miR-210-5p Promotes Pulmonary Hypertension by Blocking ATP2A2.

AIM: Aberrant expression of ATPase sarcoplasmic/endoplasmic retic Ca2+ transporting 2 (ATP2A2) has attracted attention for its pathophysiologic role in pulmonary hypertension (PH). Several miRNAs, including miR-210-5p, have also been reported to be pathogenic factors in PH, but their exact mechanisms remain unknown. This study aimed to elucidate the potential mechanisms of miR-210-5p and ATP2A2 in MCT-induced PH. METHODS: Eighteen Sprague-Dawley rats were randomly divided into two groups-monoclonal (MCT) group and control group-and then administered MCT (60 mg/kg) and saline, respectively. mPAP, PVR, RVHI, WT%, and WA% were significantly increased in PH rats after 3 weeks, confirming that the modeling of PH rats was successful. Subsequently, we determined the expression of ATP2A2 and miR-210-5p in lung tissues using WB and qRT-PCR methods. We established an in vitro model using BMP4 and TGF-ß1 treatment of pulmonary artery smooth muscle cells (PASMCs) and examined the expression of ATP2A2 and miR-210-5p using the same method. To further elucidate the regulatory relationship between ATP2A2 and miR-210-5p, we altered the expression level of miR-210-5p and detected the corresponding changes in ATP2A2 levels. In addition, we demonstrated the relationship by dual luciferase experiments. Finally, the effect of silencing ATP2A2 could be confirmed by the level of cell membrane Ca2+ in PAMSCs. RESULTS: Up-regulation of miR-210-5p and down-regulation of ATP2A2 were observed in the MCT group compared with the control group, which was confirmed in the in vitro model. In addition, elevated miR-210-5p expression decreased the level of ATP2A2 while increasing the proliferation of PASMCs, and the results of the dual luciferase assay further confirmed that ATP2A2 is a downstream target of miR-210-5p. Additionally, silencing ATP2A2 resulted in increased cytoplasmic Ca2+ levels in PAMSCs. CONCLUSION: In MCT-induced PH, miR-210-5p promotes pulmonary vascular remodeling by inhibiting ATP2A2.

Maternal micronutrient disturbance as risks of offspring metabolic syndrome.

Metabolic syndrome (MetS) is defined as a constellation of individual metabolic disturbances, including central obesity, hypertension, dyslipidemia, and insulin resistance. The established pathogenesis of MetS varies extensively with gender, age, ethnic background, and nutritional status. In terms of nutritional status, micronutrients are more likely to be discounted as essential components of required nutrition than macronutrients due to the small amount required. Numerous observational studies have shown that pregnant women frequently experience malnutrition, especially in developing and low-income countries, resulting in chronic MetS in the offspring due to the urgent and increasing demands for micronutrients during gestation and lactation. Over the past few decades, scientific developments have revolutionized our understanding of the association between balanced maternal micronutrients and MetS in the offspring. Examples of successful individual, dual, or multiple maternal micronutrient interventions on the offspring include iron for hypertension, selenium for type 2 diabetes, and a combination of folate and vitamin D for adiposity. In this review, we aim to elucidate the effects of maternal micronutrient intake on offspring metabolic homeostasis and discuss potential perspectives and challenges in the field of maternal micronutrient interventions.

The Effect of FOXC2-AS1 on White Adipocyte Browning and the Possible Regulatory Mechanism.

Obesity has become a worldwide epidemic, and obesity-related problems are becoming more severe in public health. Increasing brown adipose tissue (BAT) mass or/and activity in mice and humans has been demonstrated to help lose weight and improve whole-body metabolism. Studies on the conversion of white adipose tissue (WAT) to BAT under certain conditions have provided new possibilities for treating obesity and the related disorders. It has been established that long non-coding RNAs (lncRNAs) play an important role in the regulation of mouse adipocyte differentiation and thermogenic programs; however, the function and potential mechanism of lncRNA in the process of human white adipocyte browning remains unclear. In the present study, we identified a lncRNA called Forkhead Box C2 antisense RNA 1 (FOXC2-AS1), which was first identified in osteosarcoma, and it was highly expressed in human adipocytes but decreased during the white adipocyte differentiation program. FOXC2-AS1 expression was also induced by the thermogenic agent forskolin. Lentivirus-mediated overexpression of FOXC2-AS1 in human white adipocytes did not affect lipid drop accumulation, but significantly promoted the browning phenotype, as revealed by the increased respiratory capacity and the enhanced protein expression levels of brown adipocyte-specific markers. In contrast, inhibiting FOXC2-AS1 with small interfering RNA led to attenuated thermogenic capacity in human white adipocytes. RNA-sequencing analysis and western blot were used to identify a possible regulatory role of the autophagy signaling pathway in FOXC2-AS1 to mediate white-to-brown adipocyte conversion. The autophagy inhibitor 3-methyladenine restored the reduced UCP1 protein level and thermogenic capacity caused by inhibiting FOXC2-AS1. Overall, the present study characterized the potential role of FOXC2-AS1 and further identified a lncRNA-mediated mechanism for inducing browning of human white adipocytes and maintaining thermogenesis, further providing a potential strategy for treating obesity and related disorder.

GSK3ß-Ikaros-ANXA4 signaling inhibits high-glucose-induced fibroblast migration.

Previous studies showed that the activation of Wnt signaling reduced high glucose (HG)-mediated fibroblast damage, but the molecular basis for this phenomenon remains elusive. This study aimed to analyze the level of phosphorylation of GSK3ß Ser9 (pGSK3ß Ser9) during HG damage. Moreover, the phosphomimic form of pGSK3ß Ser9 was expressed to analyze its effect on cell migration via the phosphorylation of Ikaros. The results revealed that HG treatment significantly reduced the pGSK3ß Ser9 level. The overexpression of GSK3ß Ser9D and GSK3ß Ser9A accelerated and inhibited fibroblast cell migration, respectively. P110α knockdown or treatment with SP600125, an inhibitor of JNK, also reduced the pGSK3ß Ser9 level under HG condition. Treatment with SP600125 inhibited the migration of fibroblasts, but not in GSK3ß Ser9D-expressing cells. Further, yeast two-hybrid screening and biochemical analysis identified that GSK3ß interacted and phosphorylated Ikaros at Ser391. Besides, GSK3ß Ser9D, but not GSK3ß Ser9A, activated Ikaros Ser391 phosphorylation. Expressing Ikaros or ß-catenin significantly promoted cell migration, suggesting that GSK3ß modulated cell migration partially via the activation of Ikaros besides ß-catenin signaling under HG condition. The expression of the phosphomimic form of Ikaros Ser391D resulted in a significant increase in the extent of cell migration compared with Ikaros under HG condition. Moreover, the Ikaros Ser391D DNA-binding affinity toward the ANXA4 promoter increased, and ANXA4 suppression promoted cell migration. In conclusion, the results of this study provided a new regulatory mechanism by which GSK3ß negatively regulated human skin fibroblast cell migration.

The role of microRNA-23b-5p in regulating brown adipogenesis and thermogenic program.

Enhanced brown adipose tissue (BAT) mass and activity have been demonstrated to promote the expenditure of excess stored energy and reduce prevalence of obesity. Cold is known as a potent stimulator of BAT and activates BAT primarily through the ß3-adrenergic-cAMP signaling. Here, we performed RNA-sequencing to identify differential miRNAs in mouse BAT upon cold exposure and a total of 20 miRNAs were validated. With the treatment of CL-316,243 (CL) and forskolin (Fsk) in mouse and human differentiated brown adipocyte cells in vitro, miR-23b-5p, miR-133a-3p, miR-135-5p, miR-491-5p, and miR-150-3p expression decreased and miR-455-5p expression increased. Among these deferentially expressed miRNAs, miR-23b-5p expression was differentially regulated in activated and aging mouse BAT and negatively correlated with Ucp1 expression. Overexpression of miR-23b-5p in the precursor cells from BAT revealed no significant effects on lipid accumulation, but diminished mitochondrial function and decreased expression of BAT specific markers. Though luciferase reporter assays did not confirm the positive association of miR-23b-5p with the 3'UTRs of the predicted target Ern1, miR-23b-5p overexpression may affect brown adipocyte thermogenic capacity mainly through regulating genes expression involving in lipolysis and fatty acid ß-oxidation pathways. Our results suggest that miRNAs are involved in cold-mediated BAT thermogenic activation and further acknowledged miR-23b-5p as a negative regulator in controlling thermogenic programs, further providing potential molecular therapeutic targets to increase surplus energy and treat obesity.

FGF1 protects against APAP-induced hepatotoxicity via suppression of oxidative and endoplasmic reticulum stress.

Acetaminophen (APAP) overdose/abuse is the leading cause of acute liver failure in many countries. Fibroblast growth factor 1 (FGF 1) is a metabolic regulator with several physiological functions. Previous studies suggested that FGF1 promotes differentiation and maturation of liver-derived stem cells. In this study, we investigated the protective effects of FGF1 against APAP-induced hepatotoxicity in mice. APAP markedly increased circulating levels of ALT and AST, while FGF1 significantly inhibited increases in the serum levels of ALT and AST, as compared to littermates. In addition, histopathological evaluation of the livers revealed that FGF1 prevented APAP-induced centrilobular necrosis. Livers exhibited severe inflammation, apoptosis, oxidative stress and endoplasmic reticulum stress in response to APAP toxicity, whereas these changes were reversed by a single injection of FGF1. In conclusion, our findings suggest that FGF1 protects mice from APAP-induced hepatotoxicity through suppression of inflammation, apoptosis, and oxidative and endoplasmic reticulum stress. Therefore, FGF1 may represent a promising therapeutic agent for APAP-induced acute liver injury.

Wnt3a-regulated TCF4/ß-catenin complex directly activates the key Hedgehog signalling genes Smo and Gli1.

The Wnt and Hedgehog signalling pathways serve key roles in diverse developmental processes. However, the molecular associations between these two signalling pathways remains unclear. Previous transcriptome studies on human foreskin fibroblasts have indicated that Wnt signalling activation induces the expression of key Hedgehog signalling genes, including smoothened, frizzled class receptor (Smo) and GLI family zinc finger 1 (Gli1). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results revealed that Wnt3a treatment induced the expression of the key Hedgehog signalling genes, including Smo, patched (PTCH), Gli1, Gli2 and Gli3. In addition, western blot analyses demonstrated that Wnt3a treatment resulted in the accumulation of cellular Smo and Gli proteins. Furthermore, promoter sequence analysis revealed that the putative ß-catenin/T-cell factor (TCF)-4 complex binding motifs (T/AC/GAAAG) were located within 1.5 kb of the Smo and Gli1 promoters. Results of the chromatin immunoprecipitation experiments and yeast-one hybrid assays revealed that TCF4 directly binds to the Smo and Gli1 promoters, with two binding sites for Smo and a single binding site for Gli1. Further analysis showed that the ß-catenin/TCF4 complex binds to the Smo and Gli1 promoters. To investigate the functions of TCF4 and ß-catenin in transcriptional regulation of Smo and Gli1, TCF4 and ß-catenin were transiently expressed in fibroblast cells. RT-qPCR results demonstrated that overexpression of TCF4 and ß-catenin induced the expression of Smo and Gli1. In addition, small interfering RNA-mediated suppression of ß-catenin resulted in the downregulation of Smo and Gli1 expression levels, even under Wnt3a treatment. Suppression of ß-catenin and Gli1 expression inhibited cell proliferation. Taken together, the results of the present study suggested that the ß-catenin/TCF4 complex directly activates Smo and Gli1 by binding to their promoters, which in turn controls cell proliferation in human fibroblasts.

Evaluation and optimization of differentiation conditions for human primary brown adipocytes.

As an effective way to improve energy expenditure, increasing the mass and activity of brown adipose tissue (BAT) has become a promising treatment for obesity and its associated disorders. Many efforts have been made to promote brown adipogenesis and increase the thermogenic capacity of brown adipose cells (BACs). The present culture schemes for human BAC differentiation are mostly derived from white adipocyte differentiation schemes. To solve this issue, we compared the adipogenic and thermogenic effects of various components on human BAC differentiation and optimized their concentrations as well as the culture time for BAC differentiation. In this study, we found that the induction factors did not show a dose-dependent promotion of brown adipogenesis or thermogenic capacity. The higher differentiation levels did not inevitably result in higher BAT-specific gene expression levels or increased ß3-receptor agonist sensitivity. As an important element of culture medium, triiodothyronine was found to be essential for differentiation and metabolic property maintenance. Furthermore, compared with other reported methods, this protocol induced a specific intrinsic differentiation program. Our study provides not only an optimized method for human BAC differentiation but also a cell model with good differentiation and thermogenic capacity for brown adipose research.

PID1 in adipocytes modulates whole-body glucose homeostasis.

The novel obesity-associated protein Phosphotyrosine Interaction Domain containing 1 (PID1) inhibits insulin-PI3K/Akt signaling pathway and insulin-stimulated glucose uptake in vitro. In this study, we generated fat tissue-specific aP2-PID1 transgenic (aP2-PID1tg) mice and PID1 knockout (PID1-/-) mice to explore how PID1 affects glucose metabolism in vivo. We observed insulin resistance and impaired insulin-PI3K/Akt signaling in aP2-PID1tg mice. Consistent with these data, the PID1-/- mice displayed improved glucose tolerance and insulin sensitivity under chow diet, with increased Akt phosphorylation in white adipose tissue (WAT). We further demonstrated that PID1 could interact with low density lipoprotein receptor-related protein 1 (LRP1) but not the insulin receptor (IR) in adipocytes, and its overexpression could lead to decreased GLUT4 level. Our results thus indentify PID1 as a critical regulator of glucose metabolism in adipocytes.

Activation of Wnt signaling reduces high-glucose mediated damages on skin fibroblast cells.

OBJECTIVES: High-glucose (HG) stress, a mimic of diabetes mellitus (DM) in culture cells, alters expression of a large number of genes including Wnt and NF-κB signaling-related genes; however, the role of Wnt signaling during HG-mediated fibroblast damage and the relationship between Wnt and NF-κB signaling have not been understood. In this study, we aimed to investigate the ffects of Wnt signaling on HG-mediated damages. MATERIALS AND METHODS: Wnt3a was treated to HG-stressed human primary foreskin fibroblasts and the levels of Wnt signaling markers and cell proliferation were monitored. In addition, Wnt3a and NF-κB signaling inhibitor were assisted to analyze the relationship between two pathways. RESULTS: The results indicated that HG treatment repressed ß-catenin level, and Wnt3a treatment increased the levels of ß-catenin and FZD8 as well as cell proliferation. RNA-seq based transcriptome analysis identified 207 up-regulated and 200 down-regulated genes upon Wnt3a supply. These altered genes are distributed into 20 different pathways. In addition, gene ontology (GO) analysis indicates that 20 GO terms are enriched. Wnt signaling genes were further verified by qRT-PCR and the results were similar with RNA-seq assay. Since NF-κB signaling negatively regulates Wnt marker gene expression, Bay117082, a typical NF-κB signaling inhibitor and Wnt3a were supplemented for testing ß-catenin and phosphorylated IκBα (p-IκBα), respectively. CONCLUSION: HG positively inhibits Wnt signaling, and signaling activation via supplementation of Wnt3a rescued the defect caused by HG. NF-κB signaling negatively regulates accumulation of ß-catenin, but Wnt signaling has no effects on IκBα activation.

Annexin A2 functions downstream of c­Jun N­terminal kinase to promote skin fibroblast cell migration.

Delayed healing of skin wounds is one of the outcomes of diabetes mellitus (DM), a condition that affects a significant number of patients worldwide. However, the underlying mechanisms remain unknown. In order to examine proteome alterations in DM, a rat model of type 1 diabetes was developed using streptozotocin injections. The proteomic responses of normal and DM rat skin were analyzed by two­dimensional electrophoresis, and differentially expressed proteins were identified using a liquid chromatography/mass spectrometry system. DM induced 36 and repressed 41 differentially expressed proteins, respectively. Altered proteins were involved in a number of biological processes, including RNA and protein metabolism, the tricarboxylic acid cycle, glycolysis, cytoskeleton regulation, hydrogen detoxification and calcium­mediated signal transduction. In addition, overexpression of annexin A2, one of the signaling proteins altered by DM, accelerated the rate of human skin fibroblast cell migration. Application of SP600125, an inhibitor of a key regulator of cell migration c­Jun N­terminal kinase (JNK), inhibited the migration of normal cells. By contrast, SP600125 treatment did not inhibit the migration of annexin A2­overexpressed cells, indicating that annexin A2 may function downstream of JNK. In conclusion, the results of the present study reveal the potential proteomic responses to DM in skin tissues, and demonstrate a positive functional role of annexin A2 in fibroblast cell migration.

Obesity­associated miR­148a is regulated by cytokines and adipokines via a transcriptional mechanism.

Our previous study revealed that miR­148a, a cyclic adenosine monophosphate­response element binding protein­modulated microRNA that promotes adipocyte differentiation by inhibiting Wnt1, is a biomarker of obesity in human subjects and a mouse model. The present study investigated the expression of miR­148a in human adipose tissue­derived mesenchymal stem cells (hMSCs­Ad) in response to inflammatory cytokines and adipokines to clarify its underlying mechanism. miR­148a expression was detected using reverse transcription­quantitative polymerase chain reaction analysis and its promoter activity was detected with a luciferase assay. miR­148a expression levels decreased when differentiated hMSCs­Ad were exposed to inflammatory cytokines or adipokines, which suggested that miR­148a may be important in adipocyte metabolism and inflammation. Furthermore, the promoter activity of miR­148a decreased following treatment of cells with inflammatory cytokines or adipokines. The results of the present study indicated a novel role of miR­148a in adipocyte inflammation; therefore, miR­148a may be involved in obesity complications via its own underlying transcriptional mechanism.

Expression of miR-199a-3p in human adipocytes is regulated by free fatty acids and adipokines.

Obesity is associated with a notable risk for disease, including risk of cardiovascular disorders, type 2 diabetes mellitus (T2DM) and hypertension. Adipose tissue modulates the metabolism by releasing free fatty acids (FFAs) and adipokines, including leptin, resistin, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL­6). Altered secretion patterns of FFAs and adipokines have been demonstrated to result in obesity­associated insulin resistance (IR) and inflammatory responses. MicroRNA-199a-3p (miR)-199a-3p expression is significantly induced in differentiated human adipose-derived mesenchymal stem cells and indicates the association with T2DM. However, the association between miR-199a-3p levels in adipocytes and obesity­associated IR, as well as inflammatory responses remains to be elucidated. The present study observed an elevation of miR­199a­3p expression level in mature human adipocytes (visceral) compared with pre-adipocytes. In addition, miR­199a­3p expression was higher in visceral adipose deposits from obese subjects. FFA, TNF-α, IL­6 and leptin significantly induced miR­199a­3p expression in mature human adipocytes, while resistin had the opposite effect. miR­199a­3p may represent a factor in the modulation of obesity­associated IR and inflammatory responses.

Correlations of Cerebrospinal Fluid/Plasma Fibroblast Growth Factor 21 Ratio with Metabolic Parameters in Chinese Individuals of Normal Weight.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is an important metabolic regulator that has multiple beneficial effects on glucose homeostasis and lipid metabolism. Although circulating levels of FGF21 are mainly derived from liver, FGF21 is also found in other tissues and fluids including the cerebrospinal fluid (CSF). The aim of the present study was to investigate the relationships of CSF and/or plasma FGF21 levels with metabolic parameters in a normal-weight Chinese population. METHODS: Forty-five subjects (22 males and 23 females) were recruited from a patient population undergoing surgery for lower extremity injuries due to ligament damage or bone fractures below the knee in the Beijing Jishuitan Hospital. The levels of FGF21 in CSF and plasma were determined by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. RESULTS: No significant differences were detected in the levels of FGF21 in CSF and plasma between males (CSF: 158.01 ± 12.10 pg/mL; plasma: 206.19 ± 7.22 pg/mL) and females (CSF: 159.27 ± 17.85 pg/mL; plasma: 203.10 ± 7.53 pg/mL). The level of FGF21 in CSF was about 75% of that in plasma. The FGF21 level in CSF was positively correlated with triglyceride level, whereas plasma FGF21 level was negatively correlated with alanine aminotransferase in women but not in men. The CSF/plasma FGF21 ratio was positively correlated with CSF FGF21 in both genders and with peripheral glucose, triglyceride, and gamma-glutamyl transferase levels in female Chinese patients. CONCLUSIONS: These results have important implications regarding the potential central actions of FGF21.

miR-1275 inhibits adipogenesis via ELK1 and its expression decreases in obese subjects.

Excessive adipocyte differentiation and proliferation are closely associated with the onset of obesity, which has been partially linked to microRNA expression. In previous studies, using miRNA microarray screening, we found that miR-1275 was significantly decreased in human mature adipocytes. In this study, we examined the role of miR-1275 in adipogenesis. Our results indicated that miR-1275 can inhibit the differentiation of human visceral preadipocytes without affecting their proliferation. ELK1, an E-twenty-six (ETS)-domain transcription factor associated with adipocyte differentiation, was strongly suppressed by miR-1275 in human visceral adipocytes. This was demonstrated via a dual-luciferase reporter assay and pointed to ELK1 as a direct target of miR-1275. Furthermore, miR-1275 expression was significantly diminished in the visceral adipose tissue of overweight and obese human subjects accompanied by a negative correlation with body mass index. These results suggest that miR-1275 could play a future role in the management of obesity, as a novel therapeutic target or biomarker.

Application of citrate as a tricarboxylic acid (TCA) cycle intermediate, prevents diabetic-induced heart damages in mice.

OBJECTIVES: Higher cellular reactive oxygen species (ROS) levels is important in reducing cellular energy charge (EC) by increasing the levels of key metabolic protein, and nitrosative modifications, and have been shown to damage the cardiac tissue of diabetic mice. However, the relation between energy production and heart function is unclear. MATERIALS AND METHODS: Streptozotocin (STZ, 150 mg/kg body weight) was injected intraperitoneally once to mice that had been fasted overnight for induction of diabetes. After diabetic induction, mice received citrate (5 µg/kg) through intraperitoneal injection every other day for 5 weeks. The caspase-3, plasminogen activator inhibitor 1 (PAI1), protein kinase B (PKB), commonly known as AKT and phosphorylated-AKT (p-AKT) proteins were examined to elucidate inflammation and apoptosis in the heart. For histological analysis, heart samples were fixed with 10% formalin and stained with hematoxylin-eosin (HE) and Sirius red to assess pathological changes and fibrosis. The expression levels[AGA1] of marker proteins, tyrosine nitration, activity of ATP synthase and succinyl-CoA3-ketoacid coenzyme A transferase-1 (SCOT), and EC were measured. RESULTS: Intraperitoneal injection of citrate significantly reduced caspase-3 and PAI-1 protein levels and increased p-AKT level on the 5(th) week; EC in the heart was found to be increased as well. Further, the expression level, activity, and tyrosine nitration of ATP synthase and SCOT were not affected after induction of diabetes. CONCLUSION: Results indicate that application of citrate, a tricarboxylic acid (TCA) cycle intermediate, might alleviate cardiac dysfunction by reducing cardiac inflammation, apoptosis, and increasing cardiac EC.

Transcriptomic study of high­glucose effects on human skin fibroblast cells.

Skin ulcers are a common complication of diabetes mellitus (DM). Fibroblasts are located within the dermis of skin tissue and can be damaged by diabetes. However, the underlying mechanism of how DM affects fibroblasts remains elusive. To understand the effects of DM on fibroblasts, the current study mimicked DM by high­glucose (HG) supplementation in the culture medium of human foreskin primary fibroblast cells, and the analysis of transcriptomic changes was conducted. RNA sequencing­based transcriptome analysis identified that, upon HG stress, 463 genes were upregulated and 351 genes downregulated (>1.5­fold changes; P<0.05). These altered genes were distributed into 20 different pathways. In addition, gene ontology (GO) analysis indicated that 31 GO terms were enriched. Among the pathways identified, nuclear factor κB (NF­κB) pathway genes were highly expressed, and the addition of Bay11­7082, a typical NF­κB signaling inhibitor, blocked the previously observed alterations in plasminogen activator inhibitor 1 (PAI1), an inflammation marker and frizzled class receptor 8 (FZD8), a Wnt signaling gene, expression that resulted from HG stress. Furthermore, an inhibitor of Wnt signaling diminished the role of Bay11­7082 in the regulation of PAI1 expression under HG conditions, suggesting that Wnt signaling may function downstream of the NF­κB pathway to protect fibroblast cells from HG stress. To the best of our knowledge, the current study is the first analysis of transcriptomic responses under HG stress in human fibroblasts. The data provided here may aid the understanding of the molecular mechanisms by which fibroblast cells are damaged in the skin of patients with DM.

Prediction of liver injury using the BP-ANN model with metabolic parameters in overweight and obese Chinese subjects.

Nonalcoholic fatty liver disease (NAFLD) is often associated with dyslipidemia. Metabolic disequilibrium, resulting from being overweight and obesity, increases risk to cardiovascular system and chronic liver disease. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) are standard clinical markers for liver injury. In this study, we examined association of body mass index (BMI) and metabolic markers with serum ALT, AST and GGT activity in an overweight and obese Chinese population. A total of 421 overweight and obese Chinese adults (211 males and 210 females) from The First Affiliated Hospital of Wenzhou Medical University were recruited in this study in 2014. All participants underwent anthropometric measures and phlebotomy after an overnight fast. Elevated ALT, AST and GGT levels were found in 17%, 5% and 24%, respectively. There were significant correlations between ALT and BMI, plasma triglycerides (TG), cholesterol, HDL and glucose, and between AST and plasma TG and cholesterol. GGT also correlated with plasma TG, cholesterol and glucose. The levels of ALT, AST and GGT could be predicted by BMI, plasma TG, cholesterol, HDL and glucose using the back propagation artificial neural network model (BP-ANN). These data suggest that abnormal metabolic markers could be used to monitor liver function to determine whether liver damage has occurred in overweight and obese individuals. This approach has clinical utility with respect to early scanning of liver injury or NAFLD based on routinely available metabolic data in overweight and obese population.

Bone marrow mesenchymal stem cells protect against bleomycin-induced pulmonary fibrosis in rat by activating Nrf2 signaling.

Pulmonary fibrosis is a progressive and lethal disorder. Although the precise mechanisms of pulmonary fibrosis are not fully understood, oxidant/antioxidant may play an important role in many of the processes of inflammation and fibrosis. Keap1-Nrf2-ARE pathway represents one of the most important cellular defense mechanisms against oxidative stress. Mesenchymal stem cells (MSC) are in clinical trials for widespread indications including musculoskeletal, neurological, cardiac and haematological disorders. One emerging concept is that MSCs may have paracrine, rather than a functional, roles in lung injury repair and regeneration. In the present study, we investigated bone marrow mesenchymal stem cells (BMSCs) for the treatment of bleomycin-induced pulmonary fibrosis. Our results showed that BMSCs administration significantly ameliorated the bleomycin mediated histological alterations and blocked collagen deposition with parallel reduction in the hydroxyproline level. The gene expression levels of NAD(P)H: quinine oxidoreductase 1 (NQO1), gama-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2), attenuated by bleomycin, were increased up to basal levels after BMSCs transplantation. BMSCs significantly increased superoxide dismutase (SOD) activity and inhibited malondialdehyde (MDA) production in the injured lung. The present study provides evidence that BMSCs may be a potential therapeutic reagent for the treatment of lung fibrosis.

miR-148a is Associated with Obesity and Modulates Adipocyte Differentiation of Mesenchymal Stem Cells through Wnt Signaling.

Obesity results from numerous, interacting genetic, behavioral, and physiological factors. Adipogenesis is partially regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that regulate proliferation and differentiation of human adipose-derived mesenchymal stem cells (hMSCs-Ad). In this study, we examined the roles of adipocyte-selective miRNAs in the differentiation of hMSCs-Ad to adipocytes. Results showed that the levels of miR-148a, miR-26b, miR-30, and miR-199a increased in differentiating hMSCs-Ad. Among these miRNAs, miR-148a exhibited significant effects on increasing PPRE luciferase activity (it represents PPAR-dependent transcription, a major factor in adipogenesis) than others. Furthermore, miR-148a expression levels increased in adipose tissues from obese people and mice fed high-fat diet. miR-148a acted by suppressing its target gene, Wnt1, an endogenous inhibitor of adipogenesis. Ectopic expression of miR-148a accelerated differentiation and partially rescued Wnt1-mediated inhibition of adipogenesis. Knockdown of miR-148a also inhibited adipogenesis. Analysis of the upstream region of miR-148a locus identified a 3 kb region containing a functional cAMP-response element-binding protein (CREB) required for miR-148a expression in hMSCs-Ad. The results suggest that miR-148a is a biomarker of obesity in human subjects and mouse model, which represents a CREB-modulated miRNA that acts to repress Wnt1, thereby promoting adipocyte differentiation.