Diabetes mellitus and depressive disorders are both common chronic diseases that increase functional disability and social burden. Cognitive impairment is a potentially debilitating feature of depression. Previous evidence indicates that the antidiabetic drug metformin could be suitable for diabetic patients with cognitive impairment. However, there is no direct evidence from clinical studies that metformin treatment improves cognitive function in diabetic patients suffering from depression. In the present study, 58 participants diagnosed with depression and type 2 diabetes mellitus (T2DM) were recruited and divided into two groups, one treated with metformin and the other treated with placebo for 24 weeks. Cognitive function, depressive behaviour and diabetes improvement were evaluated. Chronic treatment with metformin for 24 weeks improved cognitive performance, as assessed by the Wechsler Memory Scale-Revised, in depressed patients with T2DM. In addition, metformin significantly improved depressive performance and changed the glucose metabolism in depressed patients with diabetes. Depressive symptoms were negatively correlated with cognitive performance in metformin-treated participants. Furthermore, associations were observed between the parameters of blood glucose metabolism and the depression phenotype. These findings suggest that chronic treatment with metformin has antidepressant behavioural effects and that improved cognitive function is involved in the therapeutic outcome of metformin. The results of the present study also raise the possibility that supplementary administration of antidiabetic medications may enhance the recovery of depression, comorbid with T2DM, through improvements in cognitive performance.
BACKGROUND & AIMS Zinc-fingers and homeoboxes 2 (ZHX2) represses transcription of several genes associated with liver cancer. However, little is known about the role of ZHX2 in development of hepatocellular carcinoma (HCC). We investigated the mechanisms by which ZHX2 might affect proliferation of HCC cells. METHODS We overexpressed and knocked down ZHX2 in HCC cells and analyzed the effects on proliferation, colony formation, and the cell cycle. We also analyzed the effects of ZHX2 overexpression in growth of HepG2.2.15 tumor xenografts in nude mice. Chromatin immunoprecipitation and luciferase reporter assays were used to measure binding of ZHX2 target promoters. Levels of ZHX2 in HCC samples were evaluated by immunohistochemistry. RESULTS ZHX2 overexpression significantly reduced proliferation of HCC cells and growth of tumor xenografts in mice; it led to G1 arrest and reduced levels of cyclins A and E in HCC cell lines. ZHX2 bound to promoter regions of CCNA2 (which encodes Cyclin A) and CCNE1 (which encodes cyclin E) and inhibited their transcription. Knockdown of cyclin A or cyclin E reduced the increased proliferation mediated by ZHX2 knockdown. Nuclear localization of ZHX2 was required for it to inhibit proliferation of HCC cells in culture and in mice. Nuclear localization of ZHX2 was reduced in human HCC samples, even in small tumors (diameter<5 cm), compared to adjacent non-tumor tissues. Moreover, reduced nuclear levels of ZHX2 correlated with reduced survival times of patients, high levels of tumor microvascularization, and hepatocyte proliferation. CONCLUSIONS ZHX2 inhibits HCC cell proliferation, by preventing expression of cyclins A and E, and reduces growth of xenograft tumors in mice. Loss of nuclear ZHX2 might be an early step in the development of HCC.
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. Dysregulation of mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of PD. However, the underlying mechanism is incompletely elucidated. Here, we show that PD mimetics (6-hydroxydopamine, N-methyl-4-phenylpyridine or rotenone) suppressed phosphorylation of mTOR, S6K1 and 4E-BP1, reduced cell viability, and activated caspase-3 and PARP in PC12 cells and primary neurons. Overexpression of wild-type mTOR or constitutively active S6K1, or downregulation of 4E-BP1 in PC12 cells partially prevented cell death in response to the PD toxins, revealing that mTOR-mediated S6K1 and 4E-BP1 pathways due to the PD toxins were inhibited, leading to neuronal cell death. Furthermore, we found that the inhibition of mTOR signaling contributing to neuronal cell death was attributed to suppression of Akt and activation of AMPK. This is supported by the findings that ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPKα with compound C partially attenuated inhibition of phosphorylation of mTOR, S6K1 and 4E-BP1, activation of caspase-3, and neuronal cell death triggered by the PD toxins. The results indicate that PD stresses activate AMPK and inactivate Akt, causing neuronal cell death via inhibiting mTOR-mediated S6K1 and 4E-BP1 pathways. Our findings suggest that proper co-manipulation of AMPK/Akt/mTOR signaling may be a potential strategy for prevention and treatment of PD.
Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Recently we have shown that Cd elevates intracellular free calcium ion ([Ca2+]i) level, leading to neuronal apoptosis partly by activating mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin (mTOR) pathways. However, the underlying mechanism remains to be elucidated. Here we show that the effects of Cd elevated [Ca2+]i on MAPK and mTOR network as well as neuronal cell death are through stimulating phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). This is supported by the findings that chelating intracellular Ca2+ with BAPTA/AM or preventing Cd-induced [Ca2+]i elevation using 2-aminoethoxydiphenyl borate (2-APB) blocked Cd activation of CaMKII. Inhibiting CaMKII with KN93 or silencing CaMKII attenuated Cd activation of MAPK/mTOR pathways and cell death. Furthermore, inhibitors of mTOR (rapamycin), JNK (SP600125) and Erk1/2 (U0126), but not of p38 (PD169316), prevented Cd-induced neuronal cell death in part through inhibition of [Ca2+]i elevation and CaMKII phosphorylation. The results indicate that Cd activates MAPK/mTOR network triggering neuronal cell death, by stimulating CaMKII. Our findings underscore a central role of CaMKII in the neurotoxicology of Cd, and suggest that manipulation of intracellular Ca2+ level or CaMKII activity may be exploited for prevention of Cd-induced neurodegenerative disorders.
As an effective antiviral agent, the clinical application of oseltamivir (OTV) is limited by the appearance of drug-resistant viruses. Due to their low toxicity and excellent activity, the antiviral capabilities of selenium nanoparticles (SeNPs) has attracted increasing attention in recent years. To overcome the limitation of drug resistance, the use of modified NPs with biologics to explore novel anti-influenza drugs is developing rapidly. In this study, OTV surface-modified SeNPs with superior antiviral properties and restriction on drug resistance were synthesized. OTV decoration of SeNPs (Se@OTV) obviously inhibited H1N1 infection and had less toxicity. Se@OTV interfered with the H1N1 influenza virus to host cells through inhibiting the activity of hemagglutinin and neuraminidase. The mechanism was that Se@OTV was able to prevent H1N1 from infecting MDCK cells and block chromatin condensation and DNA fragmentation. Furthermore, Se@OTV inhibited the generation of reactive oxygen species and activation of p53 phosphorylation and Akt. These results demonstrate that Se@OTV is a promising efficient antiviral pharmaceutical for H1N1.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.