Current Issue : October - December Volume : 2019 Issue Number : 4 Articles : 5 Articles
Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, and there is no\nstandard and effcient therapy for it. Chitosan oligosaccharide (COS) is widely known to have\nvarious biological effects, and in this study we aimed to evaluate the liver-protective effect in\ndiet-induced obese mice for an enzymatically digested product of COS called COS23 which is mainly\ncomposed of dimers and trimers. An integrated analysis of the lipidome and gut microbiome\nwere performed to assess the effects of COS23 on lipids in plasma and the liver as well as on\nintestinal microbiota. Our results revealed that COS23 obviously attenuated hepatic steatosis\nand ameliorated liver injury in diet-induced obese mice. The hepatic toxic lipids-especially\ntriglycerides (TGs) and free fatty acids (FFAs)-were decreased dramatically after COS23 treatment.\nCOS23 regulated lipid-related pathways, especially inhibiting the expressions of FFA-synthesis-related\ngenes and inflammation-related genes. Furthermore, COS23 could alter lipid profiles in plasma.\nMore importantly, COS23 also decreased the abundance of Mucispirillum and increased the abundance\nof Coprococcus in gut microbiota and protected the intestinal barrier by up-regulating the expression\nof tight-junction-related genes. In conclusion, COS23, an enzymatically digested product of COS,\nmight serve as a promising candidate in the clinical treatment of NAFLD....
Obesity is a serious health problem, while the current anti-obesity drugs are not very\neffective. The Connectivity Map (C-Map), an in-silico drug screening approach based on gene\nexpression profiles, has recently been indicated as a promising strategy for drug repositioning. In this\nstudy, we performed mRNA expression profile analysis using microarray technology and identified\n435 differentially expressed genes (DEG) during adipogenesis in both C3H10T1/2 and 3T3-L1 cells.\nThen, DEG signature was uploaded into C-Map, and using pattern-matching methods we discovered\nthat pyrvinium, a classical anthelminthic, is a novel anti-adipogenic differentiation agent. Pyrvinium\nsuppressed adipogenic differentiation in a dose-dependent manner, as evidenced by Oil Red O\nstaining and the mRNA levels of adipogenic markers. Furthermore, we identified that the inhibitory\neffect of pyrvinium was resulted primarily from the early stage of adipogenesis. Molecular studies\nshowed that pyrvinium downregulated the expression of key transcription factors C/EBPa and PPAR.\nThe mRNA levels of notch target genes Hes1 and Hey1 were obviously reduced after pyrvinium\ntreatment. Taken together, this study identified many differentially expressed genes involved in\nadipogenesis and demonstrated for the first time that pyrvinium is a novel anti-adipogenic compound\nfor obesity therapy. Meanwhile, we provided a new strategy to explore potential anti-obesity drugs....
Antimalarial drug resistance is an enormous global threat. Recently, antimicrobial peptides\n(AMPs) are emerging as a new source of antimalarials. In this study, an AMP LZ1 derived from\nsnake cathelicidin was identified with antimalarial activity. In the in vitro antiplasmodial assay,\nLZ1 showed strong suppression of blood stage Plasmodium falciparum (P. falciparum) with an IC50\nvalue of 3.045 microM. In the in vivo antiplasmodial assay, LZ1 exerted a significant antimalarial activity\nagainst Plasmodium berghei (P. berghei) in a dose- and a time- dependent manner. In addition, LZ1\nexhibited anti-inflammatory effects and attenuated liver-function impairment during P. berghei\ninfection. Furthermore, by employing inhibitors against glycolysis and oxidative phosphorylation in\nerythrocytes, LZ1 specifically inhibited adenosine triphosphate (ATP) production in parasite-infected\nerythrocyte by selectively inhibiting the pyruvate kinase activity. In conclusion, the present study\ndemonstrates that LZ1 is a potential candidate for novel antimalarials development....
This study investigated the effect of a novel progestin and its combination with metformin\non the growth of endometrial cancer (EC) cells. Inhibitory effects of four progestins, including\nnomegestrol acetate (NOMAC), medroxyprogesterone acetate, levonorgestrel, and cyproterone\nacetate, were evaluated in RL95-2, HEC-1A, and KLE cells using cell counting kit-8 assay. Flow\ncytometry was performed to detect cell cycle and apoptosis. The activity of Akt (protein kinase B),\nmTOR (mammalian target of rapamycin) and its downstream substrates 4EBP1 (4E-binding protein 1)\nand eIF4G (Eukaryotic translation initiation factor 4G) were assayed by Western blotting. Nude\nmice were used to assess antitumor effects in vivo. NOMAC inhibited the growth of RL95-2 and\nHEC-1A cells, accompanied by arresting the cell cycle at G0/G1 phase, inducing apoptosis, and\nmarkedly down-regulating the level of phosphorylated mTOR/4EBP1/eIF4G in both cell lines (p < 0.05).\nMetformin significantly increased the inhibitory effect of and apoptosis induced by NOMAC and\nstrengthened the depressive effect of NOMAC on activity of mTOR and its downstream substrates,\ncompared to their treatment alone (p < 0.05). In xenograft tumor tissues, metformin (100 mg/kg)\nenhanced the suppressive effect of NOMAC (100 mg/kg) on mTOR signaling and increased the\naverage concentration of NOMAC by nearly 1.6 times compared to NOMAC treatment alone. Taken\ntogether, NOMAC suppressing the growth of EC cells likely correlates to down-regulating the activity\nof the mTOR pathway and metformin could strengthen this effect. Our findings open a new window\nfor the selection of progestins in hormone therapy of EC....
Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial\ncarcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse.\nReduced apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic\nagent, has demonstrated antitumor effects on various cancers. This study investigated the effcacy\nof TFP in inhibiting cisplatin-resistant bladder UC and explored the underlying mechanism.\nOur results revealed that cisplatin-resistantUCcells (T24/R) upregulated the antiapoptotic factor, B-cell\nlymphoma-extra large (Bcl-xL). Knockdown of Bcl-xL by siRNA resensitized cisplatin-resistant cells\nto the cisplatin cytotoxic effect. TFP (10-45 microM) alone elicited dose-dependent cytotoxicity, apoptosis,\nand G0/G1 arrest on T24/R cells. Co-treatment of TFP potentiated cisplatin-induced cytotoxicity in\nT24/R cells. The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with\nconcurrent suppression of Bcl-xL. In vivo models confirmed that TFP alone effectively suppressed\nthe T24/R xenograft in nude mice. TFP co-treatment enhanced the antitumor effect of cisplatin on the\nT24/R xenograft. Our results demonstrated that TFP effectively inhibited cisplatin-resistant UCs and\ncircumvented cisplatin resistance with concurrent Bcl-xL downregulation. These findings provide a\npromising insight to develop a therapeutic strategy for chemoresistant UCs....
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