Mohamad Fawzi Mahomoodally1,2*
Muhammad Zakariyyah Aumeeruddy3
Lesetja Jan Legoabe4
Stefano Dall’Acqua5*
Gokhan Zengin6- 1Institute of Research and Development, Duy Tan University, Da Nang, Vietnam
- 2Faculty of Natural Sciences, Duy Tan University, Da Nang, Vietnam
- 3Department of Health Sciences, Faculty of Medicine and Health Sciences, University of Mauritius, Réduit, Mauritius
- 4Centre of Excellence for Pharmaceutical Sciences (Pharmacen), North West University, Potchefstroom, South Africa
- 5Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
- 6Department of Biology, Faculty of Science, Selcuk University, Campus, Konya, Turkey
Sepsis is a severe inflammatory response to systemic infection and is a threatening cause of death in intensive care units. In recent years, a number of studies have been conducted on the protective effect of natural products against sepsis-induced organ injury. However, a comprehensive review of these studies indicating the mechanisms of action of the bioactive compounds is still lacking. In this context, this review aimed to provide an updated analysis of the mechanism of action of plants’ secondary metabolites in the management of sepsis. Scopus, Science Direct, Google Scholar, and PubMed were searched from inception to July 2022. A variety of secondary metabolites were found to be effective in sepsis management including allicin, aloin, cepharanthine, chrysin, curcumin, cyanidin, gallic acid, gingerol, ginsenoside, glycyrrhizin, hesperidin, kaempferol, narciclasine, naringenin, naringin, piperine, quercetin, resveratrol, rosmarinic acid, shogaol, silymarin, sulforaphane, thymoquinone, umbelliferone, and zingerone. The protective effects exerted by these compounds can be ascribed to their antioxidant properties as well as induction of endogenous antioxidant mechanisms, and also via the downregulation of inflammatory response and reduction of biochemical and inflammatory markers of sepsis. These findings suggest that these secondary metabolites could be of potential therapeutic value in the management of sepsis, but human studies must be performed to provide strength to their potential clinical relevance in sepsis-related morbidity and mortality reduction.
1 Introduction
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is a final common pathway to death from severe infectious diseases, such as bacterial bloodstream and lower respiratory tract infections, malaria, dengue, and systemic fungal infections. If not recognised early and managed on time, it can cause septic shock, multiple organ failure, and death (World Health Organization, 2020a). Patients who obtain severe COVID-19 complications have been also observed to be at a greater risk of death from sepsis (World Health Organization, 2020b). The incidence and mortality rate of sepsis differ considerably across areas, with the highest burden observed in sub-Saharan Africa, Oceania, South Asia, East Asia, and Southeast Asia (Rudd et al., 2020).
In 2017, 48.9 million cases and 11 million deaths were associated with sepsis globally, representing almost 20% of all deaths worldwide. Approximately 85.0% of sepsis cases and sepsis-associated deaths globally were reported in low- and middle-income countries. Almost half of all global sepsis cases were among children, with 20 million cases and 2.9 million global deaths in children estimated to be under 5 years of age (World Health Organization, 2020c). The updated review published in 2020 was based on 51 studies mostly from high-income countries (n = 46), and the estimate was a pooled incidence of 189 hospital-treated adult sepsis cases per 1,00,000 person-years and a mortality of 26.7%. Among hospital-born infants, hospital-acquired infections are responsible for an estimated 4%–56% of all deaths in the neonatal period which vary among geographical area (World Health Organization, 2020a). In the United States, the incidence of sepsis was doubled between 2000 and 2008 due to an increasing prevalence of non-communicable diseases in the aging population, together with the increase of antibiotic resistance and the high use of invasive procedures, immunosuppressive drugs, and chemotherapy. The expenses linked to sepsis management in the United States is greater than $20.3 billion every year (Dugar et al., 2020). Sepsis also frequently occurred from infections acquired in healthcare settings. In intensive care units patients, around one-half (48.7%) of sepsis cases were reported to be acquired in the hospital (World Health Organization, 2020a).
Antimicrobial resistance is a major burden in the management of sepsis. Sepsis patients with resistant pathogens were observed to show a higher risk of hospital mortality (World Health Organization, 2020c). A systematic review was carried out by Le Doare et al. (2015) on the antibiotic resistance rates in children with sepsis in resource-limited countries. In neonates, the median resistance of Klebsiella pneumoniae to ampicillin and cephalosporins in Asia was 94% and 84% respectively; while in Africa was 100% and 50%, respectively. Multidrug resistance to antibiotics such as ampicillin, chloramphenicol, and cotrimoxazole in Asia and in Africa was of 30% and 75%, respectively (Le Doare et al., 2015).
With regard to the pathophysiology of sepsis, the infection first causes an activation of the innate immune system resulting in the killing of bacteria by innate immune cells via numerous oxidative pathways (Armstrong et al., 2017). While bacterial infections continue to be the primary cause of pathogenic sepsis, viruses and fungi are also associated with a meaningful percentage of sepsis etiologies, especially among immunocompromised patients and those with other comorbidities. Antibacterial treatment has no effect on non-bacterial sepsis and is linked to increased mortality when mistakenly taken at high doses to treat fungal sepsis (Dolin et al., 2019). Normally the infectious insult is controlled with no progression to systemic process. Nonetheless, the extent of the infectious insult may sometimes cause a much more intense systemic activation. Consequently, activation of nitric oxide synthase leads to excess production of nitric oxide (NO), thereby raising oxidative stress, loss of vascular resistance, and resulting distributive shock. These oxidants damage cellular structures and biomacromolecules including DNA, mitochondrial cytochromes, signaling proteins, and membranes. The accumulating effects of dysregulation and cellular injury caused significant organ dysfunction (Armstrong et al., 2017).
The “Sepsis Six” is a series of interventions which can be undertaken during the treatment of severe sepsis condition; 1) administration of high flow oxygen, 2) take blood cultures, 3) provide broad spectrum antibiotics, 4) intravenous fluid challenges, 5) measurement of serum lactate and haemoglobin, and 6) measurement of hourly urine output (Uppu et al., 2015). In many low-income countries, important antimicrobials may not be accessible because of drug scarcity, high cost, or local import and regulation systems. Many hospitals do not have the required resources to establish current guidelines for sepsis management. Shortage of intravenous fluids, supplemental oxygen, simple positive pressure airway systems, and basic equipment to monitor health parameters such as pulse oximeters is also common (Rudd et al., 2018).
In recent years, a number of studies have been carried out considering the protective effect of some natural products, especially plants’ secondary metabolites, against sepsis-induced organ injury. Recently, a review was conducted on the mechanistic and therapeutic perspective in sepsis management with attention to some phytochemicals (Alikiaii et al., 2021). Plants provide a promising strategy in the treatment of sepsis via multiple actions including antimicrobial, anti-inflammatory or immunomodulatory properties, showing no or minimal unwanted secondary responses. Available drugs for sepsis management have not displayed promising effects so far, due to drug resistance, gastrointestinal distress, bleeding, hormonal imbalance, repetitive dosage regimen, and increasing medication cost (Usmani et al., 2020). So far, a comprehensive review of the studies investigating the mechanism of action of the plant bioactive compounds with a potential role in sepsis is still lacking. In this context, this review aimed to provide an updated analysis of the mechanism of action of secondary metabolites in the management of sepsis.
2 Methodology
The following databases were used for retrieving relevant articles: Scopus, Science Direct, Google Scholar, and PubMed. Articles were searched from inception to July 2022. We used the following keywords: “secondary metabolites + sepsis,” “phytochemicals + sepsis,” “phytocompounds + sepsis,” “plant compounds + sepsis,” “herbal compounds + sepsis,” “plant bioactive compounds + sepsis,” and “plant chemicals + sepsis.”
As for the screening procedure, full text investigation was performed when titles or abstracts provide information relevant to the study and the reference lists of the articles were further screened for related studies. Only articles in English and only studies on secondary metabolites with regard to sepsis were included. The following were excluded: 1) review articles, conferences, and case reports, 2) articles in non-English language, and 3) studies with abstract only accessible and without sufficient information.
A total of 291 studies were obtained from title screening in various databases (Scopus: n = 80; ScienceDirect: n = 32; Google Scholar: n = 93; PubMed: n = 86). The number of duplicated articles from these databases were 198 and, after removal of duplicates, 93 articles were left, of which two studies were excluded and 91 articles were included in the study (Figure 1).
FIGURE 1. Flow chart used for systematic review.
3 Plants and their secondary metabolites
Plants make a huge and wide range of organic compounds, of which a major part do not seem to be involved directly in growth and development and are termed as secondary metabolites (Croteau et al., 2000). These compounds act as a natural defence system against attack of various microorganisms and environmental stresses. The functions of these compounds are in fact more than just providing protection because of their link to many biochemical pathways and possess a wide range of therapeutic applications (Kumar et al., 2022). On the other hand, the primary metabolites have an active role in the survival of species with regard to functions as photosynthesis and respiration. Secondary metabolites can be divided into three main groups: 1) terpenes (including plant volatiles, cardiac glycosides, carotenoids, and sterols), 2) phenolics (phenolic acids, flavonoids, coumarins, lignans, stilbenes, tannins, and lignin) and 3) nitrogen containing compounds (including alkaloids and glucosinolates) (Costa et al., 2012). These metabolites can be found in different parts of the plants such as leaf, stem, root, and bark. Secondary metabolites have a limited distribution in the plant kingdom, i.e., particular secondary metabolite are present in specific plant species or related group of species, while the primary metabolites are present throughout the plant kingdom (Anulika et al., 2016).
Drug discovery through combination of high throughput technology with selection of plants based on traditional information has been successful in finding novel chemical entities with potential as drug leads. Regardless of the development of combinatorial chemistry, the role of natural products in drug discovery remains very high. Among the 1,073 new chemical entities which had been approved between 1981 and 2010, only 36% were purely synthetic, while more than half were derived from nature (Atanasov et al., 2015). Some examples are; 1) anti-cancer agents, e.g., paclitaxel and its derivatives obtained in yew (Taxus L.) species, vincristine and vinblastine isolated from Madagascar periwinkle [Catharanthus roseus (L.) G. Don], and camptothecin and its analogs originally found in Camptotheca acuminata Decne; 2) galanthamine, a cholinesterase inhibitor which has been approved for the treatment of Alzheimer’s disease and was originally discovered in Galanthus nivalis L.; 3) khellin from Ammi visnaga (L.); Lam. which was the lead compound for development of chromoglicic acid, the sodium salt of which is utilised as mast cell stabilizer for managing allergy and asthma; 4) galegine from Galega officinalis L. which became the template for metformin synthesis and led to the subsequent development of biguanidine-type antidiabetic drugs; 5) papaverine from Papaver somniferum L. which aids in the development of the antihypertensive drug verapamil; 6) quinine isolated in the bark of Peruvian Cinchona L. species which was used in malaria treatment and also led to the synthesis of chloroquine and mefloquine, 7) the antimalarial drug artemisinin isolated in Artemisia annua L. (a TCM herb) in 1971 which led to the development of derivatives, including sodium artensunate or artemether, which are now commonly used for the treatment of malaria (Atanasov et al., 2015).
4 Secondary metabolites in the management of sepsis
A number of secondary metabolites have been investigated for their protective role in sepsis management and they belong to different chemical classes ranging from flavonoids, saponins, monoterpene, coumarins, and alkaloids showing the great varieties of chemical structures (Figure 2). The mechanism of actions is summarised in Table 1 and Figures 3, 4. As recently reviewed, the main target of actions are Toll-like receptor 4 (TLR4)/nuclear factor kappa-light chain-enhancer of activated B cells (NF-k-B) signal pathway. This pathway lead to hyper-expression of inflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α). Besides high-mobility group box-1 (HMGB1), a damage associated molecular pattern (DAMPs), is also released to the circulation during the development of sepsis and phytochemicals targeted on this pathway are of high interest for their potential use in sepsis management (Alikiaii et al., 2021).
FIGURE 2. Plants’ secondary metabolites effective in the management of sepsis.
FIGURE 3. Molecular mechanism involved in sepsis.
FIGURE 4. Potential targets of bioactive compounds from plants in sepsis.
TABLE 1. Main mechanism of action of secondary metabolites in the management of sepsis.
4.1 Allicin
Shen et al. (2019) evaluated the in vivo effect and mechanisms of allicin, a volatile sulfide extracted from Allium sativum L. bulbs, in a sepsis-induced lung injury. Compared with lipopolysaccharide (LPS) group, lung injury was significantly improved by allicin which also down-regulated tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-1β concentration. Allicin also significantly suppressed toll-like receptor (TLR4), MyD88, nuclear factor-kB (NF-kB), caspase-3 and caspase-9 protein activities in comparison to LPS group in lung tissues.
4.2 Aloin
Aloin, the main anthraquinone glycoside obtained from Aloe L. species, was observed to reduce high mobility group box 1 (HMGB1)-mediated septic responses and improved survival in septic mice by activating the sirtuin 1 (SIRT1) and PI3K/Nrf2/HO-1 signaling axis (Yang et al., 2019). Lee and Bae (2021) studied the inhibitory effects of aloin on Transforming growth factor β-Induced protein (TGFBIp)-mediated septic responses. Aloin inhibited LPS-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. The compound also suppressed TGFBIp-induced sepsis lethality and pulmonary injury.
Lee et al. (2019a) investigated the renal protective properties of aloin in a mouse model of sepsis. Aloin when administered intravenously at dose of 12.4 mg/kg significantly decreased the deleterious renal functions by cecal ligation and puncture (CLP), such as the elevated blood urea nitrogen, creatinine, and urine protein. Aloin also inhibited NF-κB activation and reduced inducible nitric oxide synthase (iNOS) and excess generation of nitric acid. The compound also lowered the plasma levels of IL-6 and TNF-α, decreased lethality due to CLP-induced sepsis, raised lipid peroxidation, and improved the antioxidant defence system through the restoration of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) levels in kidney tissues.
4.3 Cepharanthine
Cepharanthine, an alkaloid isolated from Stephania cepharantha Hayata, demonstrated effectiveness in managing systemic inflammatory response syndromes including sepsis by inhibiting the rise in LPS-induced cytokine levels (IL-6, TNF-α, and nitrate/nitrite levels) in rat serum. Histologic improvements were also observed with cepharanthine co-treatment while the LPS group displayed severe pathologic abnormalities including vacuolisation, dot necrosis, striped necrosis, and bridging necrosis, and inflammatory cells were observed adjacent to the necrotic tissue. In vitro, the compound also inhibited NF-kB activation by inhibition of the IKK pathway (Kudo et al., 2011). Cepharanthine also showed beneficial effect in the treatment of endotoxic shock in newborn rats by dose-dependently reducing the 24 h mortality of endotoxic shock. At 0.2 mg/kg dosage given by injection, it effectively lowered the mortality from 90% to 21% (Goto et al., 1991).
Sakaguchi et al. (2007) also found that cepharanthine confers protection to mice from endotoxin-induced lethal shock at 0.2–5 mg/kg, p.o. and against endotoxin/rhTNF-α-induced lethal shock at 1 mg/kg, i.p. In vitro, the compound (3 μg/ml) inhibited cell death in mouse L929 fibroblast. Also, cepharanthine suppressed NO production by endotoxin-stimulated Raw 264.7 mouse macrophage cells. Moreover, cepharanthine prevented LPS-induced pulmonary vascular injury by inhibiting leukocyte activation. Cepharanthine inhibited the functions of activated neutrophils including neutrophil elastase release, oxygen radical generation, and neutrophil aggregation, possibly by inhibiting the increase in intracellular free calcium concentration (Murakami et al., 2000).
4.4 Chrysin
Chrysin is a natural flavonoid, commonly present in a variety of plants but also in propolis, honey, and mushroom. Chrysin was found to lower the oxidative stress markers and cytokines in sepsis. Oral administration of chrysin, at doses of 50 and 100 mg/kg, significantly lowered the level of IL-1β, IL-10, TNF-α, IL-6, and malondialdehyde (MDA) in rats. Chrysin also increased the levels of SOD and CAT in tissues. Histopathological findings were also consistent with biochemical findings (Koc et al., 2020). Xingyue et al. (2021) also found that chrysin ameliorated sepsis-induced cardiac dysfunction through upregulating Nfr2/Heme oxygenase 1 pathway.
Chrysin and kaempferol can act synergistically improving the septic mice survival. The kaempferol/chrysin combination at 3 mg/kg enhanced the overall 7-day survival rate by 2-fold-up to 29%. Although the combination did not display significant antibacterial properties, the anti-inflammatory and antioxidant effects significantly improved the survival rate of septic mice (Harasstani et al., 2017).
4.5 Curcumin
Curcumin, the yellow pigment considered one of the primary bioactive substance in Curcuma longa L., was tested at doses of 20, 40, and 80 mg/kg, and found to alleviate LPS induced sepsis and liver failure in rats by suppression of oxidative stress-related inflammation via phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and NF-kB related signaling. Curcumin decreased the level of cytokines such as IL-1β, IL-6, and TNF-α, and also improved liver apoptosis by suppressing PI3K/AKT signaling pathway and inhibiting Cyclic AMP-responsive element-binding protein (CREB)/Caspase expression, while decreasing oxidative stress-associated protein expression (Zhong et al., 2016). Curcumin (50 and 200 mg/kg, i.p.) also protected against sepsis-induced acute lung injury in rat model by down-regulating the inflammatory cytokines TNF-α, IL-8, and macrophage migration inhibitory factor (MIF) levels. Interestingly, curcumin enhanced the survival rate of rats by 40%–50% (Xiao et al., 2012).
Treatment with curcumin significantly ameliorated inflammatory injury of the lung and kidney in septic mice. The compound (50, 100, and 200 mg/kg) enhanced the suppressive function of CD4+CD25+ regulatory T cells (Tregs) cells and raised the plasma levels of IL-10. It also inhibited the secretion of plasma TNF-α and IL-6 and improved the survival of septic mice (Chen et al., 2018). Xu et al. (2013) also investigated the effect of curcumin, intraperitoneal injection at 200 mg/kg, on sepsis-induced acute lung injury in a rat model. Real-time PCR and Western blot analysis revealed that curcumin significantly reduced the expression of TGF-β1 and SMAD3-dependent signaling pathway compared to control groups (p < .05).
Additionally, curcumin pre-treatment, 100 mg/kg intraperitoneal administration, modulated leukocyte and platelet adhesion and blood-brain barrier dysfunction in mice with CLP via P-selectin expression and also improved survival in mice with CLP (Vachharajani et al., 2010). Also, the anti-inflammatory effect of curcumin in an experimental model of sepsis was found to be mediated by upregulation of peroxisome proliferator-activated receptor-γ (PPARγ) (Siddiqui et al., 2006).
Furthermore, Yang et al. (2013) studied the protective effect of curcumin, administered by peritoneal injection (200 mg/kg/d, 3 days), against cardiac dysfunction in septic rat model. Curcumin significantly lowered the elevated levels of cardiac troponin I (cTn I) and MDA in plasma while raising the levels of SOD. Curcumin also enhanced the myocardial contractility by increasing the reduced Ejection Fraction (EF) and Fractional Shortening (FS) in septic rats induced by CLP. Myocardial inflammation and structure damage of myocardial cells were also alleviated by curcumin treatment.
4.6 Cyanidin
Cyanidin-3-O-glucoside is one of the most common anthocyanins naturally present in black rice, black bean, purple potato, and many fruits, such as red-skinned or red-fleshed apples, hawthorn, bilberries, cranberries, chokeberries, and lingonberries (Tan et al., 2019; Liang et al., 2021). This compound, injected intraperitoneally at doses 10 or 30 mg/kg, significantly improved survival rate and attenuated CLP-induced lung injury in rat model, including reduction of lung wet/dry weight ratio, protein leak, infiltration of leukocytes, and myeloperoxidase (MPO) activity. The phytochemical markedly reduced MDA content and raised SOD activity and glutathione level. The level of TNF-α, IL-1β, and IL-6 were also lowered, as well as protein expression of cyclooxygenase-2 and production of prostaglandin E2 in the lung. Cyanidin also increased protein expression of inhibitors of NF-kBa and decreased expressions of NF-kB p65 and p-p65 in the lung, thus inhibited the NF-kB-DNA binding activity (Yan et al., 2015).
Ma et al. (2015) also found that cyanidin-3-O-glucoside suppressed the production of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in cell supernatants and bronchoalveolar lavage fluid. Histopathologic examination revealed that cyanidin-3-O-glucoside pretreatment suppressed inflammatory cell infiltration, alveolar wall thickening, and interstitial edema in lung tissues. Western blot assay also revealed that cyanidin suppressed LPS-induced activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways in lung tissues.
4.7 Gallic acid
Gallic acid is a secondary metabolite present in most plants. Its distribution covers different families of the vegetable kingdom including Anacardiaceae, Fabaceae, and Myrtaceae (Fernandes and Salgado, 2016). Gallic Acid-L-Leucine conjugate was found to enhance survival and protect mice against LPS-induced inflammation and sepsis. The compound suppressed LPS-induced overproduction of prostaglandin E2, prostaglandin F2, leukotriene B4, thromboxane B2, and also significantly reduced the levels of cyclooxygenase-2 (COX-2) and iNOS expression and the plasma concentrations of proinflammatory lipid mediators in LPS-treated mice (Cheng et al., 2018).
Maurya et al. (2014) studied the prophylactic antioxidant potential of gallic acid in murine model of sepsis. Gallic acid (20 mg/kg, orally) significantly lowered MDA level in kidney, spleen, liver, and lungs of septic mice. A significant improvement was also observed in SOD activity of kidney and spleen when compared to septic mice.
4.8 Gingerols
Gingerols, major bioactive molecules from ginger, at 25 mg/kg injected intraperitoneally, was found to enhance survival of septic rats and attenuated sepsis-induced acute kidney injury by reducing renal disturbances, oxidative stress, and inflammatory response via a mechanism possibly related to increased production of dimethylamine and methylsulfonylmethane (Rodrigues et al., 2018). Moreover, Hong et al. (2020) investigated the effects of 6-gingerol (40 mg/kg, intragastric administration) on sepsis-induced liver injury. Mice pre-treated with 6-gingerol displayed less incidences of severe liver inflammation and mortality compared to untreated CLP groups. 6-gingerol treatment also inhibited the expression of pyroptosis-related proteins, such as NOD-like receptor protein 3 (NLRP3), IL-1β, and caspase-1. 6-gingerol was also observed to activate the nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway in vivo and in vitro.
Additionally, 6-gingerol (20 mg/kg, orally) significantly improved sepsis development in CLP mice, as observed by a decrease in serum IL-1β. In bone marrow-derived macrophages and RAW264.7 cells, the compound attenuated pyroptosis and the release of caspase-1p20, HMGB1, IL-1β, IL-18 in response to ATP and LPS treatment. 6-Gingerol exhibited these effects by blocking MAPK activation (Zhang et al., 2020). 6-Gingerol-treated mice also displayed lower mortality in polymicrobial sepsis induced by CLP by enhancing bacterial clearance in the peritoneum, blood, and organs (liver, spleen, and kidney) while also suppressing the generation of TNF-α and IL-6 in TLR2 and/or TLR4-stimulated macrophages (Ju et al., 2021).
4.9 Ginsenosides
Ginsenoside Rg1, major active ingredient of Panax ginseng C.A. Mey., significantly improved survival in septic mice by lowering mortality rate (60%) in comparison to CLP group (30%). At doses of 20 mg/kg injected intravenously, Rg1 reduced IL-10, IL-6, and TNF-α, and enhanced bacterial clearance as evidenced by a reduction in bacterial counts in both blood and peritoneal lavage fluid when compared to control septic mice. Histologic examination revealed only minor abnormalities in lung and liver of Rg1-treated mice compared to CLP mice where lung injury occurred through alveolar wall thickening, neutrophils accumulation, and impaired alveoli. Also, Rg1 raised the neutrophil counts in peritoneal cavity while inhibiting lymphocyte apoptosis in thymus and spleen (Zou et al., 2013).
Rg1 improved the survival rate and provided protection against sepsis-associated learning and memory impairments (Morris water maze). The compound was administered at 40 and 200 mg/kg intraperitoneally, and found to attenuate brain histopathologic changes (hematoxylin and eosin staining), suppressed activation of Iba1, reduced the expressions of inflammatory cytokines (TNF-α, IL-1β, and IL-6), and also decreased neuronal apoptosis (cleaved caspase 3 activation) in hippocampus. Rg1 was found to suppress the expressions of light chain 3-II and p62 in hippocampus but not beclin 1 (Li et al., 2017).
Additionally, ginsenoside Rg1 relieved sepsis-induced lung injury in vitro and in vivo. The compound suppressed apoptosis rate of LPS-induced A549 cells, relieved mouse lung tissue damage, and increased survival rate. Rg1 also protected cells from LPS-induced intracellular reactive oxygen species (ROS) and suppressed the secretion of TNF-α and IL-6 and relieved cells from endoplasmic reticulum stress as evidenced by reduced expression of marker proteins via upregulating SIRT1 (Wang et al., 2019). Ginsenoside Rg3 was also observed to improve mitochondrial dysfunction by regulating autophagy in mitochondria via activation of AMP-activated protein kinase (AMPK) pathway, thus protecting cell and organ injuries caused by sepsis (Xing et al., 2017).
Moreover, ginsenoside Rh1 significantly decreased HMGB1 release in LPS-activated human umbilical vein endothelial cells (HUVECs). Rh1 inhibited the production of TNF-α, IL-6, activation of NF-κB and extracellular signal-regulated kinase (ERK) 1/2 by HMGB1. The compound inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice, and also decreased CLP-induced release of HMGB1, sepsis-related mortality and tissue injury in vivo (Lee et al., 2019). Other ginsenosides, Rk1 and Rg5, also showed suppressive effects on HMGB1-mediated septic responses (Kim et al., 2019).
Liu et al. (2022) also observed that Rg1, at 35 or 70 mg/kg injected intraperitoneally, activates the Akt/GSK-3β pathway through P2X purinoceptor 7 (P2X7) receptors to inhibit sepsis-induced cardiac dysfunction and mitochondrial dysfunction. In addition, Ginsenoside Rg3 increased taurine-upregulated gene 1 (TUG1) expression and decreased expression of microRNA (miR)-200a-3p to stimulate the silencing information regulator 1 (SIRT1)/AMPK pathway, thus enhancing autophagy to improve sepsis-induced liver injury and mitochondrial dysfunction (Wu et al., 2021).
4.10 Glycyrrhizin
Glycyrrhizin, known as glycyrrhizic acid, is a natural triterpene glycoside and a major active compound of Glycyrrhiza glabra L. (licorice) root. This compound was found to protect rats from sepsis by blocking HMGB1 signaling. The bioactive constituent attenuated the release and expression of HMGB1 and proinflammatory cytokines, while also blocking the interaction of HMGB1 with receptor for advanced glycation end products and toll-like receptor (TLR4) and suppressing the downstream MAPKs/NF-𝜅B signaling pathway. At a dose of 10 mg/kg, glycyrrhizin significantly decreased mortality caused by CLP (Zhao et al., 2017).
Likewise, Kim et al. (2015) found that glycyrrhizin decreased HMGB1 secretion in LPS-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2-dependent induction of heme oxygenase 1 (HO-1). Another study by Mollica et al. (2007) showed that glycyrrhizin inhibited the chemoattractant and mitogenic activities of HMGB1. In the same research, nuclear magnetic resonance and fluorescence studies revealed that glycyrrhizin binds directly to each of the two HMG boxes of HMGB1.
4.11 Hesperidin
Yuan et al. (2019) studied the protective effect of hesperidin, a flavanone glycoside abundant in citrus fruits (Citrus L.), at doses 10 and 20 mg/kg i.v., against sepsis CLP-induced lung injury in mice. Hesperidin was found to attenuate the partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio and lung injury score. The metabolite significantly reduced the level of proinflammatory mediators and attenuated the markers of oxidative stress. Administration of hesperidin also attenuated the expression of caspase-3, Bcl-2, TLR4, Hsp70, and MyD88 protein in the lung tissue.
Hesperidin was also observed to improve LPS-induced acute lung injury in mice when administered intragastrically at dose of 500 mg/kg. Production of proinflammatory cytokines and chemokine was inhibited, such as TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1). Also, the treatment inhibited the infiltration of macrophages and suppressed the expression and release of HMGB1 in vivo and in vitro (Liu et al., 2015).
4.12 Kaempferol
Kaempferol is a flavonoid found in many edible plants [e.g., tea (Camellia sinensis (L.) Kuntze), broccoli (Brassica oleracea var. italica Plenck), cabbage (B. oleracea var. capitata L.), kale (B. oleracea var. sabellica L.), beans (Phaseolus vulgaris L.), leek (Allium porrum L.), tomato (Solanum lycopersicum L.), strawberries (Fragaria × ananassa Duchesne ex Rozier) and grapes (Vitis vinifera L.)] (Calderón-Montaño et al., 2011). Kaempferol was synergically active with chrysin improving septic mice survival. The kaempferol/chrysin combination at dose of 3 mg/kg enhanced the overall 7-day survival rate by 2-fold-up to 29%. Although the combination did not display significant antibacterial effects, the anti-inflammatory and antioxidant effects significantly improved the survival rate of septic mice (Harasstani et al., 2017).
Rabha et al. (2018) evaluated the effect of kaempferol in sepsis-induced acute lung injury in mice with administration of 100 mg/kg orally. Kaempferol significantly reduced water content in lungs, as well as the cytokines IL-6, IL-1β, and TNF-α in plasma and lung tissue. Kaempferol also decreased the lung tissue nitrite level and iNOS level in septic mice, as well as downregulated the mRNA expression of intercellular adhesion molecule-1 (ICAM-1) and iNOS. Although no decrease in bacterial load was observed, kaempferol-treated mice displayed lesser infiltration of cells and more arranged alveolar structure.
Kaempferol (100 mg/kg, intragastrically) was also found to regulate MAPKs and NF-κB signaling pathways to attenuate LPS-induced acute lung injury in mice. Kaempferol inhibited LPS-induced alveolar wall thickness, alveolar hemorrhage and leukocytes infiltration in lung tissue, showing reduced MPO activity. Kaempferol increased SOD activity of lung tissue, which was reduced by LPS administration (Chen et al., 2012).
4.13 Narciclasine
Narciclasine is an isocarbostyril alkaloid discovered in Narcissus species (Amaryllidaceae) in 1967 (Fürst, 2016). The compound was found to improve outcome in sepsis among neonatal rats when administered at 3 mg/kg intraperitoneally. The compound lowered the plasma levels of S100A8/A9 and also suppressed its expression in the liver and lung. Narciclasine also reduced the systemic and local bacterial load as well as the generation of pro-inflammatory cytokines in plasma and organs (liver and lungs). Histopathological examinations revealed that narciclasine protected against organ damage associated with sepsis and enhanced the survival of neonatal rats. The compound also suppressed the phosphorylation of NF-κβ p65 and degradation of NF-κβ inhibitory protein alpha (Kingsley et al., 2020).
In addition, narciclasine was found to attenuate sepsis-induced myocardial injury via modulating autophagy. In this work the alkaloid was administered to mice at dose of 0.1 mg/kg by gavage. LPS-induced myocardial inflammation was attenuated and the compound also protected cardiac function and suppressed the expression of inflammatory cytokines in LPS-induced heart tissue. Also, narciclasine exhibited an inhibitory effect on the c-Jun N-terminal kinase (JNK) signaling pathway, and JNK activity was linked to narciclasine-induced autophagy and the subsequent protective effects during acute myocardial injury (Tang et al., 2021).
4.14 Naringenin
Naringin is a flavonoid found primarily in citrus species with especially high level found in grapefruit (Citrus paradisi Macfad.), bitter orange (Citrus × aurantium L.), and pomelo [Citrus grandis (L.) Osbeck] (Csuti et al., 2022). Administration of naringenin, a commonly occurring flavonoid aglycone, at 10 and 20 mg/kg to sepsis rats model significantly decreased the sepsis-induced apoptosis of kidney cells, and also reduced Bax and raised Bcl-2 expression. Naringenin also lowered the level of ROS and downregulated the expression of SOD, CAT, and ascorbate peroxidase (APX). The compound also reduced the level of urinary angiotensinogen in septic rats (Mu et al., 2019).
Ye et al. (2020) also investigated the role of naringenin in AMPK signaling pathway in LPS-induced septic cardiac dysfunction in mice. Naringenin treatment reduced IκB-α expression while raising the expressions of TNF-α, IL-6, and pNF-κB. The compound also significantly inhibited AMPK and ACC phosphorylation, reduced PGC1α expression and lowered the expression of complex I, complex II, and OPA1.
4.15 Naringin
Naringin, a well-known flavanone glycoside of grapes and citrus fruits formed by naringenin and the disaccharide neohesperidose, improved the survival rate of CLP mice and ameliorated sepsis-induced intestinal mucosal injury. The effects were observed with the compound at doses of 30 and 60 mg/kg. The compound improved impaired intestinal permeability, inhibited the release of TNF-α and IL-6, and raised the level of IL-10 in CLP mice and LPS-stimulated MODE-K cells. Using both in vivo and in vitro models, naringin showed increased expression of tight junction proteins ZO-1 and claudin-1 via RhoA/ROCK/NF-κB/MLCK/MLC signalling pathway (Li et al., 2018).
Gil et al. (2016) also studied the effect of naringin in CLP-induced sepsis mice. Naringin at dose of 200 mg/kg produced an anti-inflammatory effect by inducing HO-1 expression in macrophages through the AMPK, p38, and Nrf-2 signaling pathways. Naringin also improved sepsis-induced intestinal injury by modulating macrophage polarization via PPARγ/miR-21 axis (Li et al., 2021).
Naringin (50 and 100 mg/kg administered by oral gavage) also protected against sepsis-induced myocardial dysfunction by significantly reducing the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and myocardial enzymes including creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) induced by LPS. Naringin also inhibited NF-κB nuclear translocation and the activity of iNOS in H9c2 cardiomyocytes by activation of the PI3K/AKT signaling pathway (Sun et al., 2019).
4.16 Piperine
Piperine, an alkaloid present in black pepper (Piper nigrum L.), protected macrophages from pyroptosis and decreased IL-1β and HMGB1 release by suppression of ATP-induced AMPK activation, suggesting the potential of piperine to be a therapeutic agent against bacterial sepsis. Piperine dose-dependently inhibited ATP-induced pyroptosis, thus suppressing IL-1β or HMGB1 release in LPS-primed bone marrow-derived macrophages and J774A.1 cells. Moreover, in vivo findings revealed that piperine (20 mg/kg) decreased both peritoneal and serum IL-1β levels in mice intraperitoneally infected with Escherichia coli, suggesting the suppression of systemic inflammation and pyroptosis (Liang et al., 2016).
Additionally, piperine (1 or 5 mg/kg) was administered i.p. to mice and found to inhibit LPS-induced endotoxin shock, leukocyte accumulation and production of TNF-α, but not of IL-1β and IL-6. The compound inhibited LPS-induced expression of type 1 interferon (IFN) mRNA, as well as the levels of interferon regulatory factor (IRF)-1 and IRF-7 mRNA, and the phosphorylation and nuclear translocation of IRF-3. The bioactive compound also decreased activation of signal transducer and activator of transcription (STAT)-1, and inhibited the activation of STAT-1 in IFN-α/β-treated cells (Bae et al., 2010).
4.17 Quercetin
Quercetin, a natural flavonoid aglycone, is present in many products such as onion (Allium cepa L.), black tea [Camellia sinensis (L.) Kuntze], and broccoli (B. oleracea var. italica Plenck) (Kumar et al., 2017). In a mice model of lethal sepsis, quercetin significantly attenuated LPS-induced production of TNF-α and IL-1β in RAW264.7 macrophages, and also inhibited the LPS-stimulated phosphorylation of the inhibitors of κB kinase (IKKs), Akt, and JNK. Moreover, in vivo study showed that acute administration of quercetin (1, 10, 50, or 100 mg/kg injected intraperitoneally) decreased the lethality rate and circulating levels of TNF-α and IL-1β in C57BL/6J mice with endotoxemia induced by LPS (Chang et al., 2013).
Administration of quercetin intragastrically at a dose of 100 mg/kg was also found to be beneficial to acute lung injury by reducing the level of oxidative stress markers and raising the antioxidant enzyme activities in rat model of sepsis. The compound also lowered the serum levels of YKL-40 and periostin in the oxidative lung injury induced by the experimental sepsis model (Gerin et al., 2016).
Cui et al. (2019) showed that quercetin administration at the dosage of 15 and 20 mg/kg decreased tissue edema, congestion, and hemorrhage, while increasing the alveolar volume, and assist in maintaining the lung anatomy of septic rats. Significant reduction was observed in the ROS levels, as well as the activities and the expression of SOD, CAT, and APX. Quercetin also significantly reduced HMGB1 protein levels. Another study by (Zhu et al., 2019) revealed that intraperitoneal injection of 10 mg/kg quercetin protected murine sepsis by inducing macrophage M2 polarization via the TRPM2 dependent calcium influx and AMPK/ATF3 activation.
Additionally, Meng et al. (2016) studied the protective effect of quercetin on acute lung injury in rats with sepsis by administration of the compound at doses of 30 and 50 mg/kg. Quercetin showed improvement in arterial blood gases, lung water content, protein content, and cell counts in bronchoalveolar lavage fluid in comparison to control model group. The quercetin-treated groups also displayed lower serum ICAM-1 and macrophage inflammatory protein 2 (MIP2) expression compared to control group. In another study, intragastric administration of quercetin at a dose of 20 mg/kg also showed protective effect in hepatotoxicity induced by sepsis in rats (Doğukan et al., 2021).
Furthermore, Angeloni and Hrelia (2012) studied the protective effect of quercetin on LPS-induced septic rat cardiac dysfunction. Pretreatment of H9c2 cardiomyoblasts with 30 μM quercetin inhibited LPS-induced iNOS expression and NO production and prevented the oxidative stress resulted from unregulated NO production which generates peroxynitrite and other reactive nitrogen species. Moreover, quercetin pretreatment significantly counteracted apoptosis cell death and also inhibited the LPS-induced phosphorylation of stress-activated protein kinases (JNK/SAPK) and p38 MAP kinase.
4.18 Resveratrol
Resveratrol, a very well-known stilbenoid naturally present in dark grapes (Vitis vinifera L.) (Balanov et al., 2021), is highly considered as a nutraceutical with vasodilatory and antioxidant properties. The compound was found to suppress the overexpression of MMP-9, IL-1β, IL-6 and iNOS induced in LPS-induced sepsis mouse models and the TC-1 cell line in a dose-dependent manner. Resveratrol reduced pulmonary edema, improved lung function, and decreased pathological alterations in the septic mouse model when intraperitoneally injected at doses of 15 or 30 mg/kg (Li et al., 2013). Resveratrol also improved renal microcirculation, protected the tubular epithelium, and enhanced survival in a mouse model of sepsis-induced acute kidney injury (Holthoff et al., 2012).
In another study (Kolgazi et al., 2006) researchers used rats and induced sepsis. The animals with sepsis revealed a significant rise in MDA levels, MPO activity, and amount of collagen in lung and kidney tissues along with a decrease in glutathione levels. Microscopic examination showed severe destruction of regular morphology in both lung and kidney tissues. Septic rats also had higher serum TNF-α and LDH levels in comparison to the sham group. Resveratrol (30 mg/kg, i.p.) reversed these biochemical parameters and preserved tissue morphology as revealed by histological examination. Also, Sui et al. (2016) observed that resveratrol (30 mg/kg) showed protection against sepsis-associated encephalopathy and inhibited the NLRP3/IL-1𝛽 axis in microglia. The compound also attenuated the rate of apoptosis, decreased the number of iba-1 positive microglia in the hippocampus region, and also inhibited NLRP3 expression and IL-1𝛽 cleavage in a dose-dependent manner.
Wang et al. (2015) found that resveratrol administration (30 mg/kg injected intraperitoneally) reduced leukocyte/platelet adhesion and E-selectin/ICAM-1 expression with increased SIRT-1 expression in septic ob/ob and C57Bl/6 mice, and also reduced AC-p65 expression in HUVEC. The treated ob/ob mice also showed increased 7-day survival compared to the vehicle group. In another study by (Luo et al., 2020), CLP + resveratrol (30 mg/kg injected intraperitoneally) treated rats had greater survival rate (75.00%) compared to CLP group (41.67%). Resveratrol significantly reduced the level of serum creatinine and urea nitrogen, and relieved renal tubular swelling and luminal narrowing in CLP rats. Also, the compound significantly decreased the high expressions of GRP78, BiP, phosphorylated IRE1 and p65 proteins, as well as significantly lowered the levels TNF-α, IL-1β and IL-6 in CLP rats while increased that of IL-10.
Moreover, resveratrol alleviated sepsis-induced acute lung injury. Resveratrol treatment suppressed inflammation by reducing the production of TNF-α, IL-6, and IL-1β in LPS-stimulated MH-S cells, which was attributed to the inhibition of nuclear factor-κB, P38, and ERK signaling pathways. The compound also decreased LPS-induced apoptosis of MH-S cells by altering the unbalance of Bax/Bcl-2 and inhibition of LPS-induced autophagy (Yang et al., 2018).
Furthermore, resveratrol, intraperitoneally injected at 30 mg/kg, improved sepsis-induced acute kidney injury in rat model through the Nrf2 signaling pathway. Resveratrol decreased the LPS-induced inflammatory response in kidney cells in vitro and induced the activation of Nrf2 signaling (Wang et al., 2018). Resveratrol administration also significantly decreased the sepsis-induced oxidative DNA damage in the liver and kidney cells. In the resveratrol-treated sepsis rats (100 mg/kg, ip), the levels of MDA and TNF-α were lower while the level of reduced glutathione (GSH), SOD, and GPX activities were higher compared to septic group (Aydin et al., 2016).
In an in vitro study by (Silswal et al., 2018), resveratrol also downregulated biomarkers of sepsis by inhibiting proteasome’s proteases; chymotrypsin-like (predominantly LMP7), trypsin-like, and post-acidic protease activities. Also, resveratrol decreased LPS-induced inflammatory cytokine expression by reducing the translocation of NF-κB via an increase in inhibitor pIκBα.
In addition, resveratrol (intraperitoneal injection of 60 mg/kg) protected the myocardium in sepsis rat model via activation of the phosphatidylinositol 3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and inhibition of NF-kB signaling pathway (Shang et al., 2019). The study of An et al. (2016) also proved that intraperitoneal injection of 60 mg/kg resveratrol attenuated myocardial injury in sepsis rat model by reducing neutrophil accumulation, TNF-α expression, and myocardial apoptosis via activation of Sirt1 signaling.
4.19 Rosmarinic acid
Rosmarinic acid is an ester of caffeic acid with dihydroxyphenyl-lactic acid common in many herbs used in cuisine or as spice. This compound was first isolated from Rosmarinus officinalis L., since then, it has been successively found in more than 160 plants belonging to Lamiaceae, Boraginaceae, Apiaceae, etc. (Guan et al., 2022).
Rosmarinic acid significantly reduced DNA damage in the lymphocytes, livers, and kidneys of sepsis induced rats when administered at a dose of 100 mg/kg i.p. The compound reduced the level of MDA and increased GSH, SOD, and GPX activities in the livers and kidneys of the sepsis-induced rats. Plasma TNF-α level was also found to be lower in the rosmarinic acid-treated rats (Bacanlı et al., 2016).
Intravenous injection of rosmarinic acid alone or combined with imipenem treatment also decreased CLP-induced lethality in rats. The serum levels of TNF-α, IL-6, and HMGB1 protein were downregulated while the level of IL-10 was upregulated. Rosmarinic acid injection also ameliorated serum enzyme activities and MPO in lung, liver, and small intestine (Jiang et al., 2009).
4.20 Shogaol
Guo et al. (2021) evaluated the protective effect of 6-shogaol, a major bioactive component derived from ginger (Zingiber officinale Roscoe), on sepsis-induced liver injury. 6-shogaol, at dose of 20 mg/kg orally, was found to enhance the antioxidant defence system and suppressed MAPK/NFκB induced inflammatory responses. Transcriptomic analysis showed that the efficacy of 6-shogaol occurred via the regulation on Lcn2, Nos2, Ccl20, Cxcl1, Mmp9, Vcam1, Sele, Ptgs2, and Usp50 mRNA expression. Moreover, the protective effects of 6-Shogaol on renal injury caused by CLP was investigated in sepsis rat model. Oxidant molecules, MPO, and proinflammatory cytokine levels were reduced while antioxidant molecules were increased (Eraslan et al., 2020).
4.21 Silymarin
Silymarin is a mixture of flavolignans found in the fruits and seeds of milk thistle, Silybum marianum (L.) Gaertn. formed by silybin, silycristin, and silydianin. The compound showed protective effect against endotoxin-induced sepsis by displaying dose-dependent suppression of LPS-induced production of IL-1β and prostaglandin E2 (PGE2) in isolated mouse peritoneal macrophages and RAW 264.7 cells. Also, the mRNA expression of IL-1β and cyclooxygenase-2 was completely blocked while the LPS-induced DNA binding activity of NF-kB/Rel was also inhibited by silymarin in RAW 264.7 cells (Kang et al., 2004).
In the study of (Toklu et al., 2008), sepsis raised the level of serum TNF-α, IL-1β, IL-6, and LDH activity while reducing total antioxidant capacity. Also, CLP decreased the level of glutathione while increased that of MDA and MPO activity in both the lung and the brain tissues. Silymarin administration (50 mg/kg, p.o.), reversed these biochemical parameters and preserved tissue morphology as revealed by histological examination.
In addition, silymarin (100 mg/kg, i.p.) enhanced overall survival following sepsis compared to septic group (80% vs. 20%) in rat model, as well as improved hepatic and renal function parameters and decreased MDA, nitrite/nitrate, IL-6, and TNF-α levels. Silymarin also improved the endogenous antioxidant mechanisms by raising the level of GSH and reinforcement of SOD activity (Al-Kadi et al., 2020).
4.22 Sulforaphane
Sulforaphane is an organosulfur compound that is generated when the glucosinolate sulphoraphanin present in cruciferous vegetables such as broccoli (B. oleracea var. italica Plenck), Brussels sprout [B. oleracea var. gemmifera (DC.) Zenker], and cabbage (B. oleracea var. capitata L.), is hydrolysed by the enzyme myrosinase. Sulforaphane was found to suppress the release of HMGB1 and also downregulated HMGB1-dependent inflammatory responses in human endothelial cells. It also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice, reduced sepsis-related mortality and pulmonary injury when administered at 0.26 or 0.39 mg/kg i.v. (Lee et al., 2017a). In the study of (Zhao et al., 2017a), supplementation of sulforaphane (5 mg/kg intraperitoneally) in rat sepsis model significantly enhanced NF-E2-related factor-2 (Nrf2) and HO-1 protein expression in the lungs. The molecule dose-dependently decreased pulmonary oxidative stress and attenuated lung injuries in sepsis. Moreover, sulforaphane suppressed LPS-induced secretion and mRNA expression of TGFBIp or CLP-induced TGFBIp secretion. The compound also inhibited TGFBIp-mediated hyperpermeability and activation of p38, and also protected against CLP-induced lethality and lung damage (Lee and Bae, 2017).
4.23 Thymoquinone
Alkharfy et al. (2011) studied the effect of thymoquinone, a monoterpene considered as the active compound of Nigella sativa L., against sepsis syndrome morbidity and mortality in mice. Thymoquinone decreased mortality by 80%–90% and ameliorated both kidney and hepatic biomarker profiles. The level of IL-1α with 0.75 mg/kg thymoquinone dose was 310.8 ± 70.93 compared to controls (1187.0 ± 278.64 pg/ml). Likewise, 0.75 mg/kg thymoquinone significantly decreased IL-10 compared to controls (2885.0 ± 553.98 vs. 5505.2 ± 333.96 pg/ml). Thymoquinone-treated group also displayed relatively lower levels of TNF-α and IL-2 (p-values = 0.1817 and 0.0851, respectively).
Guo et al. (2020) assessed the effect of thymoquinone on acute kidney injury induced by sepsis in BALB/c mice. The phytocompound, at dose of 50 mg/kg, lowered the level of serum creatinine and blood urea nitrogen and significantly inhibited the high levels of NLRP3, caspase-1, caspase-3, caspase-8, TNF-α, IL-1β, and IL-6 induced by CLP. Also, NF-κB protein level was significantly reduced in the thymoquinone-treated group compared to the CLP group.
In addition, thymoquinone significantly reduced intestinal histological alterations in sepsis-induced cardiac damage. Thymoquinone (50 mg/kg) inhibited plasma troponin-T levels and also inhibited p62, NLRP3, caspase-1, IL-1β, IL-18, IL-6, TNF-α, and MCP-1 expressions, while increasing beclin 1 and IL-10 level. The thymoquinone-treated group also displayed reduced phosphatidylinositide 3-kinase level compared to the CLP group (Liu et al., 2019).
Furthermore, the effect of thymoquinone was also studied on gram-negative bacteria-induced sepsis in mice. Escherichia coli inoculation caused an increase in the level of plasma cytokines such as TNF-α, IL-1, IL-2, IL-6, and IL-10. Likewise, the level of C-reactive protein, vascular endothelial growth factor, and mouse endothelial cell-specific molecule-1 (ESM-1) were increased in the septic mice. Administration of thymoquinone (1 mg/kg intraperitoneally) significantly downregulated the circulating concentrations of the inflammatory proteins. Most importantly, ∼75% of mice in the thymoquinone group survived at 96 h of observation in comparison to ∼8% in the untreated group (p = 0.0016) (Alkharfy et al., 2018).
Moreover, thymoquinone was found to prevent sequels of the multiple organ failure syndrome of sepsis via regulating the production of NO and its inflammatory sequela, and adjustment of vascular responsiveness (Alkharfy et al., 2015). Thymoquinone restored the erythrocyte deformability observed in CLP-induced sepsis in rats, showing more effectiveness when applied before the establishment of the sepsis (Bostanci et al., 2018). Ozer et al. (2017) found that thymoquinone intraperitoneally injected in rats at 1 mg/kg exhibited protective effects on mesenteric perfusion, contractile function of aorta as well as anti-inflammatory and antioxidative effects.
4.24 Umbelliferone
Kutlu et al. (2020) studied the effects of the coumarin umbelliferone isolated from Ferulago pauciradiata Boiss. & Heldr. on cecal ligation and puncture-induced sepsis model in rats. Different doses of umbelliferone (10, 20, and 40 mg/kg) were tested on oxidant-antioxidant level and mRNA expression level of inflammatory mediators such as TNF-α and IL-1 in septic rats. Comparison of the lung, kidney, and liver tissues of septic rats with those of the control group revealed that umbelliferone dose-dependently raised superoxide dismutase activity and glutathione levels while significantly lowered malondialdehyde levels. The 40 mg/kg dose displayed higher anti-oxidative properties than the 20 mg/kg and 10 mg/kg doses for all the evaluated parameters. Also, the TNF-α mRNA expression of the CLP + 40 mg/kg group was decreased to a level comparable to that of the control group. The findings suggest that umbelliferone intake may represent a promising treatment for the prevention of lung, kidney, and liver damage caused by septic conditions.
4.25 Zingerone
Lee et al. (2017b) investigated the renal protective properties of zingerone, a phenolic alkanone isolated from ginger, in a mouse model of sepsis. Zingerone treatment (0.72 mg/kg) inhibited NF-κB activation and reduced iNOS and excess production of nitric acid. Zingerone also lowered the plasma levels of IL-6 and TNF-α, reduced lethality due to CLP-induced sepsis, raised lipid peroxidation, and improved the antioxidant defence system by restoring the concentrations of SOD, GPX, and CAT in kidney tissues. Similarly in the study of (Wali et al., 2020), zingerone (150 mg/kg, orally) significantly restored plasma enzymes, antioxidant markers and attenuated proinflammatory cytokines and sepsis biomarker, thus prevented multi-organ and tissue damage in LPS-induced rats as confirmed by histopathological examination.
Another study by (Lee et al., 2017b) showed that zingerone significantly decreased HMGB1 release in LPS-activated HUVECs via SIRT1-mediated deacetylation of HMGB1. The phytochemical suppressed the production of TNF-α and IL-6 and the activation of NF-κB and ERK 1/2 by HMGB1. Also, HMGB1-mediated hyperpermeability and leukocyte migration were inhibited in mice by zingerone (0.36 or 0.72 mg/kg, i.v.).
Zingerone treatment (25 and 50 mg/kg) in septic mice also attenuated neutrophil extracellular traps (NETs) formation and inflammatory response via Nrf2-mediated ROS inhibition, thereby providing a therapeutic strategy against sepsis-induced injury (Zhu et al., 2022). Furthermore, the suppressive effects of zingerone on TGFBIp-mediated septic responses was evidenced by (Min et al., 2018). The compound inhibited both LPS and CLP-mediated release of TGFBIp, expression of TGFBIp receptor (integrin αvβ5), and TGFBIp-mediated barrier disruption. Zingerone also reduced human neutrophil adhesion and migration toward HUVECs, and reduction in TGFBIp-induced mortality in mouse model, tested at doses 0.36 or 0.72 mg/kg intravenously.
5 Conclusion
Different plants’ secondary metabolites have been evaluated in several in vivo and in vitro models and the results show that these compounds can induce protection in sepsis experimental animals and reduce sepsis-induced mortality. These compounds exhibit protective effect on cardiac, lung, liver, and kidney against sepsis-induced acute organ damage, and several studies showed the ability of these phytochemicals to modulate cytokines related to inflammation such as IL-6, IL-1β, and TNF-α. Some of these phytochemicals such as naringin and naringenin (flavanones), quercetin and kaempferol (flavonols), crysin, curcumin, resveratrol and the cyanidin-3-o-glucosides (flavones) are very diffused in the vegetable food suggesting their safe use. Also, the other compounds that have been evaluated have been isolated from spices or culinary herbs supporting their use in food.
Results indicate multiple mechanism of action of these compounds but for many of these phytoconstituents, the protective effects can be attributed to bacterial clearance, antioxidant properties as well as induction of endogenous antioxidant mechanisms, and also via the downregulation of inflammatory response and reduction biochemical and inflammatory markers of sepsis. These findings suggest that these secondary metabolites could be of potential therapeutic value in the management of sepsis, but require that human studies be performed to provide further evidence to their potential clinical efficacy and safety in reducing sepsis-related morbidity and mortality.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
AMPK, AMP-activated protein kinase; CAT, catalase; CLP, cecal ligation and puncture; GPX, glutathione peroxidase; HMGB1, high mobility group box 1; HO-1, heme oxygenase 1; HUVEC, human umbilical vein endothelial cells; ICAM, intercellular adhesion molecule; IL, interleukin; iNOS, inducible nitric oxide synthase; IRF, interferon regulatory factor; JNK, c-Jun N-terminal kinase; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MPO, myeloperoxidase; NF-kB, nuclear factor-kB; NLRP3, NOD-like receptor protein 3; NO, nitric oxide; Nrf2, nuclear factor-erythroid-2-related factor 2; ROS, reactive oxygen species; SIRT1, sirtuin 1; SOD, superoxide dismutase; TGFBIp, transforming growth factor β-induced protein; TLR, toll-like receptor; TNF-α, tumor necrosis factor α.
References
Al-Kadi, A., Ahmed, A.-S., El-Tahawy, N. F. G., Khalifa, M. M. A., and El-Daly, M. (2020). Silymarin protects against sepsis-induced acute liver and kidney injury via anti-inflammatory and antioxidant mechanisms in the rat. J. Adv. Biomed. Pharm. Sci. 3, 190–197. doi:10.21608/jabps.2020.37074.1091
Alikiaii, B., Bagherniya, M., Askari, G., Johnston, T. P., and Sahebkar, A. (2021). The role of phytochemicals in sepsis: A mechanistic and therapeutic perspective. BioFactors 47, 19–40. doi:10.1002/biof.1694
Alkharfy, K. M., Ahmad, A., Jan, B. L., and Raish, M. (2018). Thymoquinone reduces mortality and suppresses early acute inflammatory markers of sepsis in a mouse model. Biomed. Pharmacother. 98, 801–805. doi:10.1016/j.biopha.2018.01.028
Alkharfy, K. M., Ahmad, A., Raish, M., and Vanhoutte, P. M. (2015). Thymoquinone modulates nitric oxide production and improves organ dysfunction of sepsis. Life Sci. 143, 131–138. doi:10.1016/j.lfs.2015.08.007
Alkharfy, K. M., Al-Daghri, N. M., Al-Attas, O. S., and Alokail, M. S. (2011). The protective effect of thymoquinone against sepsis syndrome morbidity and mortality in mice. Int. Immunopharmacol. 11, 250–254. doi:10.1016/j.intimp.2010.11.032
An, R., Zhao, L., Xu, J., Xi, C., Li, H., Shen, G., et al. (2016). Resveratrol alleviates sepsis-induced myocardial injury in rats by suppressing neutrophil accumulation, the induction of TNF-α and myocardial apoptosis via activation of Sirt1. Mol. Med. Rep. 14, 5297–5303. doi:10.3892/mmr.2016.5861
Angeloni, C., and Hrelia, S. (2012). Quercetin reduces inflammatory responses in LPS-stimulated cardiomyoblasts. Oxid. Med. Cell. Longev. 2012, 837104. doi:10.1155/2012/8371042012
Anulika, N. P., Ignatius, E. O., Raymond, E. S., Osasere, O.-I., and Abiola, A. H. (2016). The chemistry of natural product: Plant secondary metabolites. Int. J. Technol. Enhanc. Emerg. Eng. Res. 4, 1–9.
Armstrong, B. A., Betzold, R. D., and May, A. K. (2017). Sepsis and septic shock strategies. Surg. Clin. North Am. 97, 1339–1379. doi:10.1016/j.suc.2017.07.003
Atanasov, A. G., Waltenberger, B., Pferschy-Wenzig, E.-M., Linder, T., Wawrosch, C., Uhrin, P., et al. (2015). Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol. Adv. 33, 1582–1614. doi:10.1016/j.biotechadv.2015.08.001
Aydin, S., Şahin, T. T., Bacanli, M., Taner, G., Başaran, A. A., Aydin, M., et al. (2016). Resveratrol protects sepsis-induced oxidative DNA damage in liver and kidney of rats. Balk. Med. J. 33, 594–601. doi:10.5152/balkanmedj.2016.15516
Bacanlı, M., Aydın, S., Taner, G., Göktaş, H., Şahin, T., Başaran, A., et al. (2016). Does rosmarinic acid treatment have protective role against sepsis-induced oxidative damage in Wistar Albino rats? Hum. Exp. Toxicol. 35, 877–886. doi:10.1177/0960327115607971
Bae, G.-S., Kim, M.-S., Jung, W.-S., Seo, S.-W., Yun, S.-W., Kim, S. G., et al. (2010). Inhibition of lipopolysaccharide-induced inflammatory responses by piperine. Eur. J. Pharmacol. 642, 154–162. doi:10.1016/j.ejphar.2010.05.026
Balanov, P. E., Smotraeva, I. V., Abdullaeva, M. S., Volkova, D. A., and Ivanchenko, O. B., (2021). Study on resveratrol content in grapes and wine products. E3S Web of Conferences 247, 01063
Bostanci, H., Dikmen, K., Comu, F., Arslan, M., and Kucuk, A. (2018). Investigation of the effects of thymoquinone on erythrocyte deformability in sepsis treatment which created by cecal perforation in rat. Bratisl. Lek. Listy 119, 152–155. doi:10.4149/BLL_2018_029
Calderón-Montaño, J. M., Burgos-Morón, E., Pérez-Guerrero, C., and López-Lázaro, M. (2011). A review on the dietary flavonoid kaempferol. Mini Rev. Med. Chem. 11, 298–344. doi:10.2174/138955711795305335
Chang, Y.-C., Tsai, M.-H., Sheu, W. H.-H., Hsieh, S.-C., and Chiang, A.-N. (2013). The therapeutic potential and mechanisms of action of quercetin in relation to lipopolysaccharide-induced sepsis in vitro and in vivo. PLoS One 8, e80744. doi:10.1371/journal.pone.0080744
Chen, L., Lu, Y., Zhao, L., Hu, L., Qiu, Q., Zhang, Z., et al. (2018). Curcumin attenuates sepsis-induced acute organ dysfunction by preventing inflammation and enhancing the suppressive function of Tregs. Int. Immunopharmacol. 61, 1–7. doi:10.1016/j.intimp.2018.04.041
Chen, X., Yang, X., Liu, T., Guan, M., Feng, X., Dong, W., et al. (2012). Kaempferol regulates MAPKs and NF-κB signaling pathways to attenuate LPS-induced acute lung injury in mice. Int. Immunopharmacol. 14, 209–216. doi:10.1016/j.intimp.2012.07.007
Cheng, Y., Li, X., Tse, H.-F., and Rong, J. (2018). Gallic acid-L-leucine conjugate protects mice against LPS-induced inflammation and sepsis via correcting proinflammatory lipid mediator profiles and oxidative stress. Oxid. Med. Cell. Longev. 2018, 1081287. doi:10.1155/2018/1081287
Costa, T., Vieira, R. F., Bizzo, H. R., Silveira, D., and Gimenes, M. A., (2012). Secondary metabolites.
Croteau, R., Kutchan, T. M., and Lewis, N. G. (2000). Natural products (secondary metabolites). Biochem. Mol. Biol. plants 24, 1250–1319.
Csuti, A., Sik, B., and Ajtony, Z. (2022). Measurement of naringin from citrus fruits by high-performance liquid chromatography – A review. Crit. Rev. Anal. Chem. 6, 1–14. doi:10.1080/10408347.2022.2082241
Cui, W., Hu, G., Peng, J., Mu, L., Liu, J., and Qiao, L. (2019). Quercetin exerted protective effects in a rat model of sepsis via inhibition of reactive oxygen species (ROS) and downregulation of high mobility group box 1 (HMGB1) protein expression. Med. Sci. Monit. 25, 5795–5800. doi:10.12659/MSM.916044
Doğukan, M., Bıçakcıoğlu, M., Duran, M., Doğan, Z., Türk, B. A., and Uludağ, Ö. (2021). Protective and therapeutic effect of quercetin in hepatotoxicity induced by sepsis in rats. Kafkas Univ. Vet. Fak. Derg. 27, 699–706.
Dolin, H. H., Papadimos, T. J., Chen, X., and Pan, Z. K. (2019). Characterization of pathogenic sepsis etiologies and patient profiles: A novel approach to triage and treatment. Microbiol. Insights 12, 1178636118825081–1178636118825088. doi:10.1177/1178636118825081
Dugar, S., Choudhary, C., and Duggal, A. (2020). Sepsis and septic shock: Guideline-based management. Cleve. Clin. J. Med. 87, 53–64. doi:10.3949/ccjm.87a.18143
Eraslan, E., Tanyelİ, A., Akdemİr, F. N. E., and Güler, M. C. (2020). Çekal ligasyon ve delmeye bağlı polimikrobiyal sepsis sıçan modelinde 6-shogaol'ün böbrek dokusu üzerine renoprotektif etkileri. Atatürk Üniversitesi Veteriner Bilim. Derg. 15, 244–250. doi:10.17094/ataunivbd.729360
Fernandes, F. H. A., and Salgado, H. R. N. (2016). Gallic acid: Review of the methods of determination and quantification. Crit. Rev. Anal. Chem. 46, 257–265. doi:10.1080/10408347.2015.1095064
Fürst, R. (2016). Narciclasine – An amaryllidaceae alkaloid with potent antitumor and anti-inflammatory properties. Planta Med. 82, 1389–1394. doi:10.1055/s-0042-115034
Gerin, F., Sener, U., Erman, H., Yilmaz, A., Aydin, B., Armutcu, F., et al. (2016). The effects of quercetin on acute lung injury and biomarkers of inflammation and oxidative stress in the rat model of sepsis. Inflammation 39, 700–705. doi:10.1007/s10753-015-0296-9
Gil, M., Kim, Y. K., Hong, S. B., and Lee, K. J. (2016). Naringin decreases TNF-α and HMGB1 release from LPS-stimulated macrophages and improves survival in a CLP-induced sepsis mice. PLoS One 11, 1–16. doi:10.1371/journal.pone.0164186
Goto, M., Zeller, W. P., and Hurley, R. M. (1991). Cepharanthine (biscoclaurine alkaloid) treatment in endotoxic shock of suckling rats. J. Pharm. Pharmacol. 43, 589–591. doi:10.1111/j.2042-7158.1991.tb03542.x
Guan, H., Luo, W., Bao, B., Cao, Y., Cheng, F., Yu, S., et al. (2022). A comprehensive review of rosmarinic acid: From phytochemistry to Pharmacology and its new insight. Molecules 27, 3292. doi:10.3390/molecules27103292
Guo, L.-P., Liu, S.-X., Yang, Q., Liu, H.-Y., Xu, L.-L., Hao, Y.-H., et al. (2020). Erratum to "effect of thymoquinone on acute kidney injury induced by sepsis in BALB/c mice". Biomed. Res. Int. 2020, 3182919. doi:10.1155/2020/3182919
Guo, X., Qiu, J., and Qian, Y. (2021). 6-shogaol mitigates sepsis-associated hepatic injury through transcriptional regulation. Nutrients 13, 3427. doi:10.3390/nu13103427
Harasstani, O. A., Tham, C. L., and Israf, D. A. (2017). Kaempferol and chrysin synergies to improve septic mice survival. Molecules 22, 92. doi:10.3390/molecules22010092
Holthoff, J. H., Wang, Z., Seely, K. A., Gokden, N., and Mayeux, P. R. (2012). Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury. Kidney Int. 81, 370–378. doi:10.1038/ki.2011.347
Hong, M.-K., Hu, L.-L., Zhang, Y.-X., Xu, Y.-L., Liu, X.-Y., He, P.-K., et al. (2020). 6-Gingerol ameliorates sepsis-induced liver injury through the Nrf2 pathway. Int. Immunopharmacol. 80, 106196. doi:10.1016/j.intimp.2020.106196
Jiang, W.-L., Chen, X.-G., Qu, G.-W., Yue, X.-D., Zhu, H.-B., Tian, J.-W., et al. (2009). Rosmarinic acid protects against experimental sepsis by inhibiting proinflammatory factor release and ameliorating hemodynamics. Shock 32, 608–613. doi:10.1097/SHK.0b013e3181a48e86
Ju, S.-A., Nguyen, Q.-T., Nguyen, T.-H. T., Suh, J.-H., An, W. G., Callaway, Z., et al. (2021). Pretreatment with 6-gingerol ameliorates sepsis-induced immune dysfunction by regulating the cytokine balance and reducing lymphocyte apoptosis. Oxid. Med. Cell. Longev. 2021, 5427153. doi:10.1155/2021/5427153
Kang, J. S., Jeon, Y. J., Park, S.-K., Yang, K.-H., and Kim, H. M. (2004). Protection against lipopolysaccharide-induced sepsis and inhibition of interleukin-1beta and prostaglandin E2 synthesis by silymarin. Biochem. Pharmacol. 67, 175–181. doi:10.1016/j.bcp.2003.08.032
Kim, Y. M., Kim, H. J., and Chang, K. C. (2015). Glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2-dependent induction of HO-1. Int. Immunopharmacol 26, 112–118. doi:10.1016/j.intimp.2015.03.014
Kim, J.-E., Lee, W., Yang, S., Cho, S.-H., Baek, M.-C., Song, G.-Y., et al. (2019). Suppressive effects of rare ginsenosides, Rk1 and Rg5, on HMGB1-mediated septic responses. Food Chem. Toxicol. 124, 45–53. doi:10.1016/j.fct.2018.11.057
Kingsley, M. K., Bhat, B. V., Badhe, B. A., Dhas, B. B., and Parija, S. C. (2020). Narciclasine improves outcome in sepsis among neonatal rats via inhibition of calprotectin and alleviating inflammatory responses. Sci. Rep. 10, 1–14. doi:10.1038/s41598-020-59716-7
Koc, F., Tekeli, M. Y., Kanbur, M., KarayigitÖ., M., and Liman, B. C. (2020). The effects of chrysin on lipopolysaccharide-induced sepsis in rats. J. Food Biochem. 44, e13359. doi:10.1111/jfbc.13359
Kolgazi, M., Şener, G., Çetinel, Ş., Gedik, N., and Alican, I. N. (2006). Resveratrol reduces renal and lung injury caused by sepsis in rats. J. Surg. Res. 134, 315–321. doi:10.1016/j.jss.2005.12.027
Kudo, K., Hagiwara, S., Hasegawa, A., Kusaka, J., Koga, H., and Noguchi, T. (2011). Cepharanthine exerts anti-inflammatory effects via NF-κB inhibition in a LPS-induced rat model of systemic inflammation. J. Surg. Res. 171, 199–204. doi:10.1016/j.jss.2010.01.007
Kumar, R., Vijayalakshmi, S., and Nadanasabapathi, S. (2017). Health benefits of quercetin. Def. Life Sci. J. 2, 142–151. doi:10.14429/dlsj.2.11359
Kumar, S., Saini, R., Suthar, P., Kumar, V., and Sharma, R. (2022). “Plant secondary metabolites: Their food and therapeutic importance,” in Plant secondary metabolites. Editors A. K. Sharma, and A. Sharma (Singapore: Springer).
Kutlu, Z., Celik, M., Bilen, A., Halıcı, Z., Yıldırım, S., Karabulut, S., et al. (2020). Effects of umbelliferone isolated from the Ferulago pauciradiata Boiss. & Heldr. Plant on cecal ligation and puncture-induced sepsis model in rats. Biomed. Pharmacother. 127, 110206. doi:10.1016/j.biopha.2020.110206
Le Doare, K., Bielicki, J., Heath, P. T., and Sharland, M. (2015). Systematic review of antibiotic resistance rates among gram-negative bacteria in children with sepsis in resource-limited countries. J. Pediatr. Infect. Dis. Soc. 4, 11–20. doi:10.1093/jpids/piu014
Lee, I.-C., and Bae, J.-S. (2021). Inhibitory effects of aloin on TGFBIp-mediated septic responses. J. Asian Nat. Prod. Res. 23, 189–203. doi:10.1080/10286020.2019.1711066
Lee, I.-C., and Bae, J.-S. (2017). Suppressive effects of sulforaphane on TGFBIp-mediated sepsis. Nat. Product. Commun. 12, 1934578X1701201. doi:10.1177/1934578x1701201026
Lee, I.-C., Kim, D. Y., and Bae, J.-S. (2017a). Sulforaphane reduces HMGB1-mediated septic responses and improves survival rate in septic mice. Am. J. Chin. Med. 45, 1253–1271. doi:10.1142/S0192415X17500690
Lee, W., Cho, S.-H., Kim, J.-E., Lee, C., Lee, J.-H., Baek, M.-C., et al. (2019). Suppressive effects of ginsenoside Rh1 on HMGB1-mediated septic responses. Am. J. Chin. Med. 47, 119–133. doi:10.1142/S0192415X1950006X
Lee, W., Jeong, G.-S., Baek, M.-C., Ku, S.-K., and Bae, J.-S. (2019a). Renal protective effects of aloin in a mouse model of sepsis. Food Chem. Toxicol. 132, 110651. doi:10.1016/j.fct.2019.110651
Lee, W., Ku, S.-K., and Bae, J.-S. (2017b). Zingerone reduces HMGB1-mediated septic responses and improves survival in septic mice. Toxicol. Appl. Pharmacol. 329, 202–211. doi:10.1016/j.taap.2017.06.006
Li, T., Zhang, J., Feng, J., Li, Q., Wu, L., Ye, Q., et al. (2013). Resveratrol reduces acute lung injury in a LPS-induced sepsis mouse model via activation of Sirt1. Mol. Med. Rep. 7, 1889–1895. doi:10.3892/mmr.2013.1444
Li, Y., Wang, F., and Luo, Y. (2017). Ginsenoside Rg1 protects against sepsis-associated encephalopathy through beclin 1–independent autophagy in mice. J. Surg. Res. 207, 181–189. doi:10.1016/j.jss.2016.08.080
Li, Z.-L., Yang, B.-C., Gao, M., Xiao, X.-F., Zhao, S.-P., and Liu, Z.-L. (2021). Naringin improves sepsis-induced intestinal injury by modulating macrophage polarization via PPARγ/miR-21 axis. Mol. Ther. - Nucleic Acids 25, 502–514. doi:10.1016/j.omtn.2021.07.005
Li, Z., Gao, M., Yang, B., Zhang, H., Wang, K., Liu, Z., et al. (2018). Naringin attenuates MLC phosphorylation and NF-κB activation to protect sepsis-induced intestinal injury via RhoA/ROCK pathway. Biomed. Pharmacother. 103, 50–58. doi:10.1016/j.biopha.2018.03.163
Liang, Y.-D., Bai, W.-J., Li, C.-G., Xu, L.-H., Wei, H.-X., Pan, H., et al. (2016). Piperine suppresses pyroptosis and interleukin-1β release upon ATP triggering and bacterial infection. Front. Pharmacol. 7, 390. doi:10.3389/fphar.2016.00390
Liang, Z., Liang, H., Guo, Y., and Yang, D. (2021). Cyanidin 3-O-galactoside: A natural compound with multiple health benefits. Int. J. Mol. Sci. 22, 2261. doi:10.3390/ijms22052261
Liu, H., Sun, Y., Zhang, Y., Yang, G., Guo, L., Zhao, Y., et al. (2019). Role of thymoquinone in cardiac damage caused by sepsis from BALB/c mice. Inflammation 42, 516–525. doi:10.1007/s10753-018-0909-1
Liu, X.-X., Yu, D.-D., Chen, M.-J., Sun, T., Li, G., Huang, W.-J., et al. (2015). Hesperidin ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting HMGB1 release. Int. Immunopharmacol. 25, 370–376. doi:10.1016/j.intimp.2015.02.022
Liu, Z., Pan, H., Zhang, Y., Zheng, Z., Xiao, W., Hong, X., et al. (2022). Ginsenoside-Rg1 attenuates sepsis-induced cardiac dysfunction by modulating mitochondrial damage via the P2X7 receptor-mediated Akt/GSK-3β signaling pathway. J. Biochem. Mol. Toxicol. 36, e22885. doi:10.1002/jbt.22885
Luo, C.-J., Luo, F., Bu, Q.-D., Jiang, W., Zhang, W., Liu, X.-M., et al. (2020). Protective effects of resveratrol on acute kidney injury in rats with sepsis. Biomed. Pap. Med. Fac. Univ. Palacky. Olomouc Czech. Repub. 164, 49–56. doi:10.5507/bp.2019.006
Ma, M.-M., Li, Y., Liu, X.-Y., Zhu, W.-W., Ren, X., Kong, G.-Q., et al. (2015). Cyanidin-3-O-glucoside ameliorates lipopolysaccharide-induced injury both in vivo and in vitro suppression of NF-κB and MAPK pathways. Inflammation 38, 1669–1682. doi:10.1007/s10753-015-0144-y
Maurya, H., Mangal, V., Gandhi, S., Prabhu, K., and Ponnudurai, K. (2014). Prophylactic antioxidant potential of gallic acid in murine model of sepsis. Int. J. Inflam. 2014, 580320. doi:10.1155/2014/580320
Meng, L., Lv, Z., Yu, Z., Xu, D., and Yan, X. (2016). Protective effect of quercetin on acute lung injury in rats with sepsis and its influence on ICAM-1 and MIP-2 expression. Genet. Mol. Res. 15, gmr726529. doi:10.4238/gmr.15037265
Min, G., Ku, S.-K., Lee, T., and Bae, J.-S. (2018). Suppressive effects of zingerone on TGFBIp-mediated septic responses. Arch. Pharm. Res. 41, 276–287. doi:10.1007/s12272-017-0919-9
Mollica, L., De Marchis, F., Spitaleri, A., Dallacosta, C., Pennacchini, D., Zamai, M., et al. (2007). Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities. Chem. Biol. 14, 431–441. doi:10.1016/j.chembiol.2007.03.007
Mu, L., Hu, G., Liu, J., Chen, Y., Cui, W., and Qiao, L. (2019). Protective effects of naringenin in a rat model of sepsis-triggered acute kidney injury via activation of antioxidant enzymes and reduction in urinary angiotensinogen. Med. Sci. Monit. 25, 5986–5991. doi:10.12659/MSM.916400
Murakami, K., Okajima, K., and Uchiba, M. (2000). The prevention of lipopolysaccharide-induced pulmonary vascular injury by pretreatment with cepharanthine in rats. Am. J. Respir. Crit. Care Med. 161, 57–63. doi:10.1164/ajrccm.161.1.9808142
Ozer, E. K., Goktas, M. T., Toker, A., Pehlivan, S., Bariskaner, H., Ugurluoglu, C., et al. (2017). Thymoquinone protects against the sepsis induced mortality, mesenteric hypoperfusion, aortic dysfunction and multiple organ damage in rats. Pharmacol. Rep. 69, 683–690. doi:10.1016/j.pharep.2017.02.021
Rabha, D. J., Singh, T. U., Rungsung, S., Kumar, T., Parida, S., Lingaraju, M. C., et al. (2018). Kaempferol attenuates acute lung injury in caecal ligation and puncture model of sepsis in mice. Exp. Lung Res. 44, 63–78. doi:10.1080/01902148.2017.1420271
Rodrigues, F. a. D. P., Santos, A. D. D. C., De Medeiros, P. H. Q. S., Prata, M. D. M. G., Santos, T. C. D. S., Da Silva, J. A., et al. (2018). Gingerol suppresses sepsis-induced acute kidney injury by modulating methylsulfonylmethane and dimethylamine production. Sci. Rep. 8, 1–10. doi:10.1038/s41598-018-30522-6
Rudd, K. E., Johnson, S. C., Agesa, K. M., Shackelford, K. A., Tsoi, D., Kievlan, D. R., et al. (2020). Global, regional, and national sepsis incidence and mortality, 1990–2017: Analysis for the global burden of disease study. Lancet 395, 200–211. doi:10.1016/S0140-6736(19)32989-7
Rudd, K. E., Kissoon, N., Limmathurotsakul, D., Bory, S., Mutahunga, B., Seymour, C. W., et al. (2018). The global burden of sepsis: Barriers and potential solutions. Crit. Care 22, 123305059. doi:10.1186/s13054-018-2157-z
Sakaguchi, S., Furusawa, S., Wu, J., and Nagata, K. (2007). Preventive effects of a biscoclaurine alkaloid, cepharanthine, on endotoxin or tumor necrosis factor-α-induced septic shock symptoms: Involvement of from cell death in L929 cells and nitric oxide production in raw 264.7 cells. Int. Immunopharmacol. 7, 191–197. doi:10.1016/j.intimp.2006.09.008
Shang, X., Lin, K., Yu, R., Zhu, P., Zhang, Y., Wang, L., et al. (2019). Resveratrol protects the myocardium in sepsis by activating the phosphatidylinositol 3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and inhibiting the nuclear factor-κB (NF-κB) signaling pathway. Med. Sci. Monit. 25, 9290–9298. doi:10.12659/MSM.918369
Shen, N., Cheng, A., Qiu, M., and Zang, G. (2019). Allicin improves lung injury induced by sepsis via regulation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MYD88)/nuclear factor kappa B (NF-κB) pathway. Med. Sci. Monit. 25, 2567–2576. doi:10.12659/MSM.914114
Siddiqui, A. M., Cui, X., Wu, R., Dong, W., Zhou, M., Hu, M., et al. (2006). The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma. Crit. Care Med. 34, 1874–1882. doi:10.1097/01.CCM.0000221921.71300.BF
Silswal, N., Reddy, N. S., Qureshi, A. A., and Qureshi, N. (2018). Resveratrol downregulates biomarkers of sepsis via inhibition of proteasome’s proteases. Shock (Augusta, Ga.) 50, 579–588. doi:10.1097/SHK.0000000000001080
Sui, D.-M., Xie, Q., Yi, W.-J., Gupta, S., Yu, X.-Y., Li, J.-B., et al. (2016). Resveratrol protects against sepsis-associated encephalopathy and inhibits the NLRP3/IL-1β axis in microglia. Mediat. Inflamm. 2016, 1045657. doi:10.1155/2016/1045657
Sun, L.-J., Qiao, W., Xiao, Y.-J., Cui, L., Wang, X., and Ren, W.-D. (2019). Naringin mitigates myocardial strain and the inflammatory response in sepsis-induced myocardial dysfunction through regulation of PI3K/AKT/NF-κB pathway. Int. Immunopharmacol. 75, 105782. doi:10.1016/j.intimp.2019.105782
Tan, J., Li, Y., Hou, D-X., and Wu, S. (2019). The effects and mechanisms of cyanidin-3-glucoside and its phenolic metabolites in maintaining intestinal integrity. Antioxidants 8, 479. doi:10.3390/antiox8100479
Tang, R., Jia, L., Li, Y., Zheng, J., and Qi, P. (2021). Narciclasine attenuates sepsis-induced myocardial injury by modulating autophagy. Aging (Albany NY) 13, 15151–15163. doi:10.18632/aging.203078
Toklu, H. Z., Akbay, T. T., Velioglu-Ogunc, A., Ercan, F., Gedik, N., Keyer-Uysal, M., et al. (2008). Silymarin, the antioxidant component of Silybum marianum, prevents sepsis-induced acute lung and brain injury. J. Surg. Res. 145, 214–222. doi:10.1016/j.jss.2007.03.072
Uppu, D. S., Ghosh, C., and Haldar, J. (2015). Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to antibiotic therapy? Microb. Pathog. 80, 7–13. doi:10.1016/j.micpath.2015.02.001
Usmani, J., Khan, T., Ahmad, R., and Sharma, M. (2020). Potential role of herbal medicines as a novel approach in sepsis treatment. Biomed. Pharmacother. 144, 112337. doi:10.1016/j.biopha.2021.112337
Vachharajani, V., Wang, S. W., Mishra, N., El Gazzar, M., Yoza, B., and Mccall, C. (2010). Curcumin modulates leukocyte and platelet adhesion in murine sepsis. Microcirculation 17, 407–416. doi:10.1111/j.1549-8719.2010.00039.x
Wali, A. F., Rehman, M. U., Raish, M., Kazi, M., Rao, P. G., Alnemer, O., et al. (2020). Zingerone [4-(3-methoxy-4-hydroxyphenyl)-butan-2] attenuates lipopolysaccharide-induced inflammation and protects rats from sepsis associated multi organ damage. Molecules 25, 5127. doi:10.3390/molecules25215127
Wang, X., Buechler, N. L., Yoza, B. K., Mccall, C. E., and Vachharajani, V. T. (2015). Resveratrol attenuates microvascular inflammation in sepsis via SIRT-1-Induced modulation of adhesion molecules in ob/ob mice. Obesity 23, 1209–1217. doi:10.1002/oby.21086
Wang, Y., Feng, F., Liu, M., Xue, J., and Huang, H. (2018). Resveratrol ameliorates sepsis-induced acute kidney injury in a pediatric rat model via Nrf2 signaling pathway. Exp. Ther. Med. 16, 3233–3240. doi:10.3892/etm.2018.6533
Wang, Q. L., Yang, L., Peng, Y., Gao, M., Yang, M. S., Xing, W., et al. (2019). Ginsenoside Rg1 regulates SIRT1 to ameliorate sepsis-induced lung inflammation and injury via inhibiting endoplasmic reticulum stress and inflammation. Mediators Inflamm 2019, 1–11. doi:10.1155/2019/6453296
World Health Organization (2020a). Global report on the epidemiology and burden of sepsis: Current evidence, identifying gaps and future directions. Geneva: Licence.CC BY-NC-SA 3.0 IGO.
World Health Organization (2020c). Sepsis. Available at:https://www.who.int/news-room/fact-sheets/detail/sepsis. (Accessed 13.03.2022).
World Health Organization (2020b). WHO calls for global action on sepsis - cause of 1 in 5 deaths worldwide. Available at:https://www.who.int/news/item/08-09-2020-who-calls-for-global-action-on-sepsis–-cause-of-1-in-5-deaths-worldwide. (Accessed 13.03.2022).
Wu, P., Yu, X., Peng, Y., Wang, Q.-L., Deng, L.-T., and Xing, W. (2021). Ginsenoside Rg3 alleviates septic liver injury by regulating the lncRNA TUG1/miR-200c-3p/SIRT1 axis. J. Inflamm. 18, 31–13. doi:10.1186/s12950-021-00296-2
Xiao, X., Yang, M., Sun, D., and Sun, S. (2012). Curcumin protects against sepsis-induced acute lung injury in rats. J. Surg. Res. 176, e31–e39. doi:10.1016/j.jss.2011.11.1032
Xing, W., Yang, L., Peng, Y., Wang, Q., Gao, M., Yang, M., et al. (2017). Ginsenoside Rg3 attenuates sepsis-induced injury and mitochondrial dysfunction in liver via AMPK-mediated autophagy flux. Biosci. Rep. 37, BSR20170934. doi:10.1042/BSR20170934
Xingyue, L., Shuang, L., Qiang, W., Jinjuan, F., and Yongjian, Y. (2021). Chrysin ameliorates sepsis-induced cardiac dysfunction through upregulating Nfr2/Heme oxygenase 1 pathway. J. Cardiovasc. Pharmacol. 77, 491–500. doi:10.1097/FJC.0000000000000989
Xu, F., Lin, S.-H., Yang, Y.-Z., Guo, R., Cao, J., and Liu, Q. (2013). The effect of curcumin on sepsis-induced acute lung injury in a rat model through the inhibition of the TGF-β1/SMAD3 pathway. Int. Immunopharmacol. 16, 1–6. doi:10.1016/j.intimp.2013.03.014
Yan, X., Wu, L., Li, B., Meng, X., Dai, H., Zheng, Y., et al. (2015). Cyanidin-3-O-glucoside attenuates acute lung injury in sepsis rats. J. Surg. Res. 199, 592–600. doi:10.1016/j.jss.2015.06.013
Yang, C., Wu, K., Li, S.-H., and You, Q. (2013). Protective effect of curcumin against cardiac dysfunction in sepsis rats. Pharm. Biol. 51, 482–487. doi:10.3109/13880209.2012.742116
Yang, L., Zhang, Z., Zhuo, Y., Cui, L., Li, C., Li, D., et al. (2018). Resveratrol alleviates sepsis-induced acute lung injury by suppressing inflammation and apoptosis of alveolar macrophage cells. Am. J. Transl. Res. 10, 1961–1975.
Yang, S., Lee, W., Lee, B.-S., Lee, C., Park, E. K., Ku, S.-K., et al. (2019). Aloin reduces HMGB1-mediated septic responses and improves survival in septic mice by activation of the SIRT1 and PI3K/Nrf2/HO-1 signaling axis. Am. J. Chin. Med. 47, 613–633. doi:10.1142/S0192415X19500320
Ye, G., Wang, M., Liu, D., Cheng, L., Yin, X., Zhang, Q., et al. (2020). Mechanism of naringenin blocking the protection of LTB4/BLT1 receptor against septic cardiac dysfunction. Ann. Clin. Lab. Sci. 50, 769–774.
Yuan, X., Zhu, J., Kang, Q., He, X., and Guo, D. (2019). Protective effect of hesperidin against sepsis-induced lung injury by inducing the heat-stable protein 70 (Hsp70)/toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88) pathway. Med. Sci. Monit. 25, 107–114. doi:10.12659/MSM.912490
Zhang, F. L., Zhou, B. W., Yan, Z. Z., Zhao, J., Zhao, B. C., Liu, W. F., et al. (2020). 6-Gingerol attenuates macrophages pyroptosis via the inhibition of MAPK signaling pathways and predicts a good prognosis in sepsis. Cytokine 125. doi:10.1016/j.cyto.2019.154854
Zhao, B., Gao, W., Gao, X., Leng, Y., Liu, M., Hou, J., et al. (2017a). Sulforaphane attenuates acute lung injury by inhibiting oxidative stress via Nrf2/HO-1 pathway in a rat sepsis model. Int. J. Clin. Exp. Pathol. 10, 9021–9028.
Zhao, F., Fang, Y., Deng, S., Li, X., Zhou, Y., Gong, Y., et al. (2017b). Glycyrrhizin protects rats from sepsis by blocking HMGB1 signaling. Biomed. Res. Int. 2017, 9719647. doi:10.1155/2017/9719647
Zhong, W., Qian, K., Xiong, J., Ma, K., Wang, A., and Zou, Y. (2016). Curcumin alleviates lipopolysaccharide induced sepsis and liver failure by suppression of oxidative stress-related inflammation via PI3K/AKT and NF-κB related signaling. Biomed. Pharmacother. 83, 302–313. doi:10.1016/j.biopha.2016.06.036
Zhu, Y., Fan, S., Lu, Y., Wei, Y., Tang, J., Yang, Y., et al. (2019). Quercetin confers protection of murine sepsis by inducing macrophage M2 polarization via the TRPM2 dependent calcium influx and AMPK/ATF3 activation. J. Funct. Foods 56, 1–13. doi:10.1016/j.jff.2019.03.001
Zhu, Y., Wang, D., Luo, J., Jie, J., Liu, H., Peng, L., et al. (2022). Zingerone inhibits the neutrophil extracellular trap formation and protects against sepsis via nrf2-mediated ROS inhibition. Oxid. Med. Cell. Longev. 2022, 3990607. doi:10.1155/2022/3990607
Keywords: sepsis, plants, secondary metabolites, phytochemicals, inflammation
Citation: Mahomoodally MF, Aumeeruddy MZ, Legoabe LJ, Dall’Acqua S and Zengin G (2022) Plants’ bioactive secondary metabolites in the management of sepsis: Recent findings on their mechanism of action. Front. Pharmacol. 13:1046523. doi: 10.3389/fphar.2022.1046523
Received: 16 September 2022; Accepted: 01 December 2022;
Published: 16 December 2022.
Edited by:
Jules-Roger Kuiate, University of Dschang, CameroonReviewed by:
Waqas Ahmad, University of Science Malaysia, MalaysiaSongül Karakaya, Atatürk University, Turkey
Copyright © 2022 Mahomoodally, Aumeeruddy, Legoabe, Dall’Acqua and Zengin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mohamad Fawzi Mahomoodally, mohamadfawzimahomoodally@duytan.edu.vn; Stefano Dall’Acqua, stefano.dallacqua@unipd.it