Naoxinqing tablet protects against cerebral ischemic/reperfusion injury by regulating ampkα/NAMPT/SIRT1/PGC-1α pathway.

AIM OF THE STUDY: Naoxinqing (NXQ) tablets are derived from persimmon leaves and are widely used in China for promoting blood circulation and removing blood stasis in China. We aimed to explore whether NXQ has the therapeutic effect on ischemic stroke and explored its possible mechanism. MATERIALS AND METHODS: The cerebral artery occlusion/reperfusion (MCAO/R) surgery was used to establish the cerebral ischemic/reperfusion rat model. NXQ (60 mg/kg and 120 mg/kg) were administered orally. The TTC staining, whole brain water content, histopathology staining, immunofluorescent staining, enzyme-linked immunosorbent assay (ELISA) and Western blot analyses were performed to determine the therapeutical effect of NXQ on MCAO/R rats. RESULTS: The study demonstrated that NXQ reduced the cerebral infarction volumes and neurologic deficits in MCAO/R rats. The neuroprotective effects of NXQ were accompanied by inhibited oxidative stress and inflammation. The nerve regeneration effects of NXQ were related to regulating the AMPKα/NAMPT/SIRT1/PGC-1α pathway. CONCLUSION: In summary, our results revealed that NXQ had a significant protective effect on cerebral ischemia-reperfusion injury in rats. This study broadens the therapeutic scope of NXQ tablets and provides new neuroprotective mechanisms of NXQ as an anti-stroke therapeutic agent.

Targeting kinase ITK treats autoimmune arthritis via orchestrating T cell differentiation and function.

IL-2 inducible T cell kinase (ITK) is critical in T helper subset differentiation and its inhibition has been suggested for the treatment of T cell-mediated inflammatory diseases. T follicular helper (Tfh), Th17 and regulatory T cells (Treg) also play important roles in the development of rheumatoid arthritis (RA), while the role of ITK in the development of RA and the intricate balance between effector T and regulatory T cells remains unclear. Here, we found that CD4+ T cells from RA patients presented with an elevated ITK activation. ITK inhibitor alleviated existing collagen-induced arthritis (CIA) and reduced antigen specific antibody production. Blocking ITK kinase activity interferes Tfh cell generation. Moreover, ITK inhibitor effectively rebalances Th17 and Treg cells by regulating Foxo1 translocation. Furthermore, we identified dihydroartemisinin (DHA) as a potential ITK inhibitor, which could inhibit PLC-γ1 phosphorylation and the progression of CIA by rebalancing Th17 and Treg cells. Out data imply that ITK activation is upregulated in RA patients, and therefore blocking ITK signal may provide an effective strategy to treat RA patients and highlight the role of ITK on the Tfh induction and RA progression.

Berberine Suppressed the Progression of Human Glioma Cells by Inhibiting the TGF-ß1/SMAD2/3 Signaling Pathway.

BACKGROUND: Previous studies have shown that berberine can inhibit glioma progression, although the underlying molecular mechanisms needed to be explored further. The aim of this study was to evaluate the suppressive effects of berberine on human glioma cells, and identify the underlying signaling pathways. MATERIAL AND METHODS: The cytotoxic effect of different concentrations of berberine against normal human glial cells (HEB) and 4 glioma cell lines was evaluated by the CCK-8 assay. Apoptosis was assayed by flow cytometry. In vitro migration and invasion were analyzed by the wound healing and transwell assays. The expression levels of specific proteins were measured by western blotting and ELISA. RESULTS: Berberine significantly inhibited the proliferation of human glioma U-87 cells, and induced apoptosis in the U-87 and LN229 cells by downregulating Bcl-2, and upregulating Bax and caspase-3. In addition, berberine also inhibited migration and invasion of the glioma cells. Furthermore, berberine exerted its effects on the proliferation, migration, invasion, and apoptosis of glioma cells by inhibiting the TGF-ß1/SMAD2/3 signaling pathway, and exogenous TGF-ß abrogated the pro-apoptotic and anti-oncogenic effects of berberine. CONCLUSIONS: Berberine inhibits glioma progression by targeting the TGF-ß1/SMAD2/3 signaling pathway.

Mutyh deficiency downregulates mitochondrial fusion proteins and causes cardiac dysfunction via α-ketoglutaric acid reduction with oxidative stress.

MutY homolog (MUTYH), an important protein in base excision repair (BER) system, excises adenine in the nascent strand opposite 8-oxoguanine in template DNA and restores G:C base-pair to maintain the fidelity of DNA replication. The loss of MUTYH causes oxidative stress and influences cardiac function, but the mechanism remains to be addressed. Here we demonstrate that Mutyh deficiency alters mitochondrial structure and impairs mitochondrial function through downregulation of mitochondrial fusion protein Mfn2 and alteration of the ratio of L-Opa1/S-Opa1 accompanied by reduction of α-ketoglutaric acid (α-KG) under oxidative stress condition. Further analysis reveals that the Mutyh deficiency may cause downregulation of histone demethylases and DNA demethylases and inhibition of the Mfn2 transcription. Oxidative stress associated with tert-butyl hydroperoxide (t-BHP) exposure results in the degradation of L-Opa1 and impairs the balance of L-Opa1/S-Opa1. Interestingly, α-KG supplementation alleviates the damage associated with Mutyh deficiency, restores the expression of Mfn2 and prevents degradation of L-Opa1. The current study demonstrates the relationship among Mutyh deficiency-coupled oxidative stress, the altered expressions of Mfn2 and Opa1, and the mitochondrial dysfunction, in which an intermediate in the tricarboxylic acid (TCA) cycle, α-KG has a key regulatory role.