FXR/ASS1 axis attenuates the TAA-induced liver injury through arginine metabolism.

Previous studies demonstrated that arginine biosynthesis was frequently impaired in acute liver injury. However, the underlying mechanisms remain elusive. In this study, we found that Argininosuccinate synthetase 1 (ASS1), a rate-limiting enzyme in arginine metabolism, was downregulated in the TAA-induced liver injury model. Single-cell RNA-seq data found that ASS1 was highly enriched in the hepatocytes. The reduction of ASS1 was attributed to the decreased expression of Farnesoid X receptor (FXR), which is a bile acid-activated nuclear hormone receptor with high expression in the liver. Subsequent studies demonstrated that activation of FXR by its agonist obeticholic acid (OCA) directly promoted ASS1 transcription and enhanced arginine synthesis, leading to the alleviation of TAA-mediated liver injury. Further experiments found that OCA, ASS1, and arginine supplement can rescue TAA-mediated hepatocytes apoptosis by decreasing the protein levels of Cyto C, PARP, and Caspase 3. Taken together, our study illustrated a protective role of the FXR/ASS1 axis in TAA-induced liver injury by targeting arginine metabolism, which might shed light on the development of novel therapeutic approaches for acute liver injury.

Dahuang Zhechong pill attenuates CCl4-induced rat liver fibrosis via the PI3K-Akt signaling pathway.

It is well characterized that activated hepatic stellate cells (HSCs) exert critical functions in accelerating the progression of liver fibrosis. Previous studies have indicated that Dahuang Zhechong pill (DHZCP), a traditional Chinese herbal medicine, is capable of inactivating HSCs and thus attenuate the formation of liver fibrosis in rats. However, pharmacological mechanisms of DHZCP in alleviating liver fibrosis remain unclear. This study aims to investigate the antifibrotic role of DHZCP through inhibiting the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway. DHZCP was found to significantly suppresses extracellular matrix formation and immune cell infiltration, thus alleviating liver fibrosis symptoms in the in vivo model. Moreover, DHZCP reduced serum levels of transforming growth factor ß1 and tumor necrosis factor-α in rats with liver fibrosis. DHZCP treatment remarkably downregulated protein levels of PI3K and phosphorylated Akt, as well as fibrosis markers. In vitro experiments further demonstrated that DHZCP markedly suppressed HSCs proliferation by downregulating PI3K/Akt, which exerted a synergistic effect with the PI3K inhibitor LY294002. To sum up, our results confirmed that DHZCP exerted an antifibrotic effect in the animal model through inactivating the PI3K/Akt pathway, thus protecting rats from liver injury.

Apoptosis and Anti-cancer Drug Discovery: The Power of Medicinal Fungi and Plants.

The purpose of this account is to review the compounds capable of eliciting mitochondria-mediated apoptosis in cancer cells produced by medicinal fungi and plants. The medicinal fungi discussed encompass Cordyceps, Ganoderma species, Coriolus versicolor and Hypsizygus marmoreus. The medicinal plants discussed comprise Astragalus complanatus, Dendrobium spp, Dioscorea spp, Glycyrrhiza spp, Panax notoginseng, Panax ginseng, and Momordica charantia. These compounds have the potential of development into anticancer drugs.

MiR-218-targeting-Bmi-1 mediates the suppressive effect of 1,6,7-trihydroxyxanthone on liver cancer cells.

Traditional Chinese medicine is recently emerged as anti-cancer therapy or adjuvant with reduced side-effects and improved quality of life. In the present study, an active ingredient, 1,6,7-trihydroxyxanthone (THA), derived from Goodyera oblongifolia was found to strongly suppress cell growth and induce apoptosis in liver cancer cells. MicroRNAs are a group of small non-coding RNAs that regulate gene expression at post-transcriptional levels. Our results demonstrated that miR-218 was up-regulated and oncogene Bmi-1 was down-regulated by THA treatment. Further investigation showed that THA-induced-miR-218 up-regulation could lead to activation of tumor suppressor P16(Ink4a) and P14(ARF), the main down-stream targets of Bmi-1. In conclusion, THA might be a potential anti-cancer drug candidate, at least in part, through the activation of miR-218 and suppression of Bmi-1 expression.

Silibinin, a novel chemokine receptor type 4 antagonist, inhibits chemokine ligand 12-induced migration in breast cancer cells.

PURPOSE: C-X-C chemokine receptor type 4 (CXCR4) signaling has been demonstrated to be involved in cancer invasion and migration; therefore, CXCR4 antagonist can serve as an anti-cancer drug by preventing tumor metastasis. This study aimed to identify the CXCR4 antagonists that could reduce and/or inhibit tumor metastasis from natural products. METHODS AND RESULTS: According to the molecular docking screening, we reported here silibinin as a novel CXCR4 antagonist. Biochemical characterization showed that silibinin blocked chemokine ligand 12 (CXCL12)-induced CXCR4 internalization by competitive binding to CXCR4, therefore inhibiting downstream intracellular signaling. In human breast cancer cells MDA-MB-231, which expresses high levels of CXCR4, inhibition of CXCL12-induced chemomigration can be found under silibinin treatment. Overexpression of CXCL12 sensitized MDA-MB-231 cells to the inhibition of silibinin, which was abolished by CXCR4 knockdown. The inhibition of silibinin was also observed in MCF-7/CXCR4 cells rather than MCF-7 cells that express low level of CXCR4. CONCLUSIONS: Our work demonstrated that silibinin is a novel CXCR4 antagonist that may have potential therapeutic use for prevention of tumor metastasis.

Acetylshikonin, a Novel AChE Inhibitor, Inhibits Apoptosis via Upregulation of Heme Oxygenase-1 Expression in SH-SY5Y Cells.

Acetylcholinesterase inhibitors are prominent alternative in current clinical treatment for AD patients. Therefore, there is a continued need to search for novel AChEIs with good clinical efficacy and less side effects. By using our in-house natural product database and AutoDock Vina as a tool in docking study, we have identified twelve phytochemicals (emodin, aloe-emodin, chrysophanol, and rhein in Rhei Radix Et Rhizoma; xanthotoxin, phellopterin, alloisoimperatorin, and imperatorin in Angelicae dahuricae Radix; shikonin, acetylshikonin, isovalerylshikonin, and ß,ß-dimethylacrylshikonin in Arnebiae Radix) as candidates of AChEIs that were not previously reported in the literature. In addition to AChEI activity, a series of cell-based experiments were conducted for the investigation of their neuroprotective activities. We found that acetylshikonin and its derivatives prevented apoptotic cell death induced by hydrogen peroxide in human and rat neuronal SH-SY5Y and PC12 cells at 10 µM. We showed that acetylshikonin exhibited the most potent antiapoptosis activity through the inhibition of the generation of reactive oxygen species as well as protection of the loss of mitochondria membrane potential. Furthermore, we identified for the first time that the upregulation of heme oxygenase 1 by acetylshikonin is a key step mediating its antiapoptotic activity from oxidative stress in SH-SY5Y cells.