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Pre‐diabetes is characterized by impaired glucose tolerance (IGT) and/or impaired fasting glucose. Impairment of skeletal muscle function is closely associated with the progression of diabetes. However, the entire pathological characteristics and mechanisms of pre‐diabetes in skeletal muscle remain fully unknown. Here, we established a mouse model of pre‐diabetes, in which 6‐week‐old male C57BL6/J mice were fed either normal diet or high‐fat diet (HFD) for 8 or 16 weeks. Both non‐fasting and fasting glucose levels and the results of glucose and insulin tolerance tests showed that mice fed an 8‐week HFD developed pre‐diabetes with IGT; whereas mice fed a 16‐week HFD presented with impaired fasting glucose and impaired glucose tolerance (IFG‐IGT). Mice at both stages of pre‐diabetes displayed decreased numbers of mitochondria in skeletal muscle. Moreover, IFG‐IGT mice exhibited decreased mitochondrial membrane potential and ATP production in skeletal muscle and muscle degeneration characterized by a shift in muscle fibers from predominantly oxidative type I to glycolytic type II. Western blotting and histological analysis confirmed that myoblast differentiation was only inhibited in IFG‐IGT mice. For primary skeletal muscle satellite cells, inhibition of differentiation was observed in palmitic acid‐induced insulin resistance model. Moreover, enhanced myoblast differentiation increased glucose uptake and insulin sensitivity. These findings indicate that pre‐diabetes result in mitochondrial dysfunction and inhibition of myoblast differentiation in skeletal muscle. Therefore, interventions that enhance myoblast differentiation may improve insulin resistance of diabetes at the earlier stage. Mitochondrial dysfunction may occur earlier than and result in inhibition of myoblast differentiation in a mouse model of pre‐diabetes. Mitochondrial dysfunction in skeletal muscle may contribute to the progression of pre‐diabetes. [ABSTRACT FROM AUTHOR]

Triptolide (TP), a diterpenoid isolated from Tripterygium wilfordii Hook F, has an excellent pharmacological profile of immunosuppression and anti-tumor activities, but its clinical applications are severely restricted due to its severe and cumulative toxicities. The farnesoid X receptor (FXR) is the master bile acid nuclear receptor and plays an important role in maintaining hepatic metabolism homeostasis. Hepatic Sirtuin (Sirt1) is a key regulator of the FXR signaling pathway and hepatic metabolism homeostasis. The aims of this study were to determine whether Sirt1/FXR signaling pathway plays a critical role in TP-induced hepatotoxicity. Our study revealed that the intragastric administration of TP (400 mg/kg body weight) for 28 consecutive days increased bile acid accumulation, suppressed hepatic gluconeogenesis in rats. The expression of bile acid transporter BSEP was significantly reduced and cholesterol 7a-hydroxylase (CYP7A1) was markedly increased in the TP-treated group, whereas the genes responsible for hepatic gluconeogenesis were suppressed in the TP-treated group. TP also modulated the FXR and Sirt1 by decreasing its expression both in vitro and in vivo. The Sirt1 agonist SRT1720 and the FXR agonist obeticholic acid (OCA) were used both in vivo and in vitro. The remarkable liver damage induced by TP was attenuated by treatment with either SRT1720 or OCA, as reflected by decreased levels of serum total bile acids and alkaline phosphatase and increased glucose levels. Meanwhile, SRT1720 significantly alleviated TP-induced FXR suppression and FXR-targets involved in hepatic lipid and glucose metabolism. Based on these results, we conclude that Sirt1/FXR inactivation plays a critical role in TP-induced hepatotoxicity. Moreover, Sirt1/FXR axis represents a novel therapeutic target that could potentially ameliorate TP-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Osta/b, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P<.05), while Mrp3, Ntcp, Oatp1a4, and Cyp7a1 were increased (P<.05). Moreover, treatment with the FXR agonist obeticholic acid (OCA) generated obvious reductions in serum ALT, AST, and TBA levels in PZA-treated rats. Those effects were due to transcriptional regulation of pre-mentioned target genes by OCA. Taken together, these results suggested that PZA-induced cholestatic liver injury was related to FXR inhibition, leading to the dysfunction in bile acid synthesis and transport. [ABSTRACT FROM AUTHOR]

Pristimerin, a natural triterpenoid isolated form Celastrus and Maytenus spp, has been shown to possess a variety of biological and pharmacological effects. Recently, pristimerin has attracted more attention, especially for its potential anticancer activities. The anticancer activities of pristimerin have been illustrated in various cancer cell lines and animal models. It has been found to inhibit in vitro and in vivo proliferation, survival, angiogenesis and metastasis of tumor cells. These activities have been attributed to its modulation of various molecular targets such as cyclins, apoptosis- related proteins, proteasome activity, reactive oxygen species, as well as NF-kB, AKT/mTOR and MAPK/ERK pathways. This mini-review discussed the cellular impact and animal studies of pristimerin treatment, with more attention on the various molecular targets of pristimerin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)