Inhibition of TAF1B impairs ribosome biosynthesis and suppresses cell proliferation in stomach adenocarcinoma through promoting c-MYC mRNA degradation.

Hyperactivation of ribosome biosynthesis (RiBi) is a hallmark of cancer, and targeting ribosome biogenesis has emerged as a potential therapeutic strategy. The depletion of TAF1B, a major component of selectivity factor 1 (SL1), disrupts the pre-initiation complex, preventing RNA polymerase I from binding ribosomal DNA and inhibiting the hyperactivation of RiBi. Here, we investigate the role of TAF1B, in regulating RiBi and proliferation in stomach adenocarcinoma (STAD). We disclosed that the overexpression of TAF1B correlates with poor prognosis in STAD, and found that knocking down TAF1B effectively inhibits STAD cell proliferation and survival in vitro and in vivo. TAF1B knockdown may also induce nucleolar stress, and promote c-MYC degradation in STAD cells. Furthermore, we demonstrate that TAF1B depletion impairs rRNA gene transcription and processing, leading to reduced ribosome biogenesis. Collectively, our findings suggest that TAF1B may serve as a potential therapeutic target for STAD and highlight the importance of RiBi in cancer progression.

Inhibition of histone acetyltransferase by naringenin and hesperetin suppresses Txnip expression and protects pancreatic ß cells in diabetic mice.

BACKGROUND: The damage of pancreatic ß cells is a major pathogenesis of the development and progression of type 2 diabetes and there is still no effective therapy to protect pancreatic ß cells clinically. In our previous study, we found that Quzhou Fructus Aurantii (QFA), which is rich in flavanones, had the protective effect of pancreatic ß cells in diabetic mice. However, the underlying mechanism is still unclear. PURPOSE: In the current study, we administered naringenin and hesperetin, two major active components of QFA, to protect pancreatic ß cells and to investigate the underlying molecular mechanism focusing on the epigenetic modifications. METHODS: We used diabetic db/db mouse and INS-1 pancreatic ß cell line as in vivo and in vitro models to investigate the protective effect of naringenin and hesperetin on pancreatic ß cells under high glucose environment and the related mechanism. The phenotypic changes were evaluatedby immunostaining and the measurement of biochemical indexes. The molecular mechanism was explored by biological techniques such as western blotting, qPCR, ChIP-seq and ChIP-qPCR, flow cytometry and lentivirus infection. RESULTS: We found that naringenin and hesperetin had an inhibitory effect on histone acetylation. We showed that naringenin and hesperetin protected pancreatic ß cells in vivo and in vitro, and this effect was independent of their direct antioxidant capacity. The further study found that the inhibition of thioredoxin-interacting protein (Txnip) expression regulated by histone acetylation was critical for the protective role of naringenin and hesperetin. Mechanistically, the histone acetylation inhibition by naringenin and hesperetin was achieved through regulating AMPK-mediated p300 inactivation. CONCLUSION: These findings highlight flavanones and the phytomedicine rich in flavanones as important dietary supplements in protecting pancreatic ß cells in advanced diabetes. In addition, targeting histone acetylation by phytomedicine is a potential strategy to delay the development and progression of diabetes.

Hesperetin, a SIRT1 activator, inhibits hepatic inflammation via AMPK/CREB pathway.

Silent mating type information regulation 2 homolog 1 (SIRT1) is an important inflammatory regulator, which epigenetically reprograms inflammation by altering the acetylation of NF-κB. Hesperetin, as a common flavonoid, has been proven to have a significant effect on acute inflammatory diseases. However, the detailed molecular mechanism by which hesperetin alleviates inflammatory response and accompanied tissue injury is poorly understood. Our results show that SIRT1 is required for the inhibitory effect of hesperetin on inflammation. Hesperetin suppresses the acetylation of RelA/p65 to reduce NF-κB activity by inducing SIRT1 expression. Mechanistically, hesperetin increases SIRT1 expression through AMPK/CREB pathway. Additionally, the protective effect of hesperetin against LPS/D-GalN-induced hepatitis in mice is also dependent on SIRT1. Our study suggests that hesperetin is an SIRT1 activator and could be potential candidates for the treatments of inflammatory conditions.

Neohesperidin enhances PGC-1α-mediated mitochondrial biogenesis and alleviates hepatic steatosis in high fat diet fed mice.

BACKGROUNDS: Mitochondria plays a critical role in the development and pathogenesis of nonalcoholic fatty liver disease (NAFLD). Neohesperidin (NHP) could lower blood glucose and prevent obesity in mice. However, the direct effect of NHP on hepatic steatosis has not been reported. METHODS: Mice were fed with either a chow diet or HFD with or without oral gavage of NHP for 12 weeks. A variety of biochemical and histological indicators were examined. In vitro cell culture model was utilized to demonstrate underlying molecular mechanism of the effect induced by NHP treatment. RESULTS: NHP increases mitochondrial biogenesis, improves hepatic steatosis and systematic insulin resistance in high fat diet (HFD) fed mice. NHP elevates hepatic mitochondrial biogenesis and fatty acid oxidation by increasing PGC-1α expression. Mechanistically, the activation of AMP-activated protein kinase (AMPK) is involved in NHP induced PGC-1α expression. CONCLUSIONS: PGC-1α-mediated mitochondrial biogenesis plays a vital role in the mitigation of hepatic steatosis treated by NHP. Our result suggests that NHP is a good candidate to be dietary supplement for the auxiliary treatment of NAFLD.

The flavonoid-rich Quzhou Fructus Aurantii extract modulates gut microbiota and prevents obesity in high-fat diet-fed mice.

BACKGROUND: Flavonoids are reported to modulate the composition of gut microbiota, which play an important role in preventing obesity and associated metabolic diseases. In this study, we investigated the effect of Total Flavonoids of Quzhou Fructus Aurantii Extract (TFQ) on gut microbial community in mice fed with a high-fat diet (HFD). METHODS: C57BL/6J mice were fed with either a chow diet or HFD with or without oral gavage of TFQ (300 mg/kg/day) for 12 weeks. RESULTS: Our data indicate TFQ significantly reduced obesity, inflammatio,n and liver steatosis. TFQ elevates the expression of tight junction proteins and reduces metabolic endotoxemia. In addition, TFQ treatment reverses HFD-induced gut dysbiosis, as indicated by the reduction of Firmicutes to Bacteroidetes ratio, the increase of genera Akkermansia and Alistipes, and the decrease of genera Dubosiella, Faecalibaculum, and Lactobacillus. CONCLUSION: These findings support a prebiotic role of TFQ as a dietary supplement for the intervention of gut dysbiosis and obesity-related metabolic disorders.

Yes-associated protein at the intersection of liver cell fate determination.

A recent publication highlights the importance of high yes-associated protein (YAP) expressing cells in liver regeneration following partial hepatectomy. Although the names of the cell populations described in these articles [hybrid periportal hepatocytes (HybHP) or epithelial-mesenchymal transition (EMT)-reprogrammed hepatocytes] are not identical, they all express high levels of YAP. We hypothesize that the HybHP and EMT-reprogrammed hepatocytes might be a similar cell population. Hippo signaling is the primary pathway that regulates YAP activity. According to the contribution of these two types of cells to liver regeneration and the high YAP expression, Hippo-YAP signaling activation may be a common regulatory pathway experienced by cells undergoing dedifferentiation and reactivating proliferative activity during liver regeneration. Although no evidence has shown that HybHP cells contribute to hepatocellular carcinoma in mouse models, we can not rule out the possibility that these highly regenerative cells can further develop into tumor cells when they acquire mutations caused by viral infection or other risk factors like alcohol. The detailed mechanistic insight of the regulation of YAP expression and activity in HybHP (or other types of cells contributing to liver regeneration) is unknown. We hypothesize that liver regeneration under various conditions will eventually lead to divergent consequences, likely due to the duration of YAP activation regulated by Hippo-large tumor suppressor 1 and 2 pathway in a context- and cell type-dependent manner.

Cinobufacini Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice through Inhibiting M1 Macrophage Polarization.

Cinobufacini is a traditional Chinese medicine used clinically that has antitumor and anti-inflammatory effects. It improves colitis outcomes in the clinical setting, but the mechanism underlying its function yet to be uncovered. We investigated the protective effects and mechanisms of cinobufacini on colitis using a dextran sulfate sodium (DSS)-induced colitis mouse model, mainly focusing on the impact of macrophage polarization. Our results showed that cinobufacini dramatically ameliorated DSS-induced colitis in mice. Cinobufacini treatment reduced the infiltration of activated F4/80+ and/or CD68+ macrophages into the colon in DSS-induced colitis mice. More importantly, cinobufacini significantly decreased the quantity of M1 macrophages and the expression of proinflammatory cytokines such as interleukin-6, tumor necrosis factor α, and inducible nitric oxide synthase. Cinobufacini also increased the population of M2 macrophages and the expression of anti-inflammatory factors such as interleukin-10 and arginase-1 in DSS-induced colitis mice. Furthermore, our study demonstrated that cinobufacini inhibited M1 macrophage polarization in lipopolysaccharide-induced RAW 264.7 cells. Mechanistically, our in vivo and in vitro results showed that cinobufacini inhibition of M1 macrophage polarization may be associated with the suppression of nuclear factor κB activation. Our study suggests that cinobufacini could ameliorate DSS-induced colitis in mice by inhibiting M1 macrophage polarization.

Astilbin ameliorates cisplatin-induced nephrotoxicity through reducing oxidative stress and inflammation.

Oxidative stress and inflammation are considered to be the main pathogenesis of cisplatin nephrotoxicity. Astilbin, a flavonoid with anti-oxidation and anti-inflammation function, has been used to treat heavy metal induced kidney injury. In this study, we investigated the protective effects of astilbin on cisplatin-induced nephrotoxicity and its underlying mechanisms. Our results showed that astilbin markedly inhibited cisplatin-induced cell apoptosis and recovered cell growth. Astilbin significantly decreased reactive oxygen species (ROS) accumulation and alleviated ROS-induced activation of p53, MAPKs and AKT signaling cascades, which in turn attenuated cisplatin-induced HEK-293 cell apoptosis. Astilbin effectively enhanced NRF2 activation and transcription of its targeting antioxidant genes to reduce ROS accumulation in cisplatin-induced HEK-293 cells. Furthermore, we found that astilbin obviously suppressed tumor necrosis factor alpha (TNF-α) expression and NF-κB activation, and also inhibited the expression of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Finally, we confirmed that the effect of astilbin to improve renal oxidative stress and inflammation in cisplatin induced acute nephrotoxic mice. In conclusion, our study suggests that astilbin could ameliorate the cisplatin-induced nephrotoxicity by reducing oxidative stress and inflammation.