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Diabetes have been shown to cause progressive neuronal injury with pain and numbness via advanced glycation end-products (AGEs)-induced neuronal cell apoptosis; however, the valuable drug targets for diabetic neuropathy have been poorly reported so far. In this study, we discovered a natural small-molecule schisandrol A (SolA) with significant protective effect against AGEs-induced neuronal cell apoptosis. ATP6V0D1, a major subunit of vacuolar-type ATPase (V-ATPase) in lysosome was identified as a crucial cellular target of SolA. Moreover, SolA allosterically mediated ATP6V0D1 conformation via targeting a unique cysteine 335 residue to activate V-ATPase-dependent lysosomal acidification. Interestingly, SolA-induced lysosome pH downregulation resulted in a mitochondrial–lysosomal crosstalk by selectively promoting mitochondrial BH3-only protein BIM degradation, thereby preserving mitochondrial homeostasis and neuronal cells survival. Collectively, our findings reveal ATP6V0D1 is a valuable pharmacological target for diabetes-associated neuronal injury via controlling lysosomal acidification, and also provide the first small-molecule template allosterically activating V-ATPase for preventing diabetic neuropathy. Schisandrol A is identified as an activator of V-ATPase by targeting ATP6V0D1 subunit, which provides a promising target against diabetic neuropathy. [Display omitted] [ABSTRACT FROM AUTHOR]

Schisandra chinensis decoction derived from the book of Waitai Miyao (Tao Wang, Tang dynasty) is often used in the treatment of idiopathic pulmonary fibrosis (IPF), which is included in the Grand Ceremony of Chinese formulae (Huairen Peng, 1994). Schisandrae Chinensis Fructus (Sch) is one of the most important herbs in this formula. According to the "Shennong's Herbal Classicherbal" of the Han Dynasty, Sch has sour taste, warm nature, which has the effect of tonifying qi and curing cough. In addition, according to the "Compendium of Materia Medica" of the Ming Dynasty, Sch is used to treat cough and asthma, which has the effect of moistening the lung and tonifying the kidney. However, the active ingredients of Sch absorption into the plasma and its pharmacological mechanism of treatment for IPF still remained unclear. Our research aimed at identifying the absorbed active ingredients and metabolized of Sch in rat plasma and the mechanism of anti-IPF based on serum pharmacochemistry. First, the rats were divided into control group and Sch group. Sch sample was orally administrated to the rats for seven days. The blood samples were drawn into an Eppendorf tube after the last dosing. The ultrahigh performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q-TOF/MS) was applied to identify the absorption components and metabolites of Sch in rat plasma. Second, the network pharmacology combined with molecular docking analysis was further investigated to illuminate its potential mechanism of treatment for IPF by the biological targets regulating related pathways. Finally, the mechanism of action was verified by experimental in vitro and in vivo. A total of 78 compounds, consist of 13 prototype lignans and 65 metabolites (including isomers) were identified. Network pharmacology study and molecular docking analysis indicated that schisandrol A (L1) play an anti-fibrosis role by regulating the TGF-β signaling pathway. Experimental in vitro and in vivo verified that the schisandrol A could inhibiting pulmonary fibrosis through TGF-β signaling pathway. The effect and mechanism of schisandrol A inhibiting pulmonary fibrosis were reported for the first time. In this study, the absorption active ingredients of Sch in rat plasma were combined with the network pharmacology investigation and experimental in vitro and in vivo to elucidate its biological mechanism of treatment for IPF. The results provided a theoretical support for understanding the bioactive compounds and the pharmacological mechanism of Sch. [Display omitted] • Thirteen prototype lignans of Sch were identified in rat plasma via UPLC-Q-TOF/MS. • Sixty-five metabolites of Sch were identified in rat plasma via UPLC-Q-TOF/MS. • The component-target-disease associations were identified by network pharmacology. • The interaction between targets and compounds were predicted by molecular docking. • Schisandrol A played an anti-fibrosis role by regulating the TGF-β signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: We studied the effects of schisandrol A (SCH) and gomisin A (GOM), two of the main bioactive components of Fructus Schisandrae chinensis, on cytochrome P450-3A4 (CYP3A4) activity and cellular glutathione (GSH) level. In a cell-free system both SCH and GOM inhibited CYP3A4 activity with IC50 values of 32.02μM and 1.39μM, respectively. SCH or GOM at concentrations up to 100μM did not alter cellular GSH level in regular HepG2 cells and P-glycoprotein overexpressing HepG2-DR cells. Since SCH and GOM may reverse multidrug resistance (MDR) by impeding the activity of P-glycoprotein, a membrane xenobiotic exporter, SCH or GOM could affect cellular drug metabolism in addition to drug uptake. [Copyright &y& Elsevier]

Abstract: Variations of medicinal ingredients were qualitatively analyzed in beagle dog plasma after oral administration of the water and ethanol extracts of the decoction, respectively, a compound traditional Chinese herbal medicine for the irritable bowel syndrome (IBS). HPLC analysis was performed using a Waters 996 series HPLC system. The mobile phase was a water/methanol solvent or a water/acetonitrile one. Both retention times of HPLC and data of UV spectrum were used to determine the ingredients in plasma samples. It was found that no desired ingredient was detected in the plasma samples administered with the water extract of the IBS formula at different dosages. However, at least 20 compounds were able to be detected in those treated with the ethanol extract when the detection dosage was 27 times lower than in the water one. Compositions of medicinal ingredients in dog plasma significantly varied upon different solvent extracts of the formula. This presented difficulties or clues in demonstrating the effectiveness of traditional Chinese medicines. [Copyright &y& Elsevier]

Parkinson's disease is the second most common neurodegenerative disease. Its main pathological feature is the substantial nigra-striatum dopaminergic neuronal dysfunction, which causes insufficient release of DA, induces motor symptoms, and is accompanied by nonmotor symptoms. Schisandrol A belongs to lignan components and has anti-inflammatory, antioxidant and neuroprotective effects. In this experiment, we injected 6-OHDA into medial forebrain bundle of C57BL/6J male mice to establish the model. The motor function of mice was examined by open field test and pole test, the depression-like behavior of mice was examined by sucrose preference test and the memory function was examined by Y maze. We found that schisandrol A (20 mg/kg/d) could significantly improve the motor symptoms, and alleviate the depression-like symptoms and memory dysfunction of PD mice induced by 6-OHDA. Then we studied the neuroprotective mechanism of schisandrol A by H.E., ELISA assay kits and Western blot. Results showed that schisandrol A may enhance the PI3K/AKT pathway, inhibit the IKK/IκBα/NF-κB pathway, reduce neuronal inflammation and oxidative stress, and enhance the survival of DA neurons in the brain of mice. These results indicate that schisandrol A is expected to be a potential drug for improving Parkinson's disease. • Schisandrol A could improve the motor symptoms of 6-OHDA-induced PD mice. • Schisandrol A could improve the nonmotor symptoms of 6-OHDA-induced PD mice. • Schisandrol A could enhance the PI3K/AKT pathway, inhibit the IKK/IκBα/NF-κB pathway. • Schisandrol A could reduce neuronal inflammation and oxidative stress, and enhance the survival of DA neurons. [ABSTRACT FROM AUTHOR]