J. mandshurica is a tree with gray bark that can grow up to a height of approximately 20 m. The odd-pinnate compound leaves can grow up to 80 cm on the sprout, the petiole is 9–14 cm in length, the leaflets are 6–17 cm in length and 2–7 cm in width. The shape of the leaflets is elliptical, oblong, ovate-elliptic or oblong-lanceolate, serrated, first sparsely pubescent on top, the underside is flat pilose with stellate hairs, the lateral leaflets are sessile, the apex is acuminate, and the base is truncated or heart-shaped. The male catkin inflorescence is 9–20 cm long, the inflorescence rachis is pubescent and usually has 12 stamens, the drug septum is gray-black pilose, the female spike is 5–6 mm in length and usually has 4–10 flowers, and the rachis is pubescent. The infructescence is approximately 10–15 cm in length, and infructescence pendulous with up to 5–7 fruits. The fruit is globular, ovate or elliptical with a sharp tip, and it is densely covered with glandular pubescence. Generally, it is approximately 3.5–7.5 cm in length and 3–5 cm in diameter. The fruit nucleus is 2.5–5 cm long with 8 longitudinal ridges on the surface, two of which are more prominent. The flowering period is in May and the fruit period from August to September (http://ppbc.iplant.cn/sp/10792).

Local and traditional usages of J. mandshurica in China can be traced back to the Han dynasty over 2000 years ago. Available literature shows that J. mandshurica has been used as popular herbal medicine and food by ethnic groups in many regions of the world, especially in Asian countries, such as China, Japan, and Korea to treat the various diseases like leucorrhoea, diarrhea, gastritis, leukopenia, dermatosis, and uterine prolapse (Liu et al., 2004a; Li et al., 2005; Xu et al., 2010; Park et al., 2012; Park and Oh, 2014; Yao et al., 2015b; Li et al., 2017b; Park et al., 2017; Chaudhary et al., 2019).

In China, J. mandshurica, bitter and pungent in taste, was firstly listed and recorded as the “highest-grade” medicine in the famous Chinese ancient classical book “Compendium of Materia Medica” (Simplified Chinese: 本草纲目) compiled by pharmacologist Shizhen Li (1518–1593 CE) in the Ming Dynasty (Zhang et al., 2018). According to another TCM monograph of “Kaibao Bencao” (Simplified Chinese: 开宝本草) in the Song Dynasty, BQLY has the functions of nourishing lungs and relieving asthma. Moreover, the decoction of kernels, barks, roots, and immature pericarps of J. mandshurica has been used as folk remedy for treating cancer, which was consistent with their heat clearing and detoxification effects (Lee et al., 2002; Li et al., 2003; Park et al., 2012; Yao et al., 2012; Xu et al., 2013; Gao et al., 2016; Wang et al., 2017a; Zhang et al., 2019). Interestingly, J. mandshurica is traditionally decocted together with chicken eggs to effectively prevent and treat multiple tumors in Chinese folk medicine (Wang et al., 2017a; Wang et al., 2017c).

It is important that various parts of this plant, including the green walnut husks, green peels, roots, stems, barks, branches, leaves and immature fruits have a great medicinal value in indigenous medicine. The green peels were extensively used as folk remedy for removing heat and detoxication, relieving dysentery, and improving eyesight (Li et al., 2017a). The barks were commonly used to treat urinary stones, lichen planus circumscriptus, chronic bronchitis, blurred vision, shigellosis, and HIV (Xin et al., 2014; Yao et al., 2017). Its fresh rejuvenated fruit has been used traditionally as a medicine for treatment of cancer and dermatosis, and as an anodyne to relieve aches in China (Liu et al., 2004a). The nuts are extensively used as food because of its considerable nutritional value (Wang et al., 2017b; Mu et al., 2017). In Japan, several parts of this plant have been used in folk medicines and the fruits have been commonly used for the treatment of chilblains and athlete’s foot (Machida et al., 2005).

Until now, approximately 125 quinones and their derivatives have been identified from the different plant organs of J. mandshurica. Quinones found in this plant can be structurally divided into naphthoquinones (1–29), anthraquinones (30–40), naphthalenones (41–54), tetralones (55–123), and benzoquinones (124–125) based on the structural characteristics. In recent years, the study on the bioactivity of naphthoquinone compounds obtained from J. mandshurica has become a hotspot, which was recognized as major active components for the anticancer activity (Zhang et al., 2019). However, few in vivo pharmacological activity evaluation and even clinical trials of these ingredients were still reported recently.

Nowadays, a total of 69 phenolics constituents (126–194) have been isolated and structurally characterized from the different parts of J. mandshurica. Nevertheless, only few bioactive phenolic compounds of this plant have been reported in recent years. To fully utilize the phenolics constituents of J. mandshurica in the development and application of cosmetic, functional foods and pharmaceutical products, more in-depth research on chemical ingredients and bioactivities are urgently needed.

To date, approximately forty-one triterpenoids (195–235) have been isolated and identified from the different parts of J. mandshurica. Among of them, dammarane-type triterpenoids isolated and identified from different medicinal parts of J. mandshurica, have captured more and more attention around the world due to their potent pharmacological activities, especially in antitumor properties (Salehi et al., 2019).

Diarylheptanoids own multiple pharmacological activities, raising ncreasingly attention over the last few decades (Sun et al., 2020). Currently, a total of 40 diarylheptanoids (236–275) were identified from the different parts of J. mandshurica. Among of them, compound 237–239, showed outstanding cytotoxicity against the A549 and HeLa cells (Wang et al., 2019a).

Flavonoids are widespread in the plant kingdom in free form or as glycosides, and many of them are natural drugs with various medical functions (Luan et al., 2019). Up to date, a total of 39 flavonoids (276–314) have been obtained and purified from the green peel, epicarp, stem barks, roots, green walnut husks, and pericarps of J. mandshurica. Amongst the isolated compounds, taxifolin (297) exhibited the strongest anti-HIV-1 activity against MT-4 cells (Min et al., 2002). However, pharmacological investigations on other flavonoids from J. mandshurica are very limited in the existing literature, and need to urgently conduct in future study.

Lignans with chiral carbon atoms are usually consisted of a pair of enantiomers or several pairs of stereoisomers with different amount in nature, and the biological activities of enantiomers are not identical due to the chiral nature of the biological receptors (Pereira et al., 2011). Until now, 20 lignans (315–334) have been structurally identified from the barks, roots, and fruits of J. mandshurica.

Coumarins refer to the general term of o-hydroxycinnamic acid lactones with the basic skeleton of benzoben-α-pyranone parent nucleus, which is one of the main components of TCM (Jiang et al., 2020). At present, 19 coumarins (335–353) have been isolated and characterized from the stem barks of J. mandshurica, and mainly include simple coumarins and pyranocoumarins.

Phenylpropanoids displayed various biological effects including defending against herbivores, microbial attack, or other sources of injury. Nowadays, a total of 16 phenylpropanoids (354–369) have been isolated and structurally identified from the barks, leaves, pericarps, and green walnut husks of J. mandshurica. However, studies on biological effects of phenylpropanoids from J. mandshurica are very limited.

So far, phytochemical investigations from the green walnut husks, roots, and epicarp of J. mandshurica have shown the presence of 11 steroids (370–380) including daucosterol (370), daucosterin (371), 24(R)-5α-stigmasterol (372), β-sitosterol (373), stigmast-5-en-3β,7α-diol (374), stigmast-5-en-3β,7β-diol (375), stigmast-5-en-3β-ol (376), stigmast-4-en-3-one (377), 24(R)-5α-stigmastane-3,6- dione (378), ligstroside (379), and oleuropein (380). However, few bioactive steroids have been reported recently.

Alkaloids is an important secondary metabolite and represent a relatively small class of compounds from this plant and possess remarkable antitumor activity. Until now, 7 alkaloids (381–387) have been isolated and structurally elucidated from the barks of J. mandshurica. However, there are not many studies on the biological activity of these alkaloids and therefore further research need to be explored.

A few other classes of compounds (388–407) have been isolated from J. mandshurica. Among them, siaresinolic acid (391), dihydrophaseic acid (392), epi-dihydrophaseic acid (393), nodulisporone (394), 1-ethyl malate (395), 1-buthyl malate (396), succinic acid (397), ethyl-O-β-d-glucopyranoside, 3β,20-dihydroxy- 5β-pregnant (398) were first isolated from green walnut husks of this plant (Zhang et al., 2009; Qiu et al., 2017).

A variety of the crude extracts, isolated compounds, and polysaccharides from J. mandshurica displayed significant antitumor activity both in vitro and in vivo. The underlying mechanisms of action of these components included induction of cell apoptosis and autophagy, cell cycle arrest, promotion of cell differentiation and inhibition of cell adhesion and invasion. Effects on telomerase activity and regulation of mRNA and protein expression levels of tumor-related factors were observed (see Table 2 and Figure 3). In general, the antitumor activity of J. mandshurica has been effectively demonstrated in various human cancer cell lines, such as hepatocellular carcinoma HepG2, Hep3B, Huh7, and BEL-7402 cells (Yao et al., 2012; Zhang et al., 2013; Zhou et al., 2015a; Gao et al., 2016; Hou et al., 2016; Jin et al., 2016; Cheng et al., 2017; Yao et al., 2017; Wang et al., 2018a; Zhang et al., 2018; Lou et al., 2019a; Zhou et al., 2019a; Lou et al., 2019b), lung cancer A549, NCI-H460, and NCI-H1975 cells (Yao et al., 2014; Yao et al., 2015b; Gao et al., 2016; Jin et al., 2016; Li et al., 2017a; Zhang et al., 2018; Yang et al., 2019), breast cancer SKBR3, BT474, MCF-7, Bcap-37, and MDA-MB-231 cells (Gao et al., 2016; Jin et al., 2016; Sun et al., 2017; Zhang et al., 2018), cervical cancer Hela, SiHa, and CaSKi cells (Li et al., 2007a; Zhang et al., 2012a; Xin et al., 2014; Yao et al., 2014; Yao et al., 2015b; Lu et al., 2017; Wang et al., 2019a), gastric cancer SNU638, BGC-803, SGC-7901, and BGC-823 cells (Li et al., 2009; Yao et al., 2014; Yao et al., 2015b; Guo et al., 2015; Gao et al., 2016; Jin et al., 2016; Zhou et al., 2019b), prostate cancer LNCaP cells (Xu et al., 2013), pancreatic cancer BxPC-3 and PANC-1 cells (Avcı et al., 2016), colon cancer HCT 15 and CCL-228-SW 480 cells (Bayram et al., 2019; Zhou et al., 2019b), leukemia K562 and HL-60 cells (Xu et al., 2010; Yao et al., 2014; Yao et al., 2015b; Li et al., 2017a; Zhou et al., 2019b), placental choriocarcinoma JAR cells (Yao et al., 2014), and glioma C6 cells (Yang et al., 2019). It is worth noting that the isolated compounds 1, 17, 25, 30, 39, 43, 44, 71, 72, 73, 125, 180, 196, 198, 212, 216, 221, 236, 237, 238, 239, 289, 318, 335, 337, 340, 357, 358, and 381 displayed significant antitumor activity against on HepG2, A549, MCF-7, Hela, SiHa, MDA-MB-231, BGC-803, SGC-7901, BGC-823, LNCaP, BxPC-3, and PANC-1 in vitro. Besides, the antitumor activity of the compounds with mother nucleus of 1, 4-naphthoquinone substituted by hydroxy is stronger than that of methoxy substitution at the same position, and the compounds with 5-and 8-hydroxy groups have the strongest antitumor activity. The anti-tumor activity of naphthoquinone type compounds is generally stronger than that of naphthone, naphthol and thier glycosides, and the naphthone glycosides showed the weakest antitumor activity (Zhang et al., 2019).

In vivo in mouse models, it has been demonstrated that J. mandshurica and its secondary products showed protective activity on MCF-7 tumor-bearing mice (Sun et al., 2017), S180 tumor-bearing mice (Yao et al., 2009; Wang et al., 2015), and H22 tumor-bearing mouse (Wang et al., 2017c; Wang et al., 2017d). A polysaccharide, namely JRP1, purified form the fruits, at doses of 25, 50 and 100 mg/kg, i.p., for 21 days, inhibited the tumor growth with inhibition rates of 35.3%, 40.6% and 48.1%, respectively, and decreased the index of spleen and thymus and increased the serum levels of immune regulatory markers such as IL-2, TNF-α and IFN-γ with a dose-dependent manner in S180 tumor-bearing mice (Wang et al., 2015). Orally administration with JMCE (at doses of 100, 200, and 500 mg/kg) to S180 tumor-bearing mice once a day for 8 days significantly elevated the indexes thymus and spleen, inhibited the growth of tumor with inhibition rates of 48.37%, 40.81%, and 36.52%, respectively. JMCE also increased the activity of SOD and decreased the content of MDA in the serum of tumor-bearing mice (Yao et al., 2009).

In traditional Chinese medicine as described by “Zhongguo Minjian Liaofa”, branches of J. mandshurica are decocted together with chicken eggs. The eggs should be initially administered and the decoction should be administered when there are no obvious side effects. Eggs decocted with J. mandshurica branches (EDJB), at doses of 0.64, 1.28, and 2.56 g/kg i.p. once a day for 10 days, suppressed the growth of tumor tissues and increased the body weights in H22 tumor-bearing mouse in a dose- and time-dependent manner. Moreover, EDJB dramatically elevated the thymus index and spleen index of tumor mice, improved the peripheral red blood cells and hemoglobin numbers as well as reduced the white blood cells numbers (Wang et al., 2017c), suggested EDJB has good anti-tumor effect against H22 cell. In addition, total tannins (TT) obtained from J. mandshurica, at doses of 0.09 and 0.18 g/kg once a day for 10 days, prominently inhibited the growth of tumor tissues in H22 tumor bearing mouse with an inhibition rate of 34.22% and 36.92%, respectively (Wang et al., 2017d).

Multidrug resistance (MDR) is a major obstacle that hinders the treatment of cancer. Wen et al. (2017) developed a self-assembled polyjuglanin nanoparticle, namely DOX/PJAD-PEG-siRNA, and evaluated its anticancer activity both in vitro and in vivo. In vitro results showed that it improved the cytotoxicity of doxorubicin (DOX) to A549/DOX and H69/CIS cell lines with MDR. Meanwhile, at concentrations of 2, 4, and 8 μg/ml, it significantly down-regulated the mRNA expressions of Kras, P-gp, and c-Myc in a dose-dependent manner (Wen et al., 2017). Moreover, DOX/PJAD-PEG-siRNA at 2 mg/kg for 21 days, significantly suppressed the growth of tumor, decreased the volume and weight of tumor, KI-67 positive levels and expressions of RAS and c-Myc, and increased the TUNEL positive levels and protein levels of p-JNK and p53 in drug-resistant xenografted nude mice when compared to the free DOX at same dose (Wen et al., 2017). These antitumor activities reported are consistent with the traditional usage such as the treatment of liver cancer, lung cancer, breast cancer, cervical cancer, and gastric cancer, etc.

Overall, J. mandshurica has prominent antitumor potential and has a good health benefit for human. Nevertheless, it is worth noting that most of the research conducted to study antitumor activity stay in the primary stage, and has employed in vitro-based methods and further more in-depth in vivo and mechanism of action investigations as well as clinical studies should therefore be encouraged and strengthened.

Li et al. (2018) first evaluated the immunoregulatory functions of the three protein hydrolyzates (PH), namely albumin, glutelin, and globin (molecular weights: 11–35 kDa) obtained from J. mandshurica in mice. The three compounds, glutelin, albumin, and globin at doses of 200, 400, and 800 mg/kg/d, for 35 days significantly increased the thymus and spleen indexes, lymphocyte proliferation, macrophage activity, CD4⁺ and CD8⁺ T cells numbers, IgA and sIgA levels, and dose-dependently up-regulated mRNA and protein expression levels of IFN-α and IL-6 relative to that of the control group (Li et al., 2018). Simultaneously, a hydrolysate peptide (HP) isolated from J. mandshurica (molecular weight <3 kDa), at dose of 800 mg/kg/d for 28 days, obviously elevated the spleen and thymus indexes and promoting the spleen T-lymphocyte proliferation and sIgA generation in the intestinal tract of mice stimulated by exhaustion swimming experiment (Li et al., 2018).

A variety of isolated compounds and crude extracts from J. mandshurica displayed anti-inflammatory activity in various inflammatory related models, and the possible mechanism of action of active compounds were showed in Figure 4. In HaCaT cells induced by IFN-γ, 1.0, 5.0, and 10 μM 1,2,3,4,6-penta-O-galloyl-β- d-glucose (PGG, 194) notably inhibited the protein and mRNA expression levels of CCL17, reduced the protein expression of CXCL-9, CXCL-10, and CXCL-11, and prominently repressed the NF-κB activation as well as STAT1 activation (Ju et al., 2009). Furthermore, PGG obviously reduced the protein expression of CXCL-9, CXCL-10, and CXCL-11 (Ju et al., 2009). Peng et al. (2015) revealed that juglone (1), at doses of 0.25 and 1.0 mg/kg, i.g., daily, for 70 days, significantly decreased the levels of TNF-α, IL-1β and IL-6 both in serum and hypothalamus tissues in rats with high-fat diet-induced neuroinflammation. Further investigations demonstrated that juglone suppressed the inflammatory responses via inhibition of TLR4/NF-κB signaling pathway by reducing the protein expressions of TLR4, MyD88, TAK1, p-IκBα, NF-κB, and p-NF-κB (Peng et al., 2015). In LPS-induced primary astrocytes, juglone at doses of 5, 10, 15, and 20 μM, could prominently down-regulate the expressions of these indicators involved in TLR4/NF-κB signaling pathway (Peng et al., 2015). Similarly, in LPS-stimulated acute lung injury mice model, juglanin B (289), at dosages of 10 and 20 mg/kg, i.g., daily, for 21 days, significantly alleviated the lung fibrosis and inflammation cell infiltration via decreasing the mRNA and protein expressions of α-SMA, collagen type I, collagen type III, and TGF-β1 (Dong and Yuan, 2018). Moreover, juglanin B (289) notably decreased the levels of IL-4, IL-6, IL-17, IL-18, TNF-α and IL-1β as well as down-regulated the expression of phosphorylated NF-κB via suppressing the IKKα/IκBα signaling pathway (Dong and Yuan, 2018). In addition, five diarylheptanoids and their glycosides, (2S,3S,5S)- 2,3,5-trihydroxy-1,7-bis-(4-hydroxy-3-methoxyphenyl)-heptane (240), (2S,3S,5S)- 2,3-dihydroxy-5-O-β-d-xylopyranosyl-7-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)-heptane (241), rhoiptelol C (242), rhoiptelol B (243), and 3′,4″-epoxy -2-O-β-d-glucopyanosyl-1-hydroxyphenyl)-7-(3-methoxy-phenyl)-heptan-3-one (244) significantly and dose-dependently repressed the NO, IL-6 and TNF-α generation in LPS-stimulated RAW264.7 cells (Diao et al., 2019).

Besides, J. mandshurica leaves ethanol extract (JMLE) is particularly effective against allergic dermatitis. After treatment with 0.5% JMLE, the clinical skin severity scores (1.50%) were significantly decreased relative to that of the control group (3.83%), and scratching scores (96.33%) also remarkedly reduced relative to that of the control group (325.01%) in DNCB-induced allergic dermatitis-like skin lesions of mice (Park and Oh, 2014). Further study showed that JMLE obviously decreased the serum levels of TNF-α, IgE, IL-1, and IL-13 (Park and Oh, 2014), suggesting that JMLE might provide the theoretical basis for the further study of active ingredients against allergic dermatitis.

Neurodegenerative diseases are characterized by a severe and progressive loss of neurons in the central nervous system, leading to cognitive, behavioral, and motor dysfunctions (Liu et al., 2019). Natural-derived peptides are effective substances in alleviating the oxidative stress and preventing neurotoxicity (Zhao et al., 2020). The hydrolyzed peptide (HP) obtained from J. mandshurica displayed important neuroprotective activity both in vitro and in vivo, and the underlying mechanism was displayed in Figure 5.

Three different molecular-weight HP (<3 kDa; 3–10 kDa; >10 kDa) obtained from J. mandshurica, and their antioxidant capacity were evaluated in vitro after treated with different concentrations (1.0, 1.5, 2.0, and 2.5 mg/ml). Results found that the lower molecular-weight HP (<3 kDa) exhibit higher and significant antioxidant activities via repressing the production of ROS and increasing the activity of glutathione peroxidase (GSH-Px) in the H₂O₂-induced PC12 cells, which than those of higher molecular-weight HP, suggesting that the antioxidant capacity of HP might be relate to molecular-weight (Ren et al., 2018). Similarly, in vivo, orally administrated with HP at doses of 200, 400, and 800 mg/kg daily for 30 days in scopolamine-induced memory impairment in mice, the total path for searching the platform was significantly shortened, the escape latency was significantly decreased, and the dwelling distance and time in the coverage zone were notably increased in the Morris water maze test. HP also extended the latency and lessened errors in the passive avoidance response tests (Ren et al., 2018). Mechanically, HP increased the contents of ACh, ChAT, AChE, 5-HT, DA, and NE, elevated the activities of the SOD and GSH-Px as well as up-regulated the protein expression of p-CaMK II in brain tissues of mice (Ren et al., 2018). Subsequently, another antioxidant peptide obtained from J. mandshurica, namely EVSGPGLSPN, at concentrations of 12.5, 25, 50, and 100 μM, dose-dependently decreased the production of ROS, and enhanced the activities of CAT, GSH-px, and SOD in H₂O₂-induced PC12 cells (Liu et al., 2019). Simultaneously, EVSGPGLSPN inhibited the IKKβ and p65 expressions to repress the NF-κB pathway activation, alleviated the neurotoxic cascade by overexpression of IL-1β and TNF-α. Furthermore, EVSGPGLSPN significantly inhibited the apoptosis of PC12 cells by down-regulating the expression of cytochrome C, caspase-3/9, and PARP as well as up-regulating the expression of p-CREB and synaptophysin in oxidatively damaged PC12 cells (Liu et al., 2019). These results indicated that EVSGPGLSPN may protect against H₂O₂-induced neurotoxicity by increasing the activity of antioxidant enzymes and blocking the NF-κB/caspase pathways.

In a recent study, three peptides, namely YVLLPSPK, TWLPLPR, and KVPPLLY, obtained from J. mandshurica, at a concentration of 50 μM for 24 h, prominently inhibited the generation of ROS, increased the activity of GSH-Px and contents of ATP, and alleviated apoptosis in Aβ_25–35-induced PC12 cells. It also promoted autophagy and affected the Akt/mTOR signaling pathway through up-regulating the protein expression levels of Beclin-1, LC3-I, LC3-II, LAMP1, LAMP2, Cathepsin and p-Akt/Akt as well as down-regulating the protein expression level of p62 and p-mTOR/mTOR at molecule levels (Zhao et al., 2020). Results from above studies indicated that J. mandshurica may serves as sustainable dietary supplement to further develop novel functional food to prevent or defer oxidation-incurred memory impairment damage and ageing/or age-related neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Recent findings have demonstrated that J. mandshurica possess significant hypoglycemic activity in vitro and the possible mechanism of this action was showed in Figure 6. The ethyl acetate fractions extracted from ethanol extract of J. mandshurica leaves (JMEE) showed significant α-glucosidase and α-amylase inhibitory activity in vitro with IC₅₀ of 14 and 130 μg/ml, which were stronger than that of the positive drug acarbose with IC₅₀ of 44 and 158 μg/ml, respectively (Wang et al., 2019c). In insulin resistant (IR) hepatic HepG2 cells, LPLLR (Leu-Pro-Leu-Leu-Arg), a novel pentapeptide from the protein hydrolysates of J. mandshurica, at concentrations of 100 and 200 μM, increased the phosphorylation levels of insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), AMPK and GSK3β, and up-regulated the expression levels of GS and glucose transporter type 4 (GLUT4), while down-regulated the expression levels of G-6-Pase and PEPCK in IR hepatic HepG2 cells (Wang et al., 2020a). These findings suggested that LPLLR exerts anti-diabetic effect through increasing the glycogen synthesis and glucose uptake, as well as decreasing the gluconeogenesis. In addition, the peptide LPLLR possesses good stability under in vitro simulated gastrointestinal digestion, and the low molecular weight (610.4 Da) of LPLLR may be beneficial for its intestinal absorption. Nevertheless, more in-depth in vivo investigation is needed to explore the stability and absorption of LPLLR. Subsequently, in high glucose-induced IR and oxidative stress in HepG2 cells, three novel peptides, namely Leu-Val-Arg-Leu (LVRL), Leu-Arg-Tyr-Leu (LRYL), and Val-LeuLeu-Ala-Leu-Val-Leu-Leu-Arg (VLLALVLLR) from J. mandshurica at 12.5–100 μM, significantly improve glucose consumption, glucose uptake, GLUT4 translocation, and elevated the phosphorylation of IRS-1, PI3K, and Akt. The activities of GSH-Px, CAT, and SOD, the nuclear transport of Nrf2, and the protein expression of HO-1 were also increased. Furthermore, these peptides reduced high glucose-induced ROS overproduction and the phosphorylation of ERK, JNK, and p38 (Wang et al., 2020b). These results suggested that peptides from J. mandshurica could protect HepG2 cells from high glucose-induced IR and oxidative stress by activating IRS-1/PI3K/Akt and Nrf2/HO-1 signaling pathways.

Three new juglone derivatives, namely juglonol A (71), B (72), and C (73), isolated from the immature exocarps of J. mandshurica by Yang and his colleagues (2019) and their antimicrobial activity against Gram-positive (S. aureus and E. faeculis) and Gram-negative (E. coli and K. pneumonia) bacteria, yeast (C. albicans), and fungi (F. oxysporum, F. oxysporium, C. lagenarium, and P. asparagi) were evaluated. The results showed that juglonol A (71) obviously suppressed all tested strains except for E. coli. with the MIC values ranging 8 from 64 μg/ml However, juglonol B (72) only significantly inhibited the S. aureus with MIC value of 8 μg/ml (Yang et al., 2019). Juglonol A have also been demonstrated to exhibit modestly inhibitory activity against the non-small-cell lung carcinoma (NCI-H1975), lung adenocarcinoma (HCC827), hepatocellular carcinoma (HepG2), triple-negative breast cancer (MD-AMB-231), leukemia (HL-60), mouse colon cancer (CT26) and rat glioma (C6), and IC₅₀ values were ranging from 9.5 to 31.6 μg/ml (Yang et al., 2019). These results suggested that the presence of juglone core or hydroxyethyl side chain is essential to the molecules’ biological activity and that the position of substitution has a marked impact on the potency. Hence, juglonol A, as pan-inhibitors, might be cytotoxic.

Min et al. (2000) found that 1,2,6-trigalloylglucose (192) and 1,2,3,6- tetragalloylglucose (193) isolated from barks of J. mandshurica showed the most potent anti-reverse transcriptase (RT) activity of HIV-1 with the IC₅₀ values of 67 and 40 nM, respectively. In addition, compound 192 notably suppressed the ribonuclease H (RNase H) activity with IC₅₀ values of 39 μM when used illimaquinone as a positive control (Min et al., 2000). Simultaneously, Min and his colleagues further found that taxifolin (297) displayed the most potent anti-HIV-1 activity against MT-4 cells with the IC₁₀₀ value of 25 μg/ml and CC₁₀₀ value of above 100 μg/ml (Min et al., 2002). However, the certain mechanism of anti-HIV-1 activity should be performed at molecule level in the future.

Recently, Kim et al. (2019) obtained three phenolic ingredients from fruit of J. mandshurica and evaluated their anti-melanogenesis activity in B16F10 melanoma cells and primary human epidermal melanocytes. It was found that compound 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-1,3-propanediol (126) at concentrations of 0.5 and 1.0 μM, showed the highest inhibitory effect through reducing the melanin content, increasing the p-ERK protein expression and decreasing MITF and tyrosinase protein expressions. These effects also could immediately reverse by PD98059, which a potent ERK inhibitor, indicated compound 126 effectively curbed melanogenesis mainly through p-ERK-associated MITF degradation (Kim et al., 2019). Therefore, J. mandshurica has the potential to suppress melanogenesis and can become a useful resource for developing novel skin-whitening agents to cure hyperpigmentation disorders.