A New Strategy for Obesity Treatment: Revealing the Frontiers of Anti-obesity Medications.

Obesity dramatically increases the risk of type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and cancer, causing both declines in quality of life and life expectancy, which is a serious worldwide epidemic. At present, more and more patients with obesity are choosing drug therapy. However, given the high failure rate, high cost, and long design and testing process for discovering and developing new anti-obesity drugs, drug repurposing could be an innovative method and opportunity to broaden and improve pharmacological tools in this context. Because different diseases share molecular pathways and targets in the cells, anti-obesity drugs discovered in other fields are a viable option for treating obesity. Recently, some drugs initially developed for other diseases, such as treating diabetes, tumors, depression, alcoholism, erectile dysfunction, and Parkinson's disease, have been found to exert potential anti-obesity effects, which provides another treatment prospect. In this review, we will discuss the potential benefits and barriers associated with these drugs being used as obesity medications by focusing on their mechanisms of action when treating obesity. This could be a viable strategy for treating obesity as a significant advance in human health.

miR-32-5p induces hepatic steatosis and hyperlipidemia by triggering de novo lipogenesis.

BACKGROUND AND OBJECTIVES: MicroRNA-dependent regulation of hepatic lipid metabolism has been recognized recently as a key pathological mechanism contributing to the development of NAFLD. However, whether miR-32-5p (miR-32) plays a role in lipid metabolism or contributes to NAFLD remains unclear. METHODS AND RESULTS: A marked increase in miR-32 expression was observed in liver samples from patients and mice with NAFLD, as well as in palmitate-induced hepatocytes. Hepatocyte-specific miR-32 knockout (miR-32-HKO) dramatically ameliorated hepatic steatosis and metabolic disorders in high-fat diet-fed mice. Conversely, hepatic miR-32 overexpression markedly exacerbated the progression of these abnormalities. Further, combinational analysis of transcriptomics and lipidomics suggested that miR-32 was a key trigger for de novo lipogenesis in the liver. Mechanistically, RNA sequencing, luciferase assay and adenovirus-mediated downstream gene rescue assay demonstrated that miR-32 directly bound to insulin-induced gene 1 (INSIG1) and subsequently activated sterol regulatory element binding protein-mediated lipogenic gene programs, thereby promoting hepatic lipid accumulation and metabolic disorders. Notably, pharmacological administration of miR-32 antagonist significantly inhibited palmitate-induced triglyceride deposition in hepatocytes and markedly mitigated hepatic steatosis and metabolic abnormalities in obesity-associated NAFLD mice. CONCLUSION: miR-32 is an important checkpoint for lipogenesis in the liver, and targeting miR-32 could be a promising therapeutic approach for NAFLD treatment.

Feeding-induced hepatokines and crosstalk with multi-organ: A novel therapeutic target for Type 2 diabetes.

Hyperglycemia, which can be caused by either an insulin deficit and/or insulin resistance, is the main symptom of Type 2 diabetes, a significant endocrine metabolic illness. Conventional medications, including insulin and oral antidiabetic medicines, can alleviate the signs of diabetes but cannot restore insulin release in a physiologically normal amount. The liver detects and reacts to shifts in the nutritional condition that occur under a wide variety of metabolic situations, making it an essential organ for maintaining energy homeostasis. It also performs a crucial function in glucolipid metabolism through the secretion of hepatokines. Emerging research shows that feeding induces hepatokines release, which regulates glucose and lipid metabolism. Notably, these feeding-induced hepatokines act on multiple organs to regulate glucolipotoxicity and thus influence the development of T2DM. In this review, we focus on describing how feeding-induced cross-talk between hepatokines, including Adropin, Manf, Leap2 and Pcsk9, and metabolic organs (e.g.brain, heart, pancreas, and adipose tissue) affects metabolic disorders, thus revealing a novel approach for both controlling and managing of Type 2 diabetes as a promising medication.

Alcohol Consumption and Risk of Atrial Fibrillation: A Dose-Response Meta-Analysis of Prospective Studies.

Background: This study aimed to investigate the dose-response association between alcohol consumption and atrial fibrillation (AF) risk. Methods: PubMed, Embase, Cochrane Library, and Web of Science were systematically searched using keywords related to alcohol and AF from the establishment of databases up to 1 March 2021. Prospective studies examining the impact of alcohol on the risk of AF with hazard ratios (HRs) were included. Restricted cubic spline regression was performed to quantify the dose-response relationship between alcohol consumption and AF risk. Results: Thirteen eligible studies were included in the meta-analysis, with a total of 645,826 participants and 23,079 cases of AF. When compared with non-/seldom-drinkers, the pooled adjusted HRs of AF were 1.30 (95% confidence interval [CI]: 1.20-1.41) and 1.00 (95% CI: 0.96-1.05) for high and low alcohol consumption, respectively. Moderate alcohol intake significantly increased the risk of AF in males (HR, 1.21; 95% CI: 1.10-1.33) but not in females (HR, 1.02; 95% CI: 0.91-1.14). The cubic spline regression analysis illustrated that the risk of AF significantly increased with daily alcohol intake in a Non-linear manner (R2 = 0.64, P = 5.785 × 10-12). Conclusion: This study revealed a Non-linearly positive association between alcohol intake and the risk of AF. Low alcohol intake was not associated with the development of AF, whereas moderate alcohol intake significantly increased the risk of AF in males but not in females. Our meta-analysis highlighted that alcohol consumption should be restricted to a low level to reduce the risk of AF.

Charge state depletion nanoscopy with a nitrogen-vacancy center in nanodiamonds.

The development of super-resolution imaging has driven research into biological labeling, new materials' characterization, and nanoscale sensing. Here, we studied the photoinduced charge state conversion of nitrogen-vacancy (NV) centers in nanodiamonds (NDs), which show the potential for multifunction sensing and labeling at the nanoscale. Charge state depletion (CSD) nanoscopy is subsequently demonstrated for the diffraction-unlimited imaging of NDs in biological cells. A resolution of 77 nm is obtained with 50 nm NDs. The depletion laser power of CSD nanoscopy is approximately 1/16 of stimulated emission depletion (STED) microscopy with the same resolution. The results can be used to improve the spatial resolution of biological labeling and sensing with NDs and other nanoparticles.

Nitric Oxide Signaling Pathway in Ventral Tegmental Area is Involved in Regulation of 7,8-Dihydroxyflavone on Alcohol Consumption in Rats.

We recently reported that intraperitoneal injection of 7,8-dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor-mimicking small compound, could attenuate alcohol-related behaviors in a two-bottle choice ethanol consumption procedure (IA2BC) in rats via tropomyosin receptor kinase B in the ventral tegmental area (VTA), which is closely related to alcohol use disorder. However, the detailed mechanisms underlying the regulation of 7,8-DHF on alcohol drinking behavior remain elusive. In this study, we determined the role of nitric oxide (NO), a pleiotropic signaling molecule, in the VTA in the action of 7,8-DHF upon alcohol drinking behavior. Intermittent alcohol exposure led to the overexpression of NO in the VTA, especially 72 h after withdrawal from four weeks of ethanol exposure in IA2BC rats. A higher amount of alcohol intake was also found at the same time point, consistent with the overexpression of NO in the VTA. Microinjection of NG-Nitro-l-Arginine Methyl Ester, (NO synthase inhibitor) or 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (NO scavenger) into the VTA inhibited alcohol intake, whereas application of S-Nitroso-N-acetyl-DL-penicillamine (SNAP, the NO donor) in the VTA further enhanced alcohol consumption in IA2BC rats. Interestingly, either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (a sGC inhibitor) or KT5823 [a selective protein kinase G (PKG) inhibitor] blocked NO's enhancing effect on ethanol intake. Intraperitoneal injection of 7,8-DHF reduced the overexpression of NO; SNAP microinjected into the VTA reversed the inhibitory effects of 7,8-DHF on alcohol consumption. Our findings suggest that NO-cGMP-PKG might be involved in regulation of 7,8-DHF on alcohol consumption in IA2BC rats.

Preparation of Submicron Metastable Spherical ß-Bi2O3 Particles by Self-Propagating High-Temperature Synthesis Method.

Sub-micrometer particles of ß-Bi2O3 were successfully synthesized via a one-step self-propagating high-temperature synthesis (SHS) method for the first time. The experiments were carried out in the air at room temperature. The products were characterized by scanning electron microscope (SEM), energy dispersive spectroscopy (EDS) and X-ray diffraction (XRD). In this study, three experiments were designed to optimize the heat source, Bi source and additive for the reaction system. Results showed that the system composed of Al, Bi2O3 and Al2O3 powders could synthesize monodisperse high-purity ß-Bi2O3 spherical particles with the average diameter of 369 nm and the as-prepared products kept stable after being exposed in air for one month. Then, the influences of the ratio of the three components on system were investigated. Interestingly, it was found that a slight adjustment on the ratio of Al:Bi2O3:Al2O3 had significant effects on the reactions happening in a system. Specifically, when the amount of Al2O3 exceeds the molar ratio of 2:1:1 (Al:Bi2O3:Al2O3), it is difficult to ignite the reaction system; when the amount is less than 2:1:0.5, the reaction system becomes too violent to obtain pure products. However, there are no obvious differences on the morphology and structure of final products with the two ratios because of few changes in adiabatic temperature. Preparation of ß-Bi2O3 by SHS technique enjoying many advantages, such as high efficiency, inexpensive experimental equipment and simple processes, would has a promising prospect for industrial application.

Efficient GSH delivery using PAMAM-GSH into MPP-induced PC12 cellular model for Parkinson's disease.

Glutathione (GSH) depletion has been an important contributor to the dysfunction of dopamine neurons. Polyamidoamine-GSH (PAMAM-GSH) was synthesized and the delivery effect of GSH into PC12 cells was tested. MTT assessment for cytotoxicity and reactive oxygen species (ROS) as well as nitrite oxide (NO) and intracelluar superoxide dismutase (SOD) detection for antioxidative ability were performed. Furthermore, the antiapoptotic ability was analysed by assessing caspase-3, JNK1/2 and Erk1/2 expression. Our data indicated that PAMAM-GSH is an effective agent to replenish GSH into PC12 cells. PAMAM-GSH developed its antioxidative and protective ability for 1-methyl-4-phenylpyridinium (MPP)-induced PC12 cells by reducing the intracellular levels of ROS and SOD activity as well as decreasing the release of NO. Meanwhile, PAMAM-GSH could inhibit caspase-3 activation and might show its antiapoptotic ability to MPP-induced PC12 cells through JNK2/Erk1/2 pathway. In summary, these studies suggest that PAMAM-GSH conjugate has an intrinsic ability to penetrate PC12 cells and deliver GSH into these cells which may provide a new strategy for clinical applications in the treatment of Parkinson's disease.

A20 plays a critical role in the immunoregulatory function of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) possess an immunoregulatory capacity and are a therapeutic target for many inflammation-related diseases. However, the detailed mechanisms of MSC-mediated immunosuppression remain unclear. In this study, we provide new information to partly explain the molecular mechanisms of immunoregulation by MSCs. Specifically, we found that A20 expression was induced in MSCs by inflammatory cytokines. Knockdown of A20 in MSCs resulted in increased proliferation and reduced adipogenesis, and partly reversed the suppressive effect of MSCs on T cell proliferation in vitro and inhibited tumour growth in vivo. Mechanistic studies indicated that knockdown of A20 in MSCs inhibited activation of the p38 mitogen-activated protein kinase (MAPK) pathway, which potently promoted the production of tumour necrosis factor (TNF)-α and inhibited the production of interleukin (IL)-10. Collectively, these data reveal a crucial role of A20 in regulating the immunomodulatory activities of MSCs by controlling the expression of TNF-α and IL-10 in an inflammatory environment. These findings provide novel insights into the pathogenesis of various inflammatory-associated diseases, and are a new reference for the future development of treatments for such afflictions.

Phosphatase and tensin homolog overexpression decreases proliferation and invasion and increases apoptosis in oral squamous cell carcinoma cells.

Phosphatase and tensin homolog (PTEN) is a potent tumor suppressor which regulates various cellular functions. The aim of the present study was to analyze the function of PTEN gene expression in squamous cell carcinoma (SCC) cells. This gene exhibits a unique function in cell migration and proliferation during the early stages of embryonic development. However, its role as a tumor suppressor gene in tongue squamous carcinoma cells remains unclear. In the present study, an SCC-4 cell line stably expressing PTEN was established and the effects of PTEN gene expression on SCC-4 cell proliferation, invasion and apoptosis were investigated. PTEN expression was found to induce apoptosis in SCC-4 cells, possibly via negative regulation of the phosphatidylinositide 3-kinase/Akt signaling pathway and increased expression of Bcl-2-interacting mediator of cell death. In addition, PTEN was found to control the epithelial-mesenchymal transition in SCC cells, thereby reducing their invasive ability. Furthermore, Transwell assay revealed that the expression of E-cadherin was increased, while the expression of vimentin and SNAIL was decreased. This study has provided an important insight into the mechanisms by which PTEN mediates the progression and early metastasis of tongue carcinoma.

Effect of miR-15a on induction of apoptosis in breast cancer MCF-7 cells / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the effect and mechanism of miR-15a on the induction of apoptosis in breast cancer cells.</p><p><b>METHODS</b>To detect the expression level of miR-15a in breast cancer cell line MCF-7 cells and human mammary gland epithelial cell line MCF-10A cells by quantitative PCR. The target point of MCF-7 was predicted by software and was validated by luciferase report gene system. MiR-15a was transfected into MCF-7 cells with liposomes. The expression of Bcl-2 in MCF-7 cells was detected by Western blotting and the apoptosis rate of MCF-7 cells was detected by flow cytometry.</p><p><b>RESULTS</b>The expression level of miR-15a in MCF-7 cells was lower than that in the MCF-10A cells (0.253:1, P < 0.0001). The expression of MiR-15a was significantly inhibited by Bcl-2 (P < 0.05). Compared with the control, Bcl-2 expression was significantly decreased in the MCF-7 cells. The results of flow cytometry showed that the apoptosis rate was 13.4% in non-transfected MCF-7 cells, 15.9% in MCF-7 cells transfected with control RNA, and 31.5% in MCF-7 cells transfected with miR-15a (P < 0.05), indicating an evident induction of apoptosis in the MCF-7 cells.</p><p><b>CONCLUSION</b>miR-15a may have a potential application value in breast carcinoma biotherapy.</p>