampSGeregaSKYangYHParishCRDawesIWet al. The yeast homolog of Heme Oxygenase-1 affords cellular antioxidant protection via the transcriptional regulation of known antioxidant genes. J Biol Chem. (2011) 286:2205–14. doi: 10.1074/jbc.M110.187062

  • CrossRef
  • Google Scholar

• 81.

  PiantadosiCAWithersCMBartzRRMacGarveyNCFuPSweeneyTEet al. Heme Oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. J Biol Chem. (2011) 286:16374–85. doi: 10.1074/jbc.M110.207738

  • CrossRef
  • Google Scholar

• 82.

  RyterSW. Heme Oxygenase-1/carbon monoxide as modulators of autophagy and inflammation. Arch Biochem Biophys. (2019) 678:108186. doi: 10.1016/j.abb.2019.108186

  • CrossRef
  • Google Scholar

• 83.

  RashidMHBabuDSirakiAG. Interactions of the antioxidant enzymes Nad(P)H: Quinone Oxidoreductase 1 (Nqo1) and Nrh: Quinone Oxidoreductase 2 (Nqo2) with pharmacological agents, endogenous biochemicals and environmental contaminants. Chem Biol Interact. (2021) 345:109574. doi: 10.1016/j.cbi.2021.109574

  • CrossRef
  • Google Scholar

• 84.

  den Braver-SewradjSPden BraverMWToornemanRMvan LeeuwenSZhangYDekkerSJet al. Reduction and scavenging of chemically reactive drug metabolites by Nad(P)H:Quinone Oxidoreductase 1 and Nrh:Quinone Oxidoreductase 2 and variability in hepatic concentrations. Chem Res Toxicol. (2018) 31:116–26. doi: 10.1021/acs.chemrestox.7b00289

  • CrossRef
  • Google Scholar

• 85.

  ChandrasenaREEdirisinghePDBoltonJLThatcherGR. Problematic detoxification of Estrogen Quinones by Nad(P)H-dependent Quinone Oxidoreductase and glutathione-S-Transferase. Chem Res Toxicol. (2008) 21:1324–9. doi: 10.1021/tx8000797

  • CrossRef
  • Google Scholar

• 86.

  WuXLiXLiZYuYYouQZhangX. Discovery of Nonquinone substrates for Nad(P)H: Quinone Oxidoreductase 1 (Nqo1) as effective intracellular Ros generators for the treatment of drug-resistant non-small-cell lung cancer. J Med Chem. (2018) 61:11280–97. doi: 10.1021/acs.jmedchem.8b01424

  • CrossRef
  • Google Scholar

• 87.

  ShinJWChunKSKimDHKimSJKimSHChoNCet al. Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification. Biochem Pharmacol. (2020) 173:113820. doi: 10.1016/j.bcp.2020.113820

  • CrossRef
  • Google Scholar

• 88.

  DeckLMHunsakerLAVander JagtTAWhalenLJRoyerREVander JagtDL. Activation of anti-oxidant Nrf2 Signaling by Enone analogues of Curcumin. Eur J Med Chem. (2018) 143:854–65. doi: 10.1016/j.ejmech.2017.11.048

  • CrossRef
  • Google Scholar

• 89.

  PanySYouYDasJ. Curcumin inhibits protein kinase cα activity by binding to its C1 domain. Biochemistry. (2016) 55:6327–36. doi: 10.1021/acs.biochem.6b00932

  • CrossRef
  • Google Scholar

• 90.

  HanXXuBBeeversCSOdakaYChenLLiuLet al. Curcumin inhibits protein phosphatases 2a and 5, leading to activation of mitogen-activated protein kinases and death in tumor cells. Carcinogenesis. (2012) 33:868–75. doi: 10.1093/carcin/bgs029

  • CrossRef
  • Google Scholar

• 91.

  AyliEEDugas-BreitSLiWMarshallCZhaoLMeulenerMet al. Curcuminoids activate P38 map kinases and promote Uvb-dependent signalling in keratinocytes. Exp Dermatol. (2010) 19:493–500. doi: 10.1111/j.1600-0625.2010.01081.x

  • CrossRef
  • Google Scholar

• 92.

  AggarwalBBHarikumarKB. Potential therapeutic effects of Curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. (2009) 41:40–59. doi: 10.1016/j.biocel.2008.06.010

  • CrossRef
  • Google Scholar

• 93.

  HaydenMSGhoshS. Shared principles in Nf-Kappab Signaling. Cell. (2008) 132:344–62. doi: 10.1016/j.cell.2008.01.020

  • CrossRef
  • Google Scholar

• 94.

  SinghSAggarwalBB. Activation of transcription factor Nf-Κb is suppressed by Curcumin (Diferuloylmethane)(∗). J Biol Chem. (1995) 270:24995–5000. doi: 10.1074/jbc.270.42.24995

  • CrossRef
  • Google Scholar

• 95.

  JobinCBradhamCARussoMPJumaBNarulaASBrennerDAet al. Curcumin blocks cytokine-mediated Nf-Κb activation and Proinflammatory gene expression by inhibiting inhibitory factor I-Κb kinase activity. J Immunol. (1999) 163:3474–83. doi: 10.4049/jimmunol.163.6.3474

  • CrossRef
  • Google Scholar

• 96.

  ZhangMWSunXXuYWMengWTangQGaoHet al. Curcumin relieves Oxaliplatin-induced neuropathic pain via reducing inflammation and activating antioxidant response. Cell Biol Int. (2024) 48:872–82. doi: 10.1002/cbin.12153

  • CrossRef
  • Google Scholar

• 97.

  KunnumakkaraABBordoloiDHarshaCBanikKGuptaSCAggarwalBB. Curcumin mediates anticancer effects by modulating multiple cell Signaling pathways. Clin Sci. (2017) 131:1781–99. doi: 10.1042/cs20160935

  • CrossRef
  • Google Scholar

• 98.

  ZhangXGuanZWangXSunDWangDLiYet al. Curcumin alleviates Oxaliplatin-induced peripheral neuropathic pain through inhibiting oxidative stress-mediated activation of Nf-Κb and mitigating inflammation. Biol Pharm Bull. (2020) 43:348–55. doi: 10.1248/bpb.b19-00862

  • CrossRef
  • Google Scholar

• 99.

  AshrafizadehMAhmadiZMohammadinejadRFarkhondehTSamarghandianS. Curcumin activates the Nrf2 pathway and induces cellular protection against oxidative injury. Curr Mol Med. (2020) 20:116–33. doi: 10.2174/1566524019666191016150757

  • CrossRef
  • Google Scholar

• 100.

  IqbalBGhildiyalASinghSSiddiquiSKumariPArshadMet al. Combinatorial effect of Curcumin and tumor necrosis factor-Α-related apoptosis-inducing ligand (trail) in induction of apoptosis via inhibition of nuclear factor kappa activity and enhancement of Caspase-3 activity in chronic myeloid cells: An in-vitro study. J Cancer Res Ther. (2018) 14:S1193–s200. doi: 10.4103/jcrt.JCRT_348_18

  • CrossRef
  • Google Scholar

• 101.

  DongHJShangCZPengDWXuJXuPXZhanLet al. Curcumin attenuates ischemia-like injury induced Il-1β elevation in brain microvascular endothelial cells via inhibiting Mapk pathways and nuclear factor-Κb activation. Neurol Sci. (2014) 35:1387–92. doi: 10.1007/s10072-014-1718-4

  • CrossRef
  • Google Scholar

• 102.

  BaurJASinclairDA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. (2006) 5:493–506. doi: 10.1038/nrd2060

  • CrossRef
  • Google Scholar

• 103.

  LeiMWangJGXiaoDMFanMWangDPXiongJYet al. Resveratrol inhibits interleukin 1β-mediated inducible nitric oxide synthase expression in articular chondrocytes by activating Sirt1 and thereby suppressing nuclear factor-Κb activity. Eur J Pharmacol. (2012) 674:73–9. doi: 10.1016/j.ejphar.2011.10.015

  • CrossRef
  • Google Scholar

• 104.

  ZhuXLiuQWangMLiangMYangXXuXet al. Activation of Sirt1 by resveratrol inhibits Tnf-Α induced inflammation in fibroblasts. PLoS One. (2011) 6:e27081. doi: 10.1371/journal.pone.0027081

  • CrossRef
  • Google Scholar

• 105.

  OwjfardMRahimianZKarimiFBorhani-HaghighiAMallahzadehA. A comprehensive review on the Neuroprotective potential of resveratrol in ischemic stroke. Heliyon. (2024) 10:e34121. doi: 10.1016/j.heliyon.2024.e34121

  • CrossRef
  • Google Scholar

• 106.

  MorselliEMaiuriMCMarkakiMMegalouEPasparakiAPalikarasKet al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. (2010) 1:e10. doi: 10.1038/cddis.2009.8

  • CrossRef
  • Google Scholar

• 107.

  CaoWDouYLiA. Resveratrol boosts cognitive function by targeting Sirt1. Neurochem Res. (2018) 43:1705–13. doi: 10.1007/s11064-018-2586-8

  • CrossRef
  • Google Scholar

• 108.

  DenissovaNGNaselloCMYeungPLTischfieldJABrennemanMA. Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA Strand breakage. Carcinogenesis. (2012) 33:149–55. doi: 10.1093/carcin/bgr236

  • CrossRef
  • Google Scholar

• 109.

  WeiGWangJWuYZhengXZengYLiYet al. Sirtuin 1 alleviates Neuroinflammation-induced apoptosis after traumatic brain injury. J Cell Mol Med. (2021) 25:4478–86. doi: 10.1111/jcmm.16534

  • CrossRef
  • Google Scholar

• 110.

  FechtnerSSinghAChourasiaMAhmedS. Molecular insights into the differences in anti-inflammatory activities of green tea Catechins on Il-1β Signaling in rheumatoid arthritis synovial fibroblasts. Toxicol Appl Pharmacol. (2017) 329:112–20. doi: 10.1016/j.taap.2017.05.016

  • CrossRef
  • Google Scholar

• 111.

  YoshidaSInabaHNomuraRNakanoKMatsumoto-NakanoM. Green tea Catechins inhibit Porphyromonas Gulae Lps-induced inflammatory responses in human gingival epithelial cells. J Oral Biosciences. (2022) 64:352–8. doi: 10.1016/j.job.2022.05.006

  • CrossRef
  • Google Scholar

• 112.

  OhishiTGotoSMoniraPIsemuraMNakamuraY. Anti-inflammatory action of green tea. Anti-inflammatory Anti-allergy Agents Medicinal Chemistry. (2016) 15:74–90. doi: 10.2174/1871523015666160915154443

  • CrossRef
  • Google Scholar

• 113.

  BabuPLiuD. Green tea Catechins and cardiovascular health: An update. Curr Med Chem. (2008) 15:1840–50. doi: 10.2174/092986708785132979

  • CrossRef
  • Google Scholar

• 114.

  MoosaviFHosseiniRSasoLFiruziO. Modulation of Neurotrophic Signaling pathways by polyphenols. Drug Des Devel Ther. (2015) 10:23–42. doi: 10.2147/DDDT.S96936

  • CrossRef
  • Google Scholar

• 115.

  CaoCXiaoJLiuMGeZHuangRQiMet al. Active components, derived from Kai-Xin-san, a herbal formula, increase the expressions of Neurotrophic factor Ngf and Bdnf on mouse astrocyte primary cultures via camp-dependent Signaling pathway. J Ethnopharmacol. (2018) 224:554–62. doi: 10.1016/j.jep.2018.06.007

  • CrossRef
  • Google Scholar

• 116.

  XuSBiCChoiRZhuKMiernishaADongTet al. Flavonoids induce the synthesis and secretion of Neurotrophic factors in cultured rat astrocytes: a Signaling response mediated by Estrogen receptor. Evid Based Complement Alternat Med. (2013) 2013:127075. doi: 10.1155/2013/127075

  • CrossRef
  • Google Scholar

• 117.

  NumakawaTOdakaH. Brain-derived Neurotrophic factor Signaling in the pathophysiology of Alzheimer’s disease: beneficial effects of flavonoids for Neuroprotection. Int J Mol Sci. (2021) 22:5719. doi: 10.3390/ijms22115719

  • CrossRef
  • Google Scholar

• 118.

  HeYChenSTsoiBQiSGuBWangZet al. And its active compound P-Coumaric acid promote brain-derived Neurotrophic factor Signaling for inducing hippocampal neurogenesis and improving post-cerebral ischemic spatial cognitive functions. Front Cell Develop Biol. (2021) 8:577790. doi: 10.3389/fcell.2020.577790

  • CrossRef
  • Google Scholar

• 119.

  NaoiMInaba-HasegawaKShamoto-NagaiMMaruyamaW. Neurotrophic function of phytochemicals for Neuroprotection in aging and neurodegenerative disorders: modulation of intracellular Signaling and gene expression. J Neural Transm. (2017) 124:1515–27. doi: 10.1007/s00702-017-1797-5

  • CrossRef
  • Google Scholar

• 120.

  Colucci-D'AmatoLVolpicelliFSperanzaL. Neurotrophic factor Bdnf, physiological functions and therapeutic potential in depression, Neurodegeneration and brain cancer. Int J Mol Sci. (2020) 21:7777. doi: 10.3390/ijms21207777

  • CrossRef
  • Google Scholar

• 121.

  Moya-AlvaradoGGuerraMWuCMobleyWPerlsonEBronfmanF. Bdnf/Trkb Signaling endosomes in axons coordinate Creb/Mtor activation and protein synthesis in the cell body to induce dendritic growth in cortical neurons. eLife. (2023) 12:e77455. doi: 10.7554/eLife.77455

  • CrossRef
  • Google Scholar

• 122.

  AzmanKFZakariaR. Recent advances on the role of brain-derived Neurotrophic factor (Bdnf) in neurodegenerative diseases. Int J Mol Sci. (2022) 23:6827. doi: 10.3390/ijms23126827

  • CrossRef
  • Google Scholar

• 123.

  CostaRMartinsLTahiriEDuarteC. Brain-derived Neurotrophic factor-induced regulation of Rna metabolism in neuronal development and synaptic plasticity. Wiley Interdiscip Rev. (2022) 13:e1713. doi: 10.1002/wrna.1713

  • CrossRef
  • Google Scholar

• 124.

  SetchellKDCassidyA. Dietary Isoflavones: biological effects and relevance to human health. J Nutr. (1999) 129:758s–67s. doi: 10.1093/jn/129.3.758S

  • CrossRef
  • Google Scholar

• 125.

  ViscardiGBackSAhmedAYangSMejiaSBZurbauAet al. Effect of soy Isoflavones on measures of Estrogenicity: a systematic review and meta-analysis of randomized controlled trials. Adv Nutr. (2025) 16:100327. doi: 10.1016/j.advnut.2024.100327

  • CrossRef
  • Google Scholar

• 126.

  SimonsRGruppenHBoveeTFVerbruggenMAVinckenJP. Prenylated Isoflavonoids from plants as selective Estrogen receptor modulators (Phytoserms). Food Funct. (2012) 3:810–27. doi: 10.1039/c2fo10290k

  • CrossRef
  • Google Scholar

• 127.

  AdamsSAksenovaMAksenovMMactutusCBoozeR. Soy Isoflavones Genistein and Daidzein exert anti-apoptotic actions via a selective Er-mediated mechanism in neurons following Hiv-1 Tat1–86 exposure. PLoS One. (2012) 7:e37540. doi: 10.1371/journal.pone.0037540

  • CrossRef
  • Google Scholar

• 128.

  ValeriAFiorenzaniPRossiRAloisiAValotiMPessinaF. The soy phytoestrogens Genistein and Daidzein as Neuroprotective agents against anoxia-Glucopenia and reperfusion damage in rat urinary bladder. Pharmacol Res. (2012) 66:309–16. doi: 10.1016/j.phrs.2012.06.007

  • CrossRef
  • Google Scholar

• 129.

  KuiperGGJMLemmenJGCarlssonBCortonJCSafeSHvan der SaagPTet al. Interaction of estrogenic chemicals and phytoestrogens with Estrogen receptor Β. Endocrinology. (1998) 139:4252–63. doi: 10.1210/endo.139.10.6216

  • CrossRef
  • Google Scholar

• 130.

  McCartyM. Isoflavones made simple - Genistein's agonist activity for the Beta-type Estrogen receptor mediates their health benefits. Med Hypotheses. (2006) 66:1093–114. doi: 10.1016/J.MEHY.2004.11.046

  • CrossRef
  • Google Scholar

• 131.

  AjdžanovićVMedigovićIŽivanovićJMojićMMiloševićV. Membrane steroid receptor-mediated action of soy Isoflavones: tip of the iceberg. J Membr Biol. (2015) 248:1–6. doi: 10.1007/s00232-014-9745-x

  • CrossRef
  • Google Scholar

• 132.

  NakayaMTachibanaHYamadaK. Isoflavone Genistein and Daidzein up-regulate Lps-induced inducible nitric oxide synthase activity through Estrogen receptor pathway in Raw264.7 cells. Biochem Pharmacol. (2005) 71:108–14. doi: 10.1016/J.BCP.2005.10.002

  • CrossRef
  • Google Scholar

• 133.

  SohrabjiFMirandaRToran-AllerandC. Identification of a putative Estrogen response element in the gene encoding brain-derived Neurotrophic factor. Proc Natl Acad Sci USA. (1995) 92:11110–4. doi: 10.1073/PNAS.92.24.11110

  • CrossRef
  • Google Scholar

• 134.

  ChiniADebPGuhaPRishiABhanABradyBet al. Abstract 2068 Bdnf is transcriptionally regulated by Estradiol and Lncrna Hotair. J Biol Chem. (2024) 300. doi: 10.1016/j.jbc.2024.106593

  • CrossRef
  • Google Scholar

• 135.

  RishiABhanADebPMandalSGuhaPPerrottiLet al. Dynamic regulation of Bdnf gene expression by Estradiol and Lncrna Hotair. Gene. (2024) 897:148055. doi: 10.1016/j.gene.2023.148055

  • CrossRef
  • Google Scholar

• 136.

  ChowRWesselsJFosterW. Brain-derived Neurotrophic factor (Bdnf) expression and function in the mammalian reproductive tract. Hum Reprod Update. (2020) 26:545–64. doi: 10.1093/humupd/dmaa008

  • CrossRef
  • Google Scholar

• 137.

  TseMCLPangBPSBiXOoiTXChanWSZhangJet al. Estrogen regulates mitochondrial activity through inducing brain-derived Neurotrophic factor expression in skeletal muscle. J Cell Physiol. (2025) 240:e31483. doi: 10.1002/jcp.31483

  • CrossRef
  • Google Scholar

• 138.

  Lopez-VerrilliMAPicouFCourtFA. Schwann cell-derived Exosomes enhance axonal regeneration in the peripheral nervous system. Glia. (2013) 61:1795–806. doi: 10.1002/glia.22558

  • CrossRef
  • Google Scholar

• 139.

  HyungSImSKLeeBYShinJParkJCLeeCet al. Dedifferentiated Schwann cells secrete Progranulin that enhances the survival and axon growth of motor neurons. Glia. (2019) 67:360–75. doi: 10.1002/glia.23547

  • CrossRef
  • Google Scholar

• 140.

  WebberCAChristieKJChengCMartinezJASinghBSinghVet al. Schwann cells direct peripheral nerve regeneration through the Netrin-1 receptors, dcc and Unc5h2. Glia. (2011) 59:1503–17. doi: 10.1002/glia.21194

  • CrossRef
  • Google Scholar

• 141.

  LiuDLiuZLiuHLiHPanXLiZ. Brain-derived Neurotrophic factor promotes vesicular glutamate transporter 3 expression and Neurite outgrowth of dorsal root ganglion neurons through the activation of the transcription factors Etv4 and Etv5. Brain Res Bull. (2016) 121:215–26. doi: 10.1016/j.brainresbull.2016.02.010

  • CrossRef
  • Google Scholar

• 142.

  NaoiMWuYShamoto-NagaiMMaruyamaW. Mitochondria in Neuroprotection by phytochemicals: bioactive polyphenols modulate mitochondrial apoptosis system, function and structure. Int J Mol Sci. (2019) 20:2451. doi: 10.3390/ijms20102451

  • CrossRef
  • Google Scholar

• 143.

  BiasuttoLSzaboIZorattiM. Mitochondrial effects of plant-made compounds. Antioxid Redox Signal. (2011) 15:3039–59. doi: 10.1089/ars.2011.4021

  • CrossRef
  • Google Scholar

• 144.

  VargheseNWernerSGrimmAEckertA. Dietary Mitophagy enhancer: a strategy for healthy brain aging?Antioxidants. (2020) 9. doi: 10.3390/antiox9100932

  • CrossRef
  • Google Scholar

• 145.

  Vásquez-ReyesSVelázquez-VillegasLAVargas-CastilloANoriegaLGTorresNTovarAR. Dietary bioactive compounds as modulators of mitochondrial function. J Nutr Biochem. (2021) 96:108768. doi: 10.1016/j.jnutbio.2021.108768

  • CrossRef
  • Google Scholar

• 146.

  TripathiARayAMishraSBishenSMMishraHKhuranaA. Molecular and therapeutic insights of alpha-Lipoic acid as a potential molecule for disease prevention. Rev Bras. (2023) 33:272–87. doi: 10.1007/s43450-023-00370-1

  • CrossRef
  • Google Scholar

• 147.

  SongGLiuZWangLShiRChuCXiangMet al. Protective effects of Lipoic acid against acrylamide-induced neurotoxicity: involvement of mitochondrial energy metabolism and autophagy. Food Funct. (2017) 8:4657–67. doi: 10.1039/c7fo01429e

  • CrossRef
  • Google Scholar

• 148.

  SupertiFRussoR. Alpha-Lipoic acid: biological mechanisms and health benefits. Antioxidants. (2024) 13. doi: 10.3390/antiox13101228

  • CrossRef
  • Google Scholar

• 149.

  HuQSunA-J. Cardioprotective effect of alpha-Lipoic acid and its mechanisms. Cardiology Plus. (2020) 5:109–17. doi: 10.4103/cp.cp_16_20

  • CrossRef
  • Google Scholar

• 150.

  ShanaidaMLysiukRMykhailenkoOHudzNAbdulsalamAGontovaTet al. Alpha-Lipoic acid: An antioxidant with anti-aging properties for disease therapy. Curr Med Chem. (2025) 32:23–54. doi: 10.2174/0109298673300496240416114827

  • CrossRef
  • Google Scholar

• 151.

  GolbidiSBadranMLaherI. Diabetes and alpha Lipoic acid. Front Pharmacol. (2011) 2:69. doi: 10.3389/fphar.2011.00069

  • CrossRef
  • Google Scholar

• 152.

  Ventura-ClapierRGarnierAVekslerV. Transcriptional control of mitochondrial biogenesis: the central role of Pgc-1alpha. Cardiovasc Res. (2008) 79:208–17. doi: 10.1093/cvr/cvn098

  • CrossRef
  • Google Scholar

• 153.

  LiangHWardW. Pgc-1alpha: a key regulator of energy metabolism. Adv Physiol Educ. (2006) 30:145–51. doi: 10.1152/advan.00052.2006

  • CrossRef
  • Google Scholar

• 154.

  SrivastavaSDiazFIommariniLAureKLombesAMoraesCT. Pgc-1alpha/Beta induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders. Hum Mol Genet. (2009) 18:1805–12. doi: 10.1093/hmg/ddp093

  • CrossRef
  • Google Scholar

• 155.

  RamboutXChoHBlancRLyuQMianoJMChakkalakalJVet al. Pgc-1α senses the Cbc of pre-Mrna to dictate the fate of promoter-proximally paused Rnapii. Mol Cell. (2023) 83:186–202.e11. doi: 10.1016/j.molcel.2022.12.022

  • CrossRef
  • Google Scholar

• 156.

  Hernández-CamachoJBernierMLópez-LluchGNavasP. Coenzyme Q10 supplementation in aging and disease. Front Physiol. (2018) 9:44. doi: 10.3389/fphys.2018.00044

  • CrossRef
  • Google Scholar

• 157.

  RizzardiNLiparuloIAntonelliGOrsiniFRivaABergaminiCet al. Coenzyme Q10 Phytosome formulation improves Coq10 bioavailability and mitochondrial functionality in cultured cells. Antioxidants. (2021) 10:927. doi: 10.3390/antiox10060927

  • CrossRef
  • Google Scholar

• 158.

  Gutierrez-MariscalFLarrivaAA-DLimia-PérezLRomero-CabreraJYubero-SerranoELópez-MirandaJ. Coenzyme Q10 supplementation for the reduction of oxidative stress: clinical implications in the treatment of chronic diseases. Int J Mol Sci. (2020) 21:7870. doi: 10.3390/ijms21217870

  • CrossRef
  • Google Scholar

• 159.

  PradhanNSinghCSinghA. Coenzyme Q10 a mitochondrial restorer for various brain disorders. Naunyn Schmiedeberg's Arch Pharmacol. (2021) 394:2197–222. doi: 10.1007/s00210-021-02161-8

  • CrossRef
  • Google Scholar

• 160.

  KumazawaTSatoKSenoHIshiiASuzukiO. Levels of Pyrroloquinoline Quinone in various foods. Biochem J (1995) 307:331–3. doi:10.1042/bj3070331

  • CrossRef
  • Google Scholar

• 161.

  JonscherKChowanadisaiWRuckerR. Pyrroloquinoline-Quinone is more than an antioxidant: a vitamin-like accessory factor important in health and disease prevention. Biomolecules. (2021) 11:1441. doi: 10.3390/biom11101441

  • CrossRef
  • Google Scholar

• 162.

  ChowanadisaiWBauerlyKTchaparianEWongACortopassiGRuckerR. Pyrroloquinoline Quinone stimulates mitochondrial biogenesis through camp response element-binding protein phosphorylation and increased Pgc-1α expression*. J Biol Chem. (2010) 285:142–52. doi: 10.1074/jbc.M109.030130

  • CrossRef
  • Google Scholar

• 163.

  DanielMSmithEL. Promising roles of Phytocompounds and nutrients in interventions to mitigate chemotherapy-induced peripheral neuropathy. Semin Oncol Nurs. (2024) 40:151713. doi: 10.1016/j.soncn.2024.151713

  • CrossRef
  • Google Scholar

• 164.

  BramiCBaoTDengG. Natural products and complementary therapies for chemotherapy-induced peripheral neuropathy: a systematic review. Crit Rev Oncol Hematol. (2016) 98:325–34. doi: 10.1016/j.critrevonc.2015.11.014

  • CrossRef
  • Google Scholar

• 165.

  XuXJiaLXiaoranLHSunC. Application potential of plant-derived medicines in prevention and treatment of platinum-induced peripheral neurotoxicity. Front Pharmacol. (2022) 13:792331. doi: 10.3389/fphar.2021.792331

  • CrossRef
  • Google Scholar

• 166.

  EghbaliAAdibifarMGhasemiAAfzalRRMoradiKEghbaliAet al. The effect of Oral Curcumin on vincristine-induced neuropathy in Pediatric acute lymphoblastic Leukemia: a double-blind randomized controlled clinical trial. BMC Cancer. (2025) 25:344. doi: 10.1186/s12885-025-13751-7

  • CrossRef
  • Google Scholar

• 167.

  AsadiSGholamiMSSiassiFQorbaniMKhamoshianKSotoudehG. Nano Curcumin supplementation reduced the severity of diabetic sensorimotor polyneuropathy in patients with type 2 diabetes mellitus: a randomized double-blind placebo- controlled clinical trial. Complement Ther Med (2019) 43:253–60. doi:10.1016/j.ctim.2019.02.014.

  • CrossRef
  • Google Scholar

• 168.

  ZhaoWZhangBLiaoMZhangWHeW-YWangH-Bet al. Curcumin ameliorated diabetic neuropathy partially by inhibition of Nadph oxidase mediating oxidative stress in the spinal cord. Neurosci Lett. (2014) 560:81–5. doi: 10.1016/j.neulet.2013.12.019

  • CrossRef
  • Google Scholar

• 169.

  JiaTRaoJZouLZhaoSYiZWuBet al. Nanoparticle-encapsulated Curcumin inhibits diabetic neuropathic pain involving the P2y12 receptor in the dorsal root ganglia. Front Neurosci. (2018) 25:755. doi: 10.3389/fnins.2017.00755

  • CrossRef
  • Google Scholar

• 170.

  ElsayedHRabeiMElshaerMNasharEEAlghamdiMAl-QahtaniZet al. Suppression of neuronal apoptosis and glial activation with modulation of Nrf2/Ho-1 and Nf-kb Signaling by Curcumin in Streptozotocin-induced diabetic spinal cord central neuropathy. Front Neuroanat. (2023) 9:1094301. doi: 10.3389/fnana.2023.1094301

  • CrossRef
  • Google Scholar

• 171.

  CaillaudMThompsonDTomaWWhiteAMannJRobertsJet al. Formulated Curcumin prevents paclitaxel-induced peripheral neuropathy through reduction in Neuroinflammation by modulation of Α7 nicotinic acetylcholine receptors. Pharmaceutics. (2022) 14:1296. doi: 10.3390/pharmaceutics14061296

  • CrossRef
  • Google Scholar

• 172.

  FoudaWAboyoussefAMessihaBSalmanMTayeA. New insights into the Cytoprotective mechanism of Nano Curcumin on neuronal damage in a vincristine-induced neuropathic pain rat model. Pak J Pharm Sci. (2023) 36:149–57.

  • Google Scholar

• 173.

  KuhadAPilkhwalSSharmaSTirkeyNChopraK. Effect of Curcumin on inflammation and oxidative stress in Cisplatin-induced experimental nephrotoxicity. J Agric Food Chem. (2007) 55:10150–5. doi: 10.1021/jf0723965

  • CrossRef
  • Google Scholar

• 174.

  KhadrawyYAEl-GizawyMMSorourSMSawieHGHosnyEN. Effect of Curcumin nanoparticles on the Cisplatin-induced neurotoxicity in rat. Drug Chem Toxicol. (2019) 42:194–202. doi: 10.1080/01480545.2018.1504058

  • CrossRef
  • Google Scholar

• 175.

  KhalatbaryAKhademiE. The green tea Polyphenolic Catechin Epigallocatechin Gallate and Neuroprotection. Nutr Neurosci. (2018) 23:281–94. doi: 10.1080/1028415X.2018.1500124

  • CrossRef
  • Google Scholar

• 176.

  MandelSAvramovich-TiroshYReznichenkoLZhengHWeinrebOAmitTet al. Multifunctional activities of green tea Catechins in Neuroprotection. Neurosignals. (2005) 14:46–60. doi: 10.1159/000085385

  • CrossRef
  • Google Scholar

• 177.

  PervinMUnnoKTakagakiAIsemuraMNakamuraY. Function of green tea Catechins in the brain: Epigallocatechin Gallate and its metabolites. Int J Mol Sci. (2019) 20:3630. doi: 10.3390/ijms20153630

  • CrossRef
  • Google Scholar

• 178.

  NainCWMignoletEHerentMFQuetin-LeclercqJDebierCPageMMet al. The Catechins profile of green tea extracts affects the antioxidant activity and degradation of Catechins in Dha-rich oil. Antioxidants. (2022) 11:1844. doi: 10.3390/antiox11091844

  • CrossRef
  • Google Scholar

• 179.

  PervinMUnnoKOhishiTTanabeHMiyoshiNNakamuraY. Beneficial effects of green tea Catechins on neurodegenerative diseases. Molecules. (2018) 23:1297. doi: 10.3390/molecules23061297

  • CrossRef
  • Google Scholar

• 180.

  AfzalODalhatMAltamimiARasoolRAlzareaSAlmalkiWet al. Green tea Catechins attenuate neurodegenerative diseases and cognitive deficits. Molecules. (2022) 27:7604. doi: 10.3390/molecules27217604

  • CrossRef
  • Google Scholar

• 181.

  MandelSWeinrebOAmitTYoudimM. Cell Signaling pathways in the Neuroprotective actions of the green tea polyphenol (−)-Epigallocatechin-3-Gallate: implications for neurodegenerative diseases. J Neurochem. (2004) 88:1555–69. doi: 10.1046/j.1471-4159.2003.02291.x

  • CrossRef
  • Google Scholar

• 182.

  AkbarialiabadHDahroudMDKhazaeiMRazmehSZarshenasM. Green tea, a medicinal food with promising neurological benefits. Curr Neuropharmacol. (2020) 19:349–59. doi: 10.2174/1570159X18666200529152625

  • CrossRef
  • Google Scholar

• 183.

  ArafaMAtteiaH. Protective role of Epigallocatechin Gallate in a rat model of Cisplatin-induced cerebral inflammation and oxidative damage: impact of modulating Nf-Κb and Nrf2. Neurotox Res. (2019) 37:380–96. doi: 10.1007/s12640-019-00095-x

  • CrossRef
  • Google Scholar

• 184.

  El-MowafyAAl-GayyarMSalemHEl-MeseryMDarweishM. Novel chemotherapeutic and renal protective effects for the green tea (Egcg): role of oxidative stress and inflammatory-cytokine Signaling. Phytomedicine. (2010) 17:1067–75. doi: 10.1016/j.phymed.2010.08.004

  • CrossRef
  • Google Scholar

• 185.

  HuangY-JWangK-LChenH-YChiangY-FHsiaS. Protective effects of Epigallocatechin Gallate (Egcg) on endometrial, breast, and ovarian cancers. Biomolecules. (2020) 10:1481. doi: 10.3390/biom10111481

  • CrossRef
  • Google Scholar

• 186.

  FatimaSSuhailNAlrashedMWasiSAljaserFSAlSubkiRAet al. Epigallocatechin Gallate and coenzyme Q10 attenuate Cisplatin-induced hepatotoxicity in rats via targeting mitochondrial stress and apoptosis. J Biochem Mol Toxicol. (2021) 35:e22701. doi: 10.1002/jbt.22701

  • CrossRef
  • Google Scholar

• 187.

  GundimedaUMcNeillTSchiffmanJHintonDGopalakrishnaR. Green tea polyphenols potentiate the action of nerve growth factor to induce Neuritogenesis: possible role of reactive oxygen species. J Neurosci Res. (2010) 88:3644–55. doi: 10.1002/jnr.22519

  • CrossRef
  • Google Scholar

• 188.

  ZhangYHanMSunXGaoGYuGHuangLet al. Egcg promotes Neurite outgrowth through the integrin Β1/Fak/P38 Signaling pathway after subarachnoid Hemorrhage. Evid Based Complement Alternat Med. (2021) 25:8810414. doi: 10.1155/2021/8810414

  • CrossRef
  • Google Scholar

• 189.

  EssmatAHusseinMS. Green tea extract for mild-to-moderate diabetic peripheral neuropathy a randomized controlled trial. Complement Ther Clin Pract. (2021) 43:101317. doi: 10.1016/j.ctcp.2021.101317

  • CrossRef
  • Google Scholar

• 190.

  BabaYSonodaJHayashiSTosujiNSonodaSMakisumiKet al. Reduction of oxidative stress in liver cancer patients by Oral green tea polyphenol tablets during hepatic arterial infusion chemotherapy. Exp Ther Med. (2012) 4:452–8. doi: 10.3892/etm.2012.602

  • CrossRef
  • Google Scholar

• 191.

  WeiRWirkusJYangZMachucaJEsparzaYMackenzieG. Egcg sensitizes chemotherapeutic-induced cytotoxicity by targeting the Erk pathway in multiple cancer cell lines. Arch Biochem Biophys. (2020) 692:108546. doi: 10.1016/j.abb.2020.108546

  • CrossRef
  • Google Scholar

• 192.

  LiHKrstinSWinkM. Modulation of multidrug resistant in cancer cells by Egcg, tannic acid and Curcumin. Phytomedicine. (2018) 50:213–22. doi: 10.1016/j.phymed.2018.09.169

  • CrossRef
  • Google Scholar

• 193.

  HuFWeiFWangYWuBFangYXiongB. Egcg synergizes the therapeutic effect of Cisplatin and Oxaliplatin through Autophagic pathway in human colorectal cancer cells. J Pharmacol Sci. (2015) 128:27–34. doi: 10.1016/j.jphs.2015.04.003

  • CrossRef
  • Google Scholar

• 194.

  HeyzaJRAroraSZhangHConnerKLLeiWFloydAMet al. Targeting the DNA repair endonuclease Ercc1-Xpf with green tea polyphenol Epigallocatechin-3-Gallate (Egcg) and its Prodrug to enhance Cisplatin efficacy in human cancer cells. Nutrients. (2018) 10:1644. doi: 10.3390/nu10111644

  • CrossRef
  • Google Scholar

• 195.

  MiaoHLiRChenDHuJChenYXuCet al. Protective effects of vitamin E on chemotherapy-induced peripheral neuropathy: a meta-analysis of randomized controlled trials. Ann Nutr Metab. (2020) 77:127–37. doi: 10.1159/000515620

  • CrossRef
  • Google Scholar

• 196.

  ChenJShanHYangWZhangJDaiHYeZ. Vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: a meta-analysis. Front Pharmacol. (2021) 12:684550. doi: 10.3389/fphar.2021.684550

  • CrossRef
  • Google Scholar

• 197.

  PaceAGiannarelliDGalièESavareseACarpanoSGiuliaMet al. Vitamin E Neuroprotection for Cisplatin neuropathy. Neurology. (2010) 74:762–6. doi: 10.1212/WNL.0b013e3181d5279e

  • CrossRef
  • Google Scholar

• 198.

  ArgyriouAChroniEKoutrasAIconomouGPapapetropoulosSPolychronopoulosPet al. A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against Cisplatin-induced peripheral neuropathy: final results. Support Care Cancer. (2006) 14:1134–40. doi: 10.1007/s00520-006-0072-3

  • CrossRef
  • Google Scholar

• 199.

  FuXWuHLiJWangCLiMQianqianet al. Efficacy of drug interventions for chemotherapy-induced chronic peripheral neurotoxicity: a network meta-analysis. Front Neurol. (2017) 8:223. doi: 10.3389/fneur.2017.00223

  • CrossRef
  • Google Scholar

• 200.

  KottschadeLSloanJMazurczakMJohnsonDMurphyBRowlandKet al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase iii clinical trial. Support Care Cancer. (2011) 19:1769–77. doi: 10.1007/s00520-010-1018-3

  • CrossRef
  • Google Scholar

• 201.

  HeibaMAIsmailSSabryMBayoumyWKamalK. The use of vitamin E in preventing Taxane-induced peripheral neuropathy. Cancer Chemother Pharmacol. (2021) 88:931–9. doi: 10.1007/s00280-021-04347-6

  • CrossRef
  • Google Scholar

• 202.

  KottschadeLSloanJMazurczakMJohnsonDMurphyBRowlandKet al. The use of vitamin E for prevention of chemotherapy-induced peripheral neuropathy: a phase iii double-blind, placebo controlled study-N05c31. J Clin Oncol. (2016):27 15_suppl:9532. doi: 10.1200/jco.2009.27.15_suppl.9532

  • CrossRef
  • Google Scholar

• 203.

  KhanASamadFSamadSKhanAArifSZahidR. Role of vitamin E in prevention of chemotherapy induced peripheral neuropathy. Int J Approx Reason. (2020) 8:1260–5. doi: 10.21474/ijar01/11213

  • CrossRef
  • Google Scholar

• 204.

  HuangH-PHeMLiuLHuangL. Vitamin E does not decrease the incidence of chemotherapy-induced peripheral neuropathy: a meta-analysis. Contemp Oncol. (2016) 20:237–41. doi: 10.5114/wo.2016.61567

  • CrossRef
  • Google Scholar

• 205.

  EumSChoiHChangMChoiHKoY-JAhnJet al. Protective effects of vitamin E on chemotherapy-induced peripheral neuropathy: a meta-analysis of randomized controlled trials. Int J Vitamin Nutr Res. (2013) 83:101–11. doi: 10.1024/0300-9831/a000149

  • CrossRef
  • Google Scholar

• 206.

  HuangHYAppelLJ. Supplementation of diets with alpha-Tocopherol reduces serum concentrations of gamma- and Delta-Tocopherol in humans. J Nutr. (2003) 133:3137–40. doi: 10.1093/jn/133.10.3137

  • CrossRef
  • Google Scholar

• 207.

  HandelmanGJMachlinLJFitchKWeiterJJDratzEA. Oral alpha-Tocopherol supplements decrease plasma gamma-Tocopherol levels in humans. J Nutr. (1985) 115:807–13. doi: 10.1093/jn/115.6.807

  • CrossRef
  • Google Scholar

• 208.

  ReiterEJiangQChristenS. Anti-inflammatory properties of alpha- and gamma-Tocopherol. Mol Asp Med. (2007) 28:668–91. doi: 10.1016/j.mam.2007.01.003

  • CrossRef
  • Google Scholar

• 209.

  AhsanHAhadAIqbalJSiddiquiWA. Pharmacological potential of Tocotrienols: a review. Nutr Metab. (2014) 11:52. doi: 10.1186/1743-7075-11-52

  • CrossRef
  • Google Scholar

• 210.

  RazaliRANgahWZWMakpolSYanagisawaDKatoTTooyamaI. Shifting perspectives on the role of Tocotrienol Vs. Tocopherol in brain health: a scoping review. Int J Mol Sci. (2025) 26:6339. doi: 10.3390/ijms26136339

  • CrossRef
  • Google Scholar

• 211.

  ZaaboulFLiuY. Vitamin E in foodstuff: nutritional, analytical, and food technology aspects. Compr Rev Food Sci Food Saf. (2022) 21:964–98. doi: 10.1111/1541-4337.12924

  • CrossRef
  • Google Scholar

• 212.

  ShahidiFFuentesJDe CamargoACSpeiskyHPinaffi-LangleyA. Vitamin E as an essential micronutrient for human health: common, novel, and unexplored dietary sources. Free Radic Biol Med. (2021) 176:312–21. doi: 10.1016/j.freeradbiomed.2021.09.025

  • CrossRef
  • Google Scholar

• 213.

  BurtonGTraberMAcuffRWaltersDKaydenHHughesLet al. Human plasma and tissue alpha-Tocopherol concentrations in response to supplementation with Deuterated natural and synthetic vitamin E. Am J Clin Nutr. (1998) 67:669–84. doi: 10.1093/AJCN/67.4.669

  • CrossRef
  • Google Scholar

• 214.

  TraberM. Utilization of vitamin E. Biofactors. (1999) 10:115–20. doi: 10.1002/biof.5520100205

  • CrossRef
  • Google Scholar

• 215.

  ClementeHRamalhoHLimaMGriloEDimensteinR. Maternal supplementation with natural or synthetic vitamin E and its levels in human colostrum. J Pediatr Gastroenterol Nutr. (2015) 60:533–7. doi: 10.1097/MPG.0000000000000635

  • CrossRef
  • Google Scholar

• 216.

  GaurSSherryC. Alpha-Tocopherol stereoisomer profiles of lactating women supplemented with natural and synthetic vitamin E. FASEB J. (2016) 30:1150. doi: 10.1096/fasebj.30.1_supplement.1150.2

  • CrossRef
  • Google Scholar

• 217.

  ZhangACDe SilvaMMacIsaacRRobertsLKamelJCraigJet al. Omega-3 polyunsaturated fatty acid Oral supplements for improving peripheral nerve health: a systematic review and meta-analysis. Nutr Rev. (2020) 78:323–41. doi: 10.1093/nutrit/nuz054

  • CrossRef
  • Google Scholar

• 218.

  SamuelsNBen-AryeE. Integrative approaches to chemotherapy-induced peripheral neuropathy. Curr Oncol Rep. (2020) 22:23. doi: 10.1007/s11912-020-0891-2

  • CrossRef
  • Google Scholar

• 219.

  GhoreishiZEsfahaniADjazayeriADjalaliMGolestanBAyromlouHet al. Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: a randomized double-blind placebo controlled trial. BMC Cancer (2012) 12:355-. doi:10.1186/1471-2407-12-355

  • CrossRef
  • Google Scholar

• 220.

  KucharskaEMajsterekIMrowickaMMrowickiJ. Lutein and zeaxanthin and their roles in age-related macular degeneration—neurodegenerative disease. Nutrients. (2022) 14:827. doi: 10.3390/nu14040827

  • CrossRef
  • Google Scholar

• 221.

  ŞanlıerNYildizEOzlerE. An overview on the effects of some carotenoids on health: lutein and Zeaxanthin. Current Nutrition Reports. (2024) 13:828–44. doi: 10.1007/s13668-024-00579-z

  • CrossRef
  • Google Scholar

• 222.

  TanLZhangYDawsonRKongL. Roles of macular carotenoids in brain function throughout the lifespan: a review of recent research. J Agriculture Food Research. (2023) 14:100785. doi: 10.1016/j.jafr.2023.100785

  • CrossRef
  • Google Scholar

• 223.

  LindberghCRenzi-HammondLHammondBTerryDMewbornCPuenteAet al. Lutein and Zeaxanthin influence brain function in older adults: a randomized controlled trial. J Int Neuropsychol Soc. (2017) 24:77–90. doi: 10.1017/S1355617717000534

  • CrossRef
  • Google Scholar

• 224.

  JohnsonE. Role of lutein and Zeaxanthin in visual and cognitive function throughout the lifespan. Nutr Rev. (2014) 72:605–12. doi: 10.1111/nure.12133

  • CrossRef
  • Google Scholar

• 225.

  LoprestiASmithSDrummondP. The effects of lutein and Zeaxanthin supplementation on cognitive function in adults with self-reported mild cognitive complaints: a randomized, double-blind, placebo-controlled study. Front Nutr. (2022) 9:843512. doi: 10.3389/fnut.2022.843512

  • CrossRef
  • Google Scholar

• 226.

  DavinelliSAliSSolfrizziVScapagniniGCorbiG. Carotenoids and cognitive outcomes: a meta-analysis of randomized intervention trials. Antioxidants. (2021) 10:223. doi: 10.3390/antiox10020223

  • CrossRef
  • Google Scholar

• 227.

  ZhongQSunW-HQinYXuH. Association of Dietary Α-carotene and Β-carotene intake with low cognitive performance in older adults: a cross-sectional study from the National Health and nutrition examination survey. Nutrients. (2023) 15:239. doi: 10.3390/nu15010239

  • CrossRef
  • Google Scholar

• 228.

  ChristensenKGleasonCMaresJ. Dietary carotenoids and cognitive function among us adults, Nhanes 2011–2014. Nutr Neurosci. (2020) 23:554–62. doi: 10.1080/1028415X.2018.1533199

  • CrossRef
  • Google Scholar

• 229.

  ShanaidaMMykhailenkoOLysiukRHudzNBalwierzRShulhaiAet al. Carotenoids for Antiaging: Nutraceutical, pharmaceutical, and Cosmeceutical applications. Pharmaceuticals. (2025) 18:403. doi: 10.3390/ph18030403

  • CrossRef
  • Google Scholar

• 230.

  PietrasikSCichońNBijakMGorniakLSaluk-BijakJ. Carotenoids from marine sources as a new approach in neuroplasticity enhancement. Int J Mol Sci. (2022) 23:1990. doi: 10.3390/ijms23041990

  • CrossRef
  • Google Scholar

• 231.

  ChoKShinMKimSLeeSB. Recent advances in studies on the therapeutic potential of dietary carotenoids in neurodegenerative diseases. Oxidative Med Cell Longev2018;2018:4120458. doi:10.1155/2018/4120458

  • CrossRef
  • Google Scholar

• 232.

  ManochkumarJDossCEl-SeediHEfferthTRamamoorthyS. The Neuroprotective potential of carotenoids in vitro and in vivo. Phytomedicine. (2021) 91:153676. doi: 10.1016/j.phymed.2021.153676

  • CrossRef
  • Google Scholar

• 233.

  ParkH-AHaydenMMBannermanSJansenJCrowe-WhiteK. Anti-apoptotic effects of carotenoids in Neurodegeneration. Molecules. (2020) 25:3453. doi: 10.3390/molecules25153453

  • CrossRef
  • Google Scholar

• 234.

  ZaaCMarceloÁAnZMedina-FrancoJVelasco-VelázquezM. Anthocyanins: molecular aspects on their Neuroprotective activity. Biomolecules. (2023) 13:1598. doi: 10.3390/biom13111598

  • CrossRef
  • Google Scholar

• 235.

  ZhangJWuJLiuFTongLChenZChenJet al. Neuroprotective effects of Anthocyanins and its major component Cyanidin-3-O-Glucoside (C3g) in the central nervous system: An outlined review. Eur J Pharmacol. (2019) 858:172500. doi: 10.1016/j.ejphar.2019.172500

  • CrossRef
  • Google Scholar

• 236.

  MaHJohnsonSLLiuWDaSilvaNAMeschwitzSDainJAet al. Evaluation of polyphenol anthocyanin-enriched extracts of blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry for free radical scavenging, reactive carbonyl species trapping, anti-Glycation, anti-Β-amyloid aggregation, and microglial Neuroprotective effects. Int J Mol Sci. 2018;19:461. doi:10.3390/ijms19020461

  • CrossRef
  • Google Scholar

• 237.

  SinghLWaniAWShaifaliSRKKaurHBashirOFaridAet al. A comprehensive review on Neurotrophic receptors and their implications in brain health: exploring the Neuroprotective potential of berries. J Berry Research. (2024) 15:48–64. doi: 10.1177/18785093241301881

  • CrossRef
  • Google Scholar

• 238.

  AbbasSLatifMShafieNGhazaliMKorminF. Neuroprotective expression of turmeric and Curcumin. J Food Sci. (2020) 4:2366–81. doi: 10.26656/fr.2017.4(6).363

  • CrossRef
  • Google Scholar

• 239.

  SilvaGDa Cruz Monteiro SantanaTACLVAPAMGonçalvesMCoutoRDet al. Green tea intake reduces high-fat diet-induced sensory neuropathy in mice by Upregulating the antioxidant Defense system in the spinal cord. Antioxidants. (2025) 14:452. doi: 10.3390/antiox14040452

  • CrossRef
  • Google Scholar

• 240.

  Somers-EdgarTScandlynMStuartENedelecLValentineSRosengrenR. The combination of Epigallocatechin Gallate and Curcumin suppresses Erα-breast cancer cell growth in vitro and in vivo. Int J Cancer. (2008) 122:1966–71. doi: 10.1002/ijc.23328

  • CrossRef
  • Google Scholar

• 241.

  HewlingsSKalmanD. Curcumin: a review of its’ effects on human health. Foods. (2017) 6:92. doi: 10.3390/foods6100092

  • CrossRef
  • Google Scholar

• 242.

  KesarwaniKGuptaRMukerjeeA. Bioavailability enhancers of herbal origin: An overview. Asian Pac J Trop Biomed. (2013) 3:253–66. doi: 10.1016/s2221-1691(13)60060-x

  • CrossRef
  • Google Scholar

• 243.

  ShobaGJoyDJosephTMajeedMRajendranRSrinivasPS. Influence of Piperine on the pharmacokinetics of Curcumin in animals and human volunteers. Planta Med. (1998) 64:353–6. doi: 10.1055/s-2006-957450

  • CrossRef
  • Google Scholar

• 244.

  GaoQRongSLWangSLiangYZhangZ. Anti-Glycation and anti-inflammatory activities of Anthocyanins from purple vegetables. Food Funct. (2023) 14:2034–44. doi: 10.1039/d2fo03645b

  • CrossRef
  • Google Scholar

• 245.

  KhooHEAzlanATangSLimSM. Anthocyanidins and Anthocyanins: Colored pigments as food, pharmaceutical ingredients, and the potential health benefits. Food Nutr Res. (2017) 61:1361779. doi: 10.1080/16546628.2017.1361779

  • CrossRef
  • Google Scholar

• 246.

  MattioliRFranciosoAMoscaLSilvaP. Anthocyanins: a comprehensive review of their chemical properties and health effects on cardiovascular and neurodegenerative diseases. Molecules. (2020) 25:3809. doi: 10.3390/molecules25173809

  • CrossRef
  • Google Scholar

• 247.

  HeidariHHajhashemyZSaneeiP. A meta-analysis of effects of vitamin E supplementation alone and in combination with Omega-3 or magnesium on polycystic ovary syndrome. Sci Rep. (2022) 12:19927. doi: 10.1038/s41598-022-24467-0

  • CrossRef
  • Google Scholar

• 248.

  JamilianMShojaeiASamimiMEbrahimiFAAghadavodEKaramaliMet al. The effects of Omega-3 and vitamin E co-supplementation on parameters of mental health and gene expression related to insulin and inflammation in subjects with polycystic ovary syndrome. J Affect Disord. (2018) 229:41–7. doi: 10.1016/j.jad.2017.12.049

  • CrossRef
  • Google Scholar

• 249.

  ShahidiFde CamargoAC. Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits.Int J Mol Sci. (2016) 17:1745. doi: 10.3390/ijms17101745

  • CrossRef
  • Google Scholar

• 250.

  BlessoC. Dietary Anthocyanins and human health. Nutrients. (2019) 11:2107. doi: 10.3390/nu11092107

  • CrossRef
  • Google Scholar

• 251.

  PanchalSJohnOMathaiMBrownL. Anthocyanins in chronic diseases: the power of purple. Nutrients. (2022) 14:2161. doi: 10.3390/nu14102161

  • CrossRef
  • Google Scholar

• 252.

  EweysAZhaoYZhangJXiaoXBaiJDarweshOet al. Fermentation affects the antioxidant activity of plant-based food material through the release and production of bioactive components. Antioxidants. (2021) 10:2004. doi: 10.3390/antiox10122004

  • CrossRef
  • Google Scholar

• 253.

  EtuROffia-OluaBUkomA. Fermentation and Sauteing enhances the physicochemical properties, carotenoids and the antioxidant activity of some food vegetables. Measurement: Food. (2024) 15:100177. doi: 10.1016/j.meafoo.2024.100177

  • CrossRef
  • Google Scholar

• 254.

  SarıtaşSPortocarreroALopezJMLombardoMKochWRaposoAet al. The impact of fermentation on the antioxidant activity of food products. Molecules. (2024) 29:3941. doi: 10.3390/molecules29163941

  • CrossRef
  • Google Scholar

• 255.

  SteffensJPCostaCAD. The use of dietary supplements for the Management of Adverse Effects of treatment in children and adolescents with Leukemia: a scoping review. Nutr Cancer. (2025) 77:334–340. doi: 10.1080/01635581.2024.2435079

  • CrossRef
  • Google Scholar

• 256.

  GalaDWrightHZigoriBMarshallSCrichtonM. Dietary strategies for chemotherapy-induced nausea and vomiting: a systematic review. Clin Nutr. (2022) 41:2147–55. doi: 10.1016/j.clnu.2022.08.003

  • CrossRef
  • Google Scholar

• 257.

  AbeneJDengJ. Evaluating the role of dietary interventions in reducing chemotherapy toxicities in cancer patients: a systematic review. J Cancer Surviv. (2025). doi: 10.1007/s11764-025-01777-6

  • CrossRef
  • Google Scholar

• 258.

  LeardiniDBossùGVenturelliFBaccelliFMuratoreEGrassoAet al. Food safety practices and foodborne illness in Italian Pediatric oncology and Hematology Centers: a survey on behalf of the infectious disease working Group of Aieop. Pediatr Blood Cancer. (2025) 72:e31782. doi: 10.1002/pbc.31782

  • CrossRef
  • Google Scholar

• 259.

  MorrisAO'ConnorGRenshawG. A cross-sectional survey to review food safety practices within Pediatric oncology and stem cell transplant Centers in the United Kingdom. J Pediatr Hematol Oncol. (2023):45. doi: 10.1097/MPH.0000000000002649

  • CrossRef
  • Google Scholar

• 260.

  VriesYBergMDe VriesJHMBoesveldtSKruifJBuistNet al. Differences in dietary intake during chemotherapy in breast cancer patients compared to women without cancer. Support Care Cancer. (2017) 25:2581–91. doi: 10.1007/s00520-017-3668-x

  • CrossRef
  • Google Scholar

• 261.

  PutriSAdrianiMEstuningsihY. Hubungan Antara Nafsu Makan Dengan Asupan Energi Dan protein Pada Pasien Kanker Payudara post Kemoterapi[correlation between appetite with energy and protein intake of post chemotherapy breast cancer patients]. Media Gizi Indones. (2019) 14:170. doi: 10.20473/mgi.v14i2.170-176

  • CrossRef
  • Google Scholar

• 262.

  RegynaSDAdrianiMRachmahQ. A systematic review: Asupan Zat Gizi Makro dan Status Gizi Pasien Kanker yang Menjalani Kemoterapi – A systematic review: Macro nutrient intake and nutritional status of cancer patients undergoing chemotherapy. Media Gizi Indonesia. (2021) 16:182–193. doi: 10.20473/mgi.v16i2.182-193

  • CrossRef
  • Google Scholar

• 263.

  AndersonPMThomasSMSartoskiSScottJGSobiloKBewleySet al. Strategies to mitigate chemotherapy and radiation toxicities that affect eating. Nutrients. (2021) 13:4397. doi: 10.3390/nu13124397

  • CrossRef
  • Google Scholar

• 264.

  ArmeliFBonucciAMaggiEPintoABusinaroR. Mediterranean diet and neurodegenerative diseases: the neglected role of nutrition in the modulation of the Endocannabinoid system. Biomolecules. (2021) 11:790. doi: 10.3390/biom11060790

  • CrossRef
  • Google Scholar

• 265.

  ChenLZhongWChenHZhouYRanWHeYet al. Orient diet: a potential Neuroprotective dietary pattern for Chinese stroke high-risk population. J Am Med Dir Assoc. (2025) 26:105331. doi: 10.1016/j.jamda.2024.105331

  • CrossRef
  • Google Scholar

• 266.

  Di LorenzoCColomboFBiellaSStockleyCRestaniP. Polyphenols and human health: the role of bioavailability. Nutrients. (2021) 13:273. doi: 10.3390/nu13010273

  • CrossRef
  • Google Scholar

• 267.

  JägerRLoweryRPCalvaneseAVJoyJMPurpuraMWilsonJM. Comparative absorption of Curcumin formulations. Nutr J. (2014) 13:11. doi: 10.1186/1475-2891-13-11

  • CrossRef
  • Google Scholar

• 268.

  TabanelliRBrogiSCalderoneV. Improving Curcumin bioavailability: current strategies and future perspectives. Pharmaceutics. (2021) 13:1715. doi: 10.3390/pharmaceutics13101715

  • CrossRef
  • Google Scholar

• 269.

  HalliwellB. Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies?Arch Biochem Biophys. (2008) 476:107–12. doi: 10.1016/j.abb.2008.01.028

  • CrossRef
  • Google Scholar

• 270.

  BabichHSchuckAGWeisburgJHZuckerbraunHL. Research strategies in the study of the pro-oxidant nature of polyphenol Nutraceuticals. J Toxicol. (2011) 2011:467305. doi: 10.1155/2011/467305

  • CrossRef
  • Google Scholar

• 271.

  Duda-ChodakATarkoT. Possible side effects of polyphenols and their interactions with medicines. Molecules. (2023) 28:2536. doi: 10.3390/molecules28062536

  • CrossRef
  • Google Scholar

• 272.

  NabekuraTKawasakiTFurutaMKanekoTUwaiY. Effects of natural polyphenols on the expression of drug efflux transporter P-glycoprotein in human intestinal cells. Acs Omega. (2018) 3:1621–6. doi: 10.1021/acsomega.7b01679

  • CrossRef
  • Google Scholar

• 273.

  SantosWGuimarãesJPinaLSerafiniMGuimarãesA. Antinociceptive effect of plant-based natural products in chemotherapy-induced peripheral neuropathies: a systematic review. Front Pharmacol. (2022) 13:1001276. doi: 10.3389/fphar.2022.1001276

  • CrossRef
  • Google Scholar