2,3,5,4'- tetrahydroxystilbene-2-O-ß-D- glucopyranoside (TSG)-Driven immune response in the hepatotoxicity of Polygonum multiflorum.

ETHNOPHARMACOLOGICAL RELEVANCE: 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside (TSG) as the primary constituent of Polygonum multiflorum Thumb. (PM) possesses anti-oxidative, antihypercholesterolemic, anti-tumor and many more biological activities. The root of PM has been used as a tonic medicine for thousands of years. However, cases of PM-induced liver injury are occasionally reported, and considered to be related to the host immune status. AIM OF THE STUDY: The primary toxic elements and specific mechanisms PM causing liver damage are still not thoroughly clear. Our study aimed to investigate the influences of TSG on the immune response in idiosyncratic hepatotoxicity of PM. MATERIALS AND METHODS: The male C57BL/6 mice were treated with different doses of TSG and the alterations in liver histology, serum liver enzyme levels, proportions of T cells and cytokines secretion were evaluated by hematoxylin and eosin (HE), RNA sequencing, quantitative real time polymerase chain reaction (qRT-PCR), Flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA), respectively. Then, primary spleen cells from drug-naive mice were isolated and cultured with TSG in vitro. T cell subsets proliferation and cytokines secretion after treated with TSG were assessed by CCK8, FCM and ELISA. In addition, mice were pre-treated with anti-CD25 for depleting regulatory T cells (Tregs), and then administered with TSG. Liver functions and immunological alterations were analyzed to evaluate liver injury. RESULTS: Data showed that TSG induced liver damage, and immune cells infiltration in the liver tissues. FCM results showed that TSG could activate CD4+T and CD8+T in the liver. Results further confirmed that TSG notably up-regulated the levels of inflammatory cytokines including TNF-α, IFN-γ, IL-18, perforin and granzyme B in the liver tissues. Furthermore, based on transcriptomics profiles, some immune system-related pathways including leukocyte activation involved in inflammatory response, leukocyte cell-cell adhesion, regulation of interleukin-1 beta production, mononuclear cell migration, antigen processing and presentation were altered in TSG treated mice. CD8+T/CD4+T cells were also stimulated by TSG in vitro. Interestingly, increased proportion of Tregs was observed after TSG treatment in vitro and in vivo. Foxp3 and TGF-ß1 mRNA expressions were up-regulated in the liver tissues. Depletion of Tregs moderately enhanced TSG induced the secretion of inflammatory cytokines in serum. CONCLUSIONS: Our findings showed that TSG could trigger CD4+T and CD8+T cells proliferation, promote cytokines secretion, which revealed that adaptive immune response associated with the mild liver injury cause by TSG administration. Regulatory T cells (Tregs) mainly sustain immunological tolerance, and in this study, the progression of TSG induced liver injury was limited by Tregs. The results of our investigations allow us to preliminarily understand the mechanisms of PM related idiosyncratic hepatotoxicity.

Lignans and phenolic constituents from Eucommia ulmoides Oliver.

Two new lignans, noreucol A (1) and (+)-epicycloolivil (2), along with seven known compounds (3-9) were isolated from the aqueous extract of Eucommia ulmoides Oliver. Compound 1 was a new norlignan and 2 was an epimer at C-7 of (+)-cycloolivil (3). Their structures were elucidated by spectroscopic methods, and the absolute configurations of new compounds were determined by conformational analysis and DFT theoretic electronic circular dichroism spectra calculations. In addition, the neuroprotective activity of compounds 1-3 against glutamate-induced HT-22 cells injury were evaluated, and only compound 1 exhibited moderate effect at the concentrations ranging from 10 ∼ 50 µM.

The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury.

Herbal and dietary supplements (HDS)-induced liver injury has been a great concern all over the world. Polygonum multiflorum Thunb., a well-known Chinese herbal medicine, is recently drawn increasing attention because of its hepatotoxicity. According to the clinical and experimental studies, P. multiflorum-induced liver injury (PM-DILI) is considered to be immune-mediated idiosyncratic liver injury, but the role of immune response and the underlying mechanisms are not completely elucidated. Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury (DILI). However, most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury. The aim of this review is to assess current epidemiological, clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P. multiflorum. The potential effects of factors associated with immune tolerance, including immune checkpoint molecules and regulatory immune cells on the individual's susceptibility to PM-DILI are also discussed. We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.

Leucovorin ameliorated methotrexate induced intestinal toxicity via modulation of the gut microbiota.

Methotrexate (MTX) is a widely used therapeutic agent for the treatment of cancer and autoimmune diseases. However, its efficacy is often limited by adverse effects, such as intestinal toxicity. Although treatment with leucovorin (LV) is the most common method to reduce the toxic effects of MTX, it may also compromise the therapeutic effects of MTX. The gut microbiome has been reported to be associated with the intestinal toxicity of MTX. In this study, the intestinal damage of MTX was ameliorated by treatment with LV. Moreover, the population, diversity, and principal components of the gut microbiota in MTX-treated mice were restored by treatment with LV. The only element of the gut microbiota that was significantly changed after treatment with LV was Bifidobacterium, and supplementation with Bifidobacterium longum ameliorated MTX-induced intestinal damage. In conclusion, our results suggest that the balance and the composition of gut microbiota have an important role in the LV-mediated protection against MTX-induced intestinal toxicity. This work provides foundation of data in support of a new potential mechanism for the prevention of MTX-induced intestinal toxicity.

Ginsenoside compound K alleviates sodium valproate-induced hepatotoxicity in rats via antioxidant effect, regulation of peroxisome pathway and iron homeostasis.

Sodium valproate (SVP) is a first-line treatment for various forms of epilepsy; however, it can cause severe liver injury. Ginsenoside compound K (G-CK) is the main active ingredient of the traditional herbal medicine ginseng. According to our previous research, SVP-induced elevation of ALT and AST levels, as well as pathological changes of liver tissue, was believed to be significantly reversed by G-CK in LiCl-pilocarpine induced epileptic rats. Thus, we aimed to evaluate the protective effect of G-CK on hepatotoxicity caused by SVP. The rats treated with SVP showed liver injury with evident increases in hepatic index, transaminases activity, alkaline phosphatase level, hepatic triglyceride and lipid peroxidation; significant decreases in plasma albumin level and antioxidant capacity; and obvious changes in histopathological and subcellular structures. All of these changes could be mitigated by co-administration with G-CK. Proteomic analysis indicated that hepcidin, soluble epoxide hydrolase (sEH, UniProt ID P80299), and the peroxisome pathway were involved in the hepatoprotective effect of G-CK. Changes in protein expression of hepcidin and sEH were verified by ELISA and Western blot analysis, respectively. In addition, we observed that the hepatic iron rose in SVP group and decreased in the combination group. In summary, our findings demonstrate the clear hepatoprotective effect of G-CK against SVP-induced hepatotoxicity through the antioxidant effect, regulation of peroxisome pathway relying on sEH (P80299) downregulation, as well as regulation of iron homeostasis dependent on hepcidin upregulation.

A review of the pharmacology and toxicology of aucubin.

Aucubin is an iridoid glycoside that is widely prevalent in traditional medicinal herbs, such as Eucommia ulmoides Oliv., Aucuba japonica Thunb. and Plantago asiatica L. This review aims to provide a comprehensive summary of the source, biological activity, pharmacokinetics and toxicology of aucubin with the ultimate objective of providing a guide for future drug development and potential clinical applications of aucubin. Aucubin is a highly active compound possessing extensive biological effects including antioxidant, anti-aging, anti-inflammatory, anti-fibrotic, anti-cancer, hepatoprotective, neuroprotective and osteoprotective properties. Although aucubin has been shown to have poor oral bioavailability in rats, aucubin is widely distributed in multiple organs including kidney, liver, heart, spleen and lung, and there is a sex difference in the absorption of aucubin. Tolerance of aucubin is good and no serious adverse reactions have been observed to date. In short, aucubin is a compound with abundant potential sources, good safety and numerous beneficial biological activities, which exhibits high potential value for use in health care products and pharmaceuticals. In order to accelerate the development and utilization of aucubin-related products, in-depth studies should be focused on the following questions of interest. First, it is necessary to introduce advanced separation and formulation technologies to improve the yield and stability of aucubin products. Second, studies should focus on the specific pharmacological activities of aucubin to determine the structure-activity relationship so as to improve the efficacy and reduce side effects. Finally, clinical studies are needed to confirm the efficacy of aucubin in specific diseases.

The Protective Effect of Aucubin from Eucommia ulmoides Against Status Epilepticus by Inducing Autophagy and Inhibiting Necroptosis.

Eucommia ulmoides Oliv. is a famous traditional Chinese medicine which exhibits anti-oxidative stress ability and neuro-protective effects. Aucubin is the predominant component of Eucommia ulmoides Oliv. Our present study is intended to investigate aucubin's potential protective effects on neurons against epilepsy in the hippocampus by establishing the lithium-pilocarpine induced status epilepticus (SE) rat model in vivo. Aucubin (at a low dose and a high dose of 5[Formula: see text]mg/kg and 10[Formula: see text]mg/kg, respectively) was administered through gavage for two weeks before lithium-pilocarpine injection. Rats were sacrificed at 4, 24 and 72[Formula: see text]h after SE induction. Pretreatment with both low-dose and high-dose aucubin significantly reduced the number of death neurons ([Formula: see text]) and increased the number of surviving neurons ([Formula: see text]) in DG, Hilus, CA1 and CA3 hippocampal regions post SE. Meanwhile, it significantly inhibited necroptosis proteins (MLKL and RIP-1) ([Formula: see text] or [Formula: see text]) and enhanced autophagy protein (Beclin-1 and LC3BII/LC3BI) prevalence in the hippocampus ([Formula: see text] or [Formula: see text]). In conclusion, aucubin appeared to ameliorate damages in lithium-pilocarpine induced SE in hippocampus, reduce the number of apoptotic neurons, and increased the number of survival neurons by inducing autophagy and inhibiting necroptosis. These original findings might provide an important basis for the further investigation of the therapeutic role of aucubin in treatment or prevention of epilepsy-related neuronal damages.