The effect of IGF-1 on symptoms of sleep deprivation in a rat model of inflammatory heart disease and metabolic syndrome.

Sleep deprivation (SD) has become a worldwide public health concern due to the many negative health consequences associated with suboptimal sleep. SD has been linked to a catabolic hormone signature, heart disease, hypertension, diabetes, and an increase in morbidity and mortality. Herein, we investigated the effects and mechanism of SD on cardiac and metabolic health and evaluated the impact of exogenously supplied IGF-1 on these symptoms. In the present study, we show that 5 days of acute SD negatively impacted all of the various indicators of cardiac and metabolic health. All symptoms of SD were ameliorated by daily administration of IGF-1, however. IGF-1 administration also reduced the phosphorylation of Akt and expression of Bax, a promoter of apoptosis. Conversely, the expression of Bcl-2, an inhibitor of apoptosis, was elevated by IGF-1, and all IGF-1 effects were suppressed by the PI3K/Akt inhibitor LY294002, reaffirming the importance of the PI3K/Akt pathway in the maintenance of cardiac and metabolic health.

Metabolic-associated steatotic liver disease and risk of Alzheimer's disease: a real-world retrospective cohort study.

Objective: Alzheimer's Disease (AD) is increasingly recognized as being associated with metabolic disorders, including Metabolic Associated Steatotic Liver Disease (MASLD). This study aimed to assess the relative risk of AD in individuals with MASLD. Methods: In this retrospective cohort study, we analyzed data from individuals aged over 65 who underwent health check-ups between January 2018 and June 2023. MASLD was diagnosed based on ultrasound findings and cardiometabolic criteria. AD incidence was identified using ICD-10 codes and self-reports. Poisson regression models estimated the relative risk of AD in relation to MASLD, adjusting for age, BMI, sex, SBP, HbA1c, HDL-c, triglycerides, hs-CRP, GGT, and estimated GFR. Results: The study included 4,582 MASLD patients and 6,318 controls. MASLD patients showed a higher incidence of AD (127 cases) compared to controls (61 cases). The fully adjusted Poisson regression model indicated an increased AD risk in MASLD patients [RR: 2.80 (95% CI: 1.79-4.38)]. Conclusion: Our findings suggested MASLD as an independent risk factor for AD, underlining the role of metabolic dysfunctions in AD pathogenesis. The study emphasized the need for comprehensive metabolic health management in AD prevention strategies, particularly among high-risk groups.

Discovery of novel dihydropyrrolidone-thiadiazole compound crosstalk between the YycG/F two-component regulatory pathway and cell membrane homeostasis to combat methicillin-resistant Staphylococcus aureus.

The rapid emergence and spread of multidrug-resistant (MDR) Gram-positive pathogens present a significant challenge to global healthcare. Methicillin-resistant Staphylococcus aureus (MRSA) is a particular concern because of its high resistance to most antibiotics. Based on our previously reported chemical structure of compound 62, a series of novel derivatives were synthesized and evaluated for their antibacterial activities. We found that some of these derivatives displayed effective antibacterial activity against Gram-positive pathogens, with minimal cytotoxicity (CC50>100 µM) and hemolytic activity (HC50>200 µM). Among these derivatives, the minimum inhibitory concentration (MIC) of 62-7c against Gram-positive bacterial isolates ranged from 6.25 to 25 µM. This derivative also exhibited significant synergistic antibacterial effects with daptomycin both in vitro and in vivo, with an ability to eradicate planktonic and persister cells of MRSA. Additionally, 62-7c inhibited biofilm formation and eradicated mature biofilms of MRSA. Mechanistic studies revealed that 62-7c inhibited the YycG kinase activity and disrupted the cell membrane by binding to cardiolipin (CL), leading to cell death. Importantly, no development of drug resistance was observed even after 20 serial passages. Furthermore, 62-7c exhibited high biosafety and potent effectiveness in combating infections in both mouse pneumonia and mouse wound models infected with MRSA. Thus, our study revealed that 62-7c has the potential to serve as a novel antibacterial agent for treating MRSA infections.

[Defensive characteristics of cones of Pinus armandii against seed-eating animals]. / 华山松球果对食种子动物的防御特征.

During the co-evolution with animals, plants evolved different defense strategies to resist predators and ensure their own survival and reproduction. We investigated the forging preference of nutcrackers (Nucifraga caryocatactes) for seeds in different parts of bending Pinus armandii cones in Southeast Tibet. We measured the morphological characteristics (length, width, thickness, and seed hull thickness) and the physical and chemical properties of concave and convex seeds of P. armandii (crude water, dry-matter at 70 ℃, crude fat, ash, protein and crude fiber). The results showed that there were significant differences in seed shell thickness, kernel percentage and empty shell percentage between the concave and convex seeds. The seed shell thickness of convex seeds (1.11±0.12 mm) was thicker than that of concave seeds (1.07±0.15 mm). The kernel weight percentage of convex seeds (24.0%) was smaller than that of concave seeds (25.4%). The empty shell percentage (11.2%), crude fat content (47.0%) of convex seeds were significantly lower than that of concave seeds (15.8% and 50.5%). The curving cones of P. armandii cause false hints to seed eaters, and protect high-quality seeds from being eaten as much as possible. Therefore, the curving cone is a defensive characteristics of P. armandii against seed predators.

Multiple perspectives reveal the gut toxicity of polystyrene microplastics on Eisenia fetida: Insights into community signatures of gut bacteria and their translocation.

The gut is the primary pathway by which soil animals are exposed to microplastics (MPs). However, the gut toxicity of MPs has not been elucidated in earthworms. Herein, we aimed to study the gut toxicity (e.g., gut barrier dysfunction, gut bacterial translocation, and pathogen invasion) of polystyrene microplastics (PS-MPs) on Eisenia fetida and its relationship with gut bacteria. We found that PS-MPs exposure caused gut barrier damage to Eisenia fetida. This damage included apparent injury of gut epithelial cells and significantly lower transcription levels of genes coding for gut tight junction (TJ)-related proteins. We then observed significantly increased levels of bacterial lipopolysaccharide (LPS) and gut bacterial load, indicating the occurrence of gut bacterial translocation and related barrier damage. Subsequently, antibacterial immune responses were activated and accompanied by a failure of the antioxidant defense system, indicating that pathogen invasion might occur. Gut barrier damage could weaken host selective pressures (deterministic process) on gut bacteria, such as particular pathogens. Indeed, members of Proteobacteria, e.g., Aeromonas and Escherichia/Shigella, regarded as potential opportunistic pathogens, were remarkable signatures of groups exposed to PS-MPs. These potential opportunistic gut bacteria were pivotal contributors to gut TJ damage and gut bacterial translocation resulting from PS-MPs exposure. In addition, the gut bacterial networks of PS-MPs exposure groups were more uncomplicated than those of the control group, but more negative interactions were easy to observe. In conclusion, our work sheds light on the molecular mechanism of earthworm gut toxicity caused by PS-MPs exposure and provides a prospective risk assessment of MPs in soil ecosystems.

MiR-143 Targets IGF-1R to Suppress Autoimmunity in Thyroid-Associated Ophthalmopathy.

Objective: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease that involves the remodeling of orbit and periorbital tissues. Thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R) may stimulate the activation of autoimmunity in TAO, but the exact mechanism is unclear. We investigated whether IGF-1R/TSHR modulation in TAO may involve microRNA regulation. Methods: We conducted microarray analysis using RNA from the orbital connective tissue samples of 3 healthy and 3 patients with TAO. The involvement of differentially regulated microRNA in IGF-1R/TSHR modulation in TAO was evaluated in orbital fibroblasts (OFs) and female BALB/c mice. Results: Using hierarchical cluster analysis, we identified that miR-143 was downregulated in TAO. The expression levels of miR-143 in OFs were significantly reduced under IL-1B stimulation. However, OF proliferation and inflammatory responses decreased when miR-143 is overexpressed. In contrast, the suppression of miR-143 increased levels of inflammatory markers (IL-6, IL-8, MCP1) and hyaluronan accumulation. Moreover, overexpression of miR-143 significantly lowers levels of IGF-1R and TSHR. A luciferase assay indicated that miR-143 targets the 3'-UTR of IGF-1R. Increases in the expression of IGF-1R increased the expression of the inflammasome marker NLRP3 and apoptotic marker cleaved caspase-1; however, miR-143 overexpression decreased levels of IGF-1R, TSHR, NLRP3, cleaved caspase 1, IL-1B, and IL-18. In a mouse model of TAO, overexpression of miR-143 significantly reduced levels of IGF-1R and attenuated the adipogenesis associated with TAO. Conclusion: We found that miR-143 directly targets IGF-1R to alleviate the inflammatory response in TAO by indirectly decreasing levels of TSHR and inactivating NLRP3.

Association of two polymorphisms within and near SOCS3 gene with obesity in three nationalities in Xinjiang province of China.

AIM: SOCS3 gene plays an important role in the pathogenesis of obesity in animal models, but the data from human studies are relatively limited. To address this issue, a genetic association analysis on nationalities with different genetic background living in the similar environmental conditions was performed. METHODS: Two thousand seven hundred eleven subjects were randomly recruited from the Kazakh, Uygur and Han nationalities in Xinjiang of China. SNP polymorphisms rs4969168 and rs9892622 within or near the SOCS3 gene were genotyped using TaqMan-MGB™ assay. Association study between the two polymorphisms and obesity-related traits (body mass index [BMI]; waist-to-hip ratio [WHR]; weight; height, waist, and hip measurements) was conducted. RESULTS: Significant association was found between rs4969168 and the obesity-related traits, including BMI (25.32 ± 3.49 kg/m(2) for AA, 24.60 ± 3.70 kg/m(2) for AG, 24.39 ± 3.42 kg/m(2) for GG, P=0.042), weight (65.58 ± 11.42 kg for AA, 63.50 ± 11.30 kg for AG, 62.00 ± 10.78 kg for GG, P=0.011) in the Han nationality, but not in the Kazakh or Uygur nationalities. Rs9892622 was significantly associated with BMI, WHR, and WAIST in the Uygur males. Rs9892622 was also associated with BMI in Kazakh males. Linear regression analysis verified the above findings. However, neither of the two polymorphisms was associated with obesity-related traits in the total population. CONCLUSION: The polymorphism rs4969168 within or near the SOCS3 gene has a significant effect in the Han nationality, while rs9892622 was associated with obesity in Uygur and Kazakh nationalities in Xinjiang of China.

[A randomized, double blind, placebo-controlled, parallel and multicenter study to evaluate the safety and efficacy of pioglitazone with sulphonylurea in type 2 diabetic patients].

OBJECTIVE: To evaluate the safety and efficacy of 30 mg pioglitazone hydrochloride combined with sulphonylurea in the treatment of type 2 diabetic patients. METHODS: A randomized, double blind, placebo-controlled, parallel group, multicenter study was performed. A total of 236 patients, who had fasting plasma glucose (FPG) 7.5 - 13.0 mmol/L and glycosylated hemoglobin A1c (HbA1c) 7.0% - 12.0%, treated with stable dosage of a sulphonylurea for at least 30 days previously, were randomized to receive placebo or pioglitazone 30 mg once daily for 16 weeks. The sulphonylurea and dosage remained unchanged. RESULTS: The patients who had been treated with pioglitazone 30 mg showed significant decrease than that in the placebo group on the average from baseline in FPG [(1.48 ± 2.08) mmol/L vs (-0.17 ± 1.92) mmol/L, P < 0.05], and in HbA1c [(0.92 ± 0.10)% vs (0.28 ± 0.11)%, P < 0.05]. Since fasting plasma insulin (FIns) levels decreased (0.24 ± 0.04) mU/L and (0.09 ± 0.04) mU/L in the two groups. The homeostatic model assessment insulin resistant (HOMA-IR) decreased 1.42 ± 2.90 and 0.46 ± 3.53 in two groups. The triglyceride level was decreased 0.36 mmol/L and 0.14 mmol/L, and the HDL-C level increased 0.17 mmol/L and 0.05 mmol/L in two groups. There were significant differences in two groups (all P < 0.05). CONCLUSIONS: The 16-week clinical study demonstrated that pioglitazone hydrochloride with a dosage of 30mg daily, could significantly improve the blood glucose control and enhance the insulin sensitivity, lower triglyceride and raise HDL-C level as an additional therapy to a stable-dose sulphonylurea in Chinese type 2 diabetic patients previously poorly controlled by single sulphonylurea therapy, and furthermore had good safety and compliance.

Blimp-1 inhibits Th9 cell differentiation and attenuates diabetic coronary heart disease.

Diabetic coronary heart disease (DM-CHD) poses a major threat to the world. The newly described T cell subset-Th9 cells and related cytokine interleukin (IL)-9 play important roles in the pathogenesis of diabetes and atherosclerosis. B lymphocyte-induced maturation protein 1 (Blimp-1) has been indicated to negatively regulate Th9 development in allergic asthma, but its role in DM-CHD remains unclear. Hence, this study was designed to investigate the role of Blimp-1 in DM-CHD and to elucidate whether the mechanism was associated with regulation of Th9 cell differentiation. Our results showed that serum Blimp-1 mRNA level was decreased whereas proportion of Th9 cells (IL-9+ CD4+ T cells) and serum level of Th9-related IL-9 were increased in DM-CHD patients. Furthermore, serum Blimp-1 mRNA level was negatively correlated with IL-9 level in DM-CHD patients. Importantly, administration of lentiviruses expressing Blimp-1 (LV-Blimp-1) significantly inhibited Th9 cell differentiation and alleviated the severity of atherosclerotic lesions in the aorta and coronary artery, dyslipidemia, inflammation, vascular endothelial dysfunction, and oxidative stress in DM-CHD model rats. Collectively, Blimp-1 exerts a protective effect in DM-CHD rats and the mechanism might involve inhibition of Th9 cell differentiation.

Bone Morphogenetic Protein-2 Promotes Osteoclasts-mediated Osteolysis via Smad1 and p65 Signaling Pathways.

STUDY DESIGN: An in vitro biological study. OBJECTIVE: The aim of this study was to explore the role of bone morphogenetic protein-2 (BMP-2) in the regulation of osteoclast-mediated osteolysis, and the possible mechanism involving BMP-2 and nuclear factor-kappa B (NF-κB) signaling pathways. SUMMARY OF BACKGROUND DATA: Recombinant human BMP-2 (rhBMP-2) has been approved as a therapeutic agent in spinal fusion and bone defect repair. However, its efficacy and clinical application are limited by associated complications including osteoclast-mediated bone resorption. The mechanism of BMP-2-induced osteolysis remains unknown. METHODS: Bone marrow-derived macrophages (BMMs) were isolated from C57BL/6J mice and cultured with macrophage colony-stimulating factor (M-CSF) and receptor activator for nuclear factor-κB Ligand (RANKL) to induce osteoclast differentiation. An in vitro bone resorption assay was performed by co-culturing BMMs and bone slides. The expression of BMP canonical and NF-κB signaling factors and their interaction during signal transduction were quantitated by reverse transcription polymerase chain reaction, Western blot analysis, confocal microscopy, and co-immunoprecipitation. RESULTS: BMP-2 enhanced osteoclast-mediated bone resorption via inducing osteoclast differentiation in a concentration-dependent manner. In addition, a high concentration of BMP-2 significant upregulated phosphorylation of BMP signaling factors p-Smad1/5/8 and NF-κB downstream factor p65, and promoted the degeneration of IκBα. In addition, BMP-2 induced osteoclast differentiation through coupling between BMP receptor II and RANK. CONCLUSION: High concentrations of BMP-2 enhanced osteoclast-mediated bone resorption by promoting RANKL-induced pre-osteoclast differentiation, probably by mediating the cross-talk between BMP canonical and NF-κB signaling pathways.Level of Evidence: N/A.

Advanced glycation end products inhibit neural stem cell differentiation via upregualtion of HDAC3 expression.

Diabetes mellitus (DM) is a highly prevalent chronic systemic disease, which may cause cognitive decline and degenerative change of the brain. Neuronal differentiation defects of neural stem cells (NSCs) played an important role in the development and progression of diabetes-associated cognitive decline (DACD), but the intrinsic pathological mechanism remains largely unclear. In the present study, we demonstrated that expression level of HDAC3 was upregulated in diabetic mice with reduced learning and memory abilities and in cultured NSCs after advanced glycation end products (AGEs) induction. In addition, AGEs interfered with normal differentiation of the cultured NSCs, and knocking down the expression of HDAC3 could partially attenuate the inhibitory effect of AGEs on NSCs differentiation. Findings in this study demonstrate that HDAC3 may serve as an experimental clue for revealing the pathogenesis of DACD.

Cadherin Related Family Member 2 Acts As A Tumor Suppressor By Inactivating AKT In Human Hepatocellular Carcinoma.

Cadherin related family member 2 (CDHR2) belongs to the protocadherin family and is abundant in normal liver, kidney, and colon tissues, but weakly expressed in cancers arising from these tissues. In this study, we demonstrated that CDHR2 was highly expressed in para-cancer tissues of human hepatocellular carcinoma (HCC), but significantly downregulated or silenced in 85.7% (6/7) of HCC cell lines by both semi-quantitative PCR and western blot, and 79.1% (19/24) and 80.2% (89/111) of tumor tissues from patients with HCC by semi-quantitative PCR, and immunohistochemistry, respectively. Interestingly, CpG islands in the promoter of CDHR2 gene were hypermethylated in HCC cell lines and tissues compared with the para-cancer tissues by methylation-specific PCR analysis, leading to transcriptional repression and silencing of CDHR2 in HCC. In addition, CDHR2 overexpression by lentiviral vectors had suppressive effects on HCC cell growth and proliferation, as evidenced by prolonged cell doubling time and reduced colony-forming ability in vitro, as well as by decreased tumorigenicity in vivo. Mechanistically, CDHR2 overexpression resulted in AKT dephosphorylation along with downregulation of cyclooxygenase-2 (COX2), a downstream target of AKT. This effect was reversed by myristoylated AKT, a constitutively active form of AKT, suggesting an involvement of CDHR2-AKT-COX2 axis in the suppression of HCC growth. Taken together, our study identified CDHR2 as a novel tumor suppressor in HCC and provided a new therapeutic target for HCC.

High glucose upregulates osteopontin expression by FoxO1 activation in macrophages.

Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE-/- mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt -1918 ~ -713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.

Transplantation of betatrophin-expressing adipose-derived mesenchymal stem cells induces ß-cell proliferation in diabetic mice.

Recent progress in regenerative medicine has suggested that mesenchymal stem cell (MSC)-based therapy is a novel potential cure for diabetes. Betatrophin is a newly identified hormone that can increase the production and expansion of insulin-secreting ß-cells when administered to mice. In this study, we evaluated the effect of betatrophin overexpression by human adipose-derived MSCs (ADMSCs) by in vitro experiments, as well as following their transplantation into a mice with streptozotocin (STZ)-induced diabetes. The overexpression of betatrophin did not affect the ADMSCs in terms of proliferation, differentiation and morphology. However, the co-culture of human islets with ADMSCs overexpressing betatrophin (ADMSCs-BET) induced islet proliferation, ß-cell specific transcription factor expression, and the islet production of insulin under the stimulation of glucose or KCl and Arg. In addition, ADMSCs-BET enhanced the anti-inflammatory and anti-apoptotic effects of the co-cultured islets compared with ADMSCs cultured alone. In mice with STZ-induced diabetes, the transplantation of ADMSCs-BET ameliorated the hyperglycemia and weight loss associated with STZ-induced diabetes; ADMSCs-BET also significantly enhanced the ratio of ß-cells per islet compared to the transplantation of ADMSCs alone. Thus, our study demonstrates a novel strategy for inducing ß-cell regeneration. ADMSCs-BET may replace insulin injections by increasing the number of endogenous insulin-producing cells in patients with diabetes. This combined strategy of ADMSC transplantation and gene therapy may prove to be a useful therapy for the treatment of diabetes.

XRCC1 gene polymorphisms and the risk of differentiated thyroid carcinoma (DTC): a meta-analysis of case-control studies.

BACKGROUND: Previous studies investigating the association between X-ray repair cross-complementing group 1 (XRCC1) polymorphisms and thyroid cancer risk have yielded inconsistent results. This meta-analysis was performed to derive a more precise estimation of the relationship between three XRCC1 polymorphisms and thyroid cancer risk. METHODS/PRINCIPAL FINDINGS: PubMed and EMBASE database were systematically searched to identify relevant studies. 10 publications were selected for this meta-analysis, including 11 studies for Arg399Gln polymorphism (1726 cases and 3774 controls), 7 studies for Arg194Trp polymorphism (1037 cases and 2487 controls) and 8 studies for Arg280His polymorphism (1432 cases and 3356 controls). The results in total population did not show any significant association between these three polymorphisms and the risk of DTC for all genetic models. However, when stratified by ethnicity, the results showed that Arg280His polymorphism was associated with an increased risk of DTC among Caucasians (Arg/His vs. Arg/Arg: OR = 1.45, 95% CI = 1.09-1.93; dominant model: OR = 1.43, 95% CI = 1.08-1.89; additive model: OR = 1.38, 95% CI = 1.05-1.80), whereas individuals carrying Arg/His genotype have a significantly reduced risk of DTC among Asians (Arg/His vs. Arg/Arg: OR = 0.71, 95% CI = 0.51-0.98). We also detected that 399Gln variant allele carriers might presented an overall decreased risk of DTC in mixed population. Furthermore, subgroup analyses by histological subtype revealed that Arg194Trp polymorphism was significantly associated with reduced risk for papillary thyroid carcinoma (PTC) (dominant model: OR = 0.71, 95% CI = 0.50-0.99). CONCLUSIONS: This meta-analysis suggests that Arg280His polymorphism might contribute to the susceptibility of DTC among Caucasians, whereas it might provide protective effects in Asians against the risk of DTC. Additionally, our results support the protective role of Arg194Trp polymorphism in developing PTC, and show evidence of an association between Arg399Gln polymorphism and decreased risk of DTC in mixed population.

High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol.

Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. Hyperglycemia-induced oxidative stress is implicated in the etiology of diabetic nephropathy. Resveratrol has potent antioxidative and protective effects on diabetic nephropathy. We aimed to examine whether high glucose (HG)-induced NADPH oxidase activation and reactive oxygen species (ROS) production contribute to glomerular mesangial cell proliferation and fibronectin expression and the effect of resveratrol on HG action in mesangial cells. By using rat mesangial cell line and primary mesangial cells, we found that NADPH oxidase inhibitor (apocynin) and ROS inhibitor (N-acetyl cysteine) both inhibited HG-induced mesangial cell proliferation and fibronectin expression. HG-induced elevation of NADPH oxidase activity and production of ROS in mesangial cells was inhibited by apocynin. These results suggest that HG induces mesangial cell proliferation and fibronectin expression through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunits p22(phox) and p47(phox) expression through JNK/NF-κB pathway, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced mesangial cell proliferation and fibronectin expression through inhibiting HG-induced JNK and NF-κB activation, NADPH oxidase activity elevation and ROS production. These results demonstrate that HG enhances mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide novel therapeutic targets for diabetic nephropathy.

Serum biomarker of diabetic peripheral neuropathy indentified by differential proteomics.

At least one in four diabetic patients is affected by peripheral neuropathy. In this study, the MALDI-TOF-MS mass spectra of peptides and proteins were generated following WCX CLINPROT bead fractionation of 39 diabetic peripheral neuropathy (DPN), 39 diabetes mellitus (DM), and 35 control (CON) serum samples. The spectra were analyzed statistically using flexAnalysisTM and Clin-ProtTM bioinformatics software. Identification of the selected markers was performed and affinity bead-purified plasma protein was subjected to LTQ Orbitrap XL MS/MS analysis followed by Mascot identification of the peptide sequences. 89 differentially expressed peaks of serum proteins were identified. 17, 10 and 4 most significant peaks between CON vs. DM, CON vs. DPN, DM vs. DPN, respectively, were selected out using the ClinProTool software package and used to train a Supervised Neural Network. A veracity rate of 100% was obtained for all sets. Following this analysis, a 6631-Da marker was identified as a fragment of the Apolipoprotein C-I precursor. The peptides identified may have clinical utility as surrogate markers for detection and classification of DM and DPN.

Tumor necrosis factor-α increases angiopoietin-like protein 2 gene expression by activating Foxo1 in 3T3-L1 adipocytes.

Angiopoietin-like protein 2 (Angptl2) is a key adipocyte-derived inflammatory mediator linking obesity to systemic insulin resistance, which is overexpressed in obesity and related metabolic diseases. However, its regulatory mechanism remains unclear. In this study, we showed that tumor necrosis factor (TNF)-α treatment increased the expression of Angptl2 gene in 3T3-L1 adipocytes. The cloning and sequence analysis of the Angptl2 gene promoter revealed the presence of several putative-binding sites for transcriptional factors, including two IREs. Insulin suppressed Angptl2 mRNA expression in dose-dependent manners, which could be attenuated by a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. The interactions between IRE sites within Angptl2 promoter and forkhead transcription factor Foxo1 were identified by EMSA and ChIP assay. Furthermore, lentivirus-mediated knockdown of Foxo1 expression inhibited the transcriptional activity of Angptl2 promoter and decreased Angptl2 mRNA expression. Finally, TNF-α inhibited Foxo1 phosphorylation and enhanced its transcriptional activity, through which TNF-α increased the expression of Angptl2 in adipocytes. These results suggest that TNF-α up-regulates Angptl2 mRNA expression via PI3K/Foxo1 pathway in 3T3-L1 adipocytes, which may be involved in obesity-induced inflammation and insulin resistance.

MicroRNA-1 regulates cardiomyocyte apoptosis by targeting Bcl-2.

MicroRNA-1 (miR-1) is preferentially expressed in cardiac muscles, and the expression has been demonstrated to be involved in cardiac development and cardiovascular diseases. Here we report that miR-1 is closely related with ischemia/reperfusion injury in a rat model. The level of miR-1 is inversely correlated with Bcl-2 protein expression in cardiomyocytes of the I/R rat model. In vitro, the level of miR-1 was dramatically increased in response to H(2)O(2). Overexpression of miR-1 facilitated H(2)O(2)-induced apoptosis in cardiomyocytes. Inhibition of miR-1 by antisense inhibitory oligonucleotides caused marked resistance to H(2)O(2). Through bioinformatics, we identified the potential target sites for miR-1 on the 3' UTR of Bcl-2. miR-1 significantly reduced the expression of Bcl-2 in the levels of mRNA and protein. The post-transcriptional repression of Bcl-2 was further confirmed by luciferase reporter experiments. These data demonstrated that miR-1 plays an important role in the regulation of cardiomyocyte apoptosis, which is involved in post-transcriptional repression of Bcl-2.