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.

Roles of Gut Microbial Metabolites in Diabetic Kidney Disease.

Diabetes is a highly prevalent metabolic disease that has emerged as a global challenge due to its increasing prevalence and lack of sustainable treatment. Diabetic kidney disease (DKD), which is one of the most frequent and severe microvascular complications of diabetes, is difficult to treat with contemporary glucose-lowering medications. The gut microbiota plays an important role in human health and disease, and its metabolites have both beneficial and harmful effects on vital physiological processes. In this review, we summarize the current findings regarding the role of gut microbial metabolites in the development and progression of DKD, which will help us better understand the possible mechanisms of DKD and explore potential therapeutic approaches for DKD.

Renal function is associated with plasma trimethylamine-N-oxide, choline, L-carnitine and betaine: a pilot study.

INTRODUCTION: Chronic kidney disease (CKD) is characterized by decreased glomerular filtration rate (GFR) due to a variety of causes. Most patients remain undiagnosed at early stage of CKD and proceed to end stage CKD due to unawareness and lacking of efficient biomarkers. Trimethylamine-N-oxide (TMAO) and its predecessor products: choline, L-carnitine and betaine are associated with reduced renal function. However, whether the combined variation of the four metabolites could contribute in prediction and stratification of impaired glomerular function in Chinese CKD patients is unknown. Our aim is to investigate the associations of plasma TMAO, choline, L-carnitine and betaine with glomerular filtration in CKD patients. MATERIALS AND METHODS: A total of 65 CKD patients and 64 healthy controls were enrolled in this study. Fasting plasma metabolites were detected using liquid chromatography-based method. RESULTS: Plasma TMAO, choline, betaine and L-carnitine levels were differentially correlated with eGFR. The four metabolites were independently associated with CKD after adjustment for multiple traditional risk factors. The combination of the four metabolites had good performance at discriminating CKD from healthy controls (AUC = 0.96) as well as discriminating low eGFR from high eGFR in CKD (AUC = 0.96). CONCLUSION: Combinations of TMAO and its precursors were associated with glomerular function and might be utilized in evaluation of CKD.

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.

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.

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.

Ginsenoside compound K attenuates cognitive deficits in vascular dementia rats by reducing the Aß deposition.

Ginsenoside compound K (CK) is the main metabolite of protopanaxadiol-type ginsenosides and has been demonstrated to exert neuroprotective and cognition-enhancing effects. The effects of CK on cognitive function in vascular dementia (VD) has not been elucidated. Therefore, the present study aims to elucidate the effects of CK on memory function as well as its potential mechanism in VD rats. Sprague-Dawley rats were subjected to Chronic Cerebral Hypoperfusion (CCH) by permanent bilateral common carotid artery occlusion (2VO). CCH induced neuronal damage and aggravated the aggregation of Amyloid-ß1-42 peptides (Aß1-42), which plays a critical role in the neurotoxicity and cognitive impairment. CK treatment attenuated CCH-induced Aß1-42 deposition and ameliorated cognition impairment. Furthermore, CK enhanced the activity of the pSer9-Glycogen synthase kinase 3ß (pSer9-GSK3ß) and the insulin degrading enzyme (IDE), which mainly involved the production and clearance of Aß1-42. Moreover, CK treatment enhanced the activity of protein kinase B (PKB/Akt), a key kinase in phosphatidylinositol 3 kinase (PI3K)/Akt pathway that can regulate the activity of GSK-3ß and IDE. In short, our findings provide the first evidence that CK might attenuate cognitive deficits and Aß1-42 deposition in the hippocampus via enhancing the expression of pSer9-GSK-3ß and IDE.

Aucubin Alleviates Seizures Activity in Li-Pilocarpine-Induced Epileptic Mice: Involvement of Inhibition of Neuroinflammation and Regulation of Neurotransmission.

Neuroinflammation and imbalance of neurotransmitters play pivotal roles in seizures and epileptogenesis. Aucubin (AU) is an iridoid glycoside derived from Eucommia ulmoides that possesses anti-inflammatory and neuroprotective effects. However, the anti-seizure effects of AU have not been reported so far. The present study was designed to investigate the effects of AU on pilocarpine (PILO) induced seizures and its role in the regulation of neuroinflammation and neurotransmission. We found that AU reduced seizure intensity and prolonged the latency of seizures. AU significantly attenuated the activation of astrocytes and microglia and reduced the levels of interleukine-1 beta (IL-1ß), high mobility group box 1 (HMGB1), tumor necrosis factor-α (TNF-α). Furthermore, the contents of γ-aminobutyric acid (GABA) were increased while the levels of glutamate were decreased in the hippocampus with AU treatment. The expression of γ-aminobutyric acid type A receptor subunit α1 (GABAARα1) and glutamate transporter-1 (GLT-1) protein were up-regulated in AU treatment group. However, AU had no significant effect on N-methyl-d-aspartate receptor subunit 2B (NR2B) expression in status epilepticus (SE). In conclusion, our findings provide the first evidence that AU can exert anti-seizure effects by attenuating gliosis and regulating neurotransmission. The results suggest that AU may be developed as a drug candidate for the treatment of epilepsy.

Curcumin protects neuronal cells against status-epilepticus-induced hippocampal damage through induction of autophagy and inhibition of necroptosis.

Status epilepticus, the most severe form of epilepsy, is characterized by progressive functional and structural damage in the hippocampus, ultimately leading to the development and clinical appearance of spontaneous, recurrent seizures. Although the pathogenesis underlying epileptogenesis processes remains unclear, a substantial body of evidence has shown that status epilepticus acts as an important initial factor in triggering epileptogenesis. Notably, besides classical cell death mechanisms such as apoptosis and necrosis, 2 novel regulators of cell fate known as necroptosis and autophagy, are demonstrated to be involved in neuronal damage in various neurodegenerative and neuropsychiatric disorders. However, whether necroptosis and autophagy play a role in post-status-epilepticus rat hippocampus and other epilepsy mechanisms deserves further research effort. In addition, research is needed to determine whether compounds from traditional Chinese herbs possess antiepileptic effects through the modulation of necroptosis and autophagy. In this study, we found that curcumin, a polyphenolic phytochemical extracted from the Curcuma longa plant, protects neuronal cells against status-epilepticus-induced hippocampal neuronal damage in the lithium-pilocarpine-induced status epilepticus rat model through induction of autophagy and inhibition of necroptosis.