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Background. Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia, which can induce the development of atherosclerosis (AS). Calcification of vascular smooth muscle cells (VSMCs) exerts an important role in the process of AS. In this study, the effects of liraglutide (LIRA) on VSMC under high-glucose condition and its mechanism were explored. Method. After VSMC was treated by high glucose with or without LIRA in vitro, the alkaline phosphatase (ALP) activity was measured by the detection kit, osteogenic marker protein expression was detected by Western blotting, and calcification was determined by alizarin red staining. Subsequently, the DM rat model was established and the ALP activity, calcification, and osteogenic marker proteins were determined in vivo. Immunohistochemical (IHC) staining and hematoxylin-eosin staining were performed on the thoracic aorta of DM rats. Result. The positive rate of SMα-actin expression in the DM + AS group was significantly lower than that in control rats, but LIRA administration increased the positive rate in the model. The expression of Cbfα-1 and OPN in the DM + AS group was significantly higher than that in the control group, while it was decreased after treatment of LIRA. The ALP activity and calcium content were increased in DM + AS rats, and the treatment of LIRA decreased the phenotypes in the rats, so as to delay the progression of AS in DM rats. Meanwhile, LIRA inhibited the ALP activity, upregulated SM-α expression, and downregulated expression of OPN and Cbfα-1 in VSMC under high-glucose (HG) conditions. Mechanically, HG-enhanced ALP activity, AKT, and ERK phosphorylation were inhibited by LIRA, PI3K antagonist LY294002, or ERK1/2 antagonist PD98059, in which cotreatment of LIRA with LY294002 and PD98059 could further enhance the effect of LIRA on VSMC, and GLP-1R antagonists reversed the phenotypes in the model. LIRA blocked the osteogenic transformation of VSMC through PI3K and ERK1/2 signaling pathways, which can be reversed by GLP-1R antagonists. Conclusion. LIRA inhibited the abnormalities in VSMC calcification mediated by the GLP-1R, which was related to PI3K/Akt and ERK1/2 MAPK pathways. Therefore, the prospect and significance of LIRA in the treatment of DM complicated with AS were clarified.

In diabetic patients, diabetic retinopathy (DR) is the leading cause of blindness and seriously affects the quality of life. However, current treatment methods of DR are not satisfactory. Advances have been made in understanding abnormal protein interactions and signaling pathways in DR pathology, but little is known about epigenetic regulation. Non-coding RNAs, such as circular RNAs (circRNAs), have been shown to be associated with DR. In this review, we summarized the function of circRNAs and indicated their roles in the pathogenesis of DR, which may provide new therapeutic targets for clinical treatment.

Retinal pericyte migration occurs in the early stage of diabetic retinopathy (DR), which is one of the important causes of pericyte loss. Autophagy has been found to play essential roles in the regulation of many types of cell migration. In this study, we explored the relationship between autophagy and retinal pericyte migration. In diabetic rats, the retinas became thinner, and the level of autophagy in each cell layer increased. In the primary culture of bovine retinal pericytes, we found that advanced glycation end products (AGEs) increased the migratory cell ability without influencing cell viability, which also increased the phosphorylation of focal adhesion kinase (FAK) and the expression of matrix metalloproteinase (MMP)-2 and decreased the expression of vinculin. AGEs-induced retinal pericyte autophagy and the inhibition of autophagy with chloroquine significantly inhibited cell migration, reversed AGEs-induced FAK phosphorylation, and changed vinculin and MMP-2 protein expression. These results provide a new insight into the migration mechanism of retinal pericytes. The early control of autophagy has a potential effect on regulating pericyte migration, which may contribute to keeping the integrity of retinal vessels in DR.

This systematic review and meta-analysis was conducted to identify if long-term bosentan is an effective and safe treatment for pulmonary arterial hypertension (PAH) regardless of type, including idiopathic PAH (IPAH), and PAH associated with congenital heart disease (APAH-CHD), connective tissue disease (APAH-CTD), and human immunodeficiency virus (APAH-HIV). All relevant observations were systematically searched by two independent investigators and obtained from three databases, including PubMed, EMBASE and the Cochrane Library, from the inception of each database to February 2020. Currently, long-term administration was defined as no less than 12 months. A random-effects or fixed-effects model was selected according to outcomes of the heterogeneity test for meta-analysis, where standardized mean difference (SMD) with 95% confidence intervals (CIs) was used for continuous outcomes, in addition to the estimated effect (ES; 95% CI) for the synthesized survival rate. Furthermore, subgroup analysis was applied to analyze the differences of efficacy and survivals in each type of PAH cohort. Fifteen studies including a total of 659 subjects undergoing oral bosentan administration for at least 12 months were pooled in this quantitative review. Meta-analysis and subgroup analysis indicated that significant clinical benefits existed, including an improved 6-min walk distance (6MWD) and functional class (FC), in patients with APAH-CHD (6MWD: SMD 0.72, 95% CI 0.52–0.93, p

Background and aims: Obesity often coexists with diabetes has been recognized as a risk factor for diabetic complications. Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes, and the metabolic syndrome (MetS) is one of the most common symptoms of diabetes. The purpose of this study was to explore the relationship between DR and some induces, including NC, CVAI, PWNC and so on; as well as the relationship between DR and MetS.Methods: From 2018 to 2019, a total of 562 diabetics from the Hulan District of Harbin, Heilongjiang, were selected and completed a questionnaire survey. The questionnaire included basic patient information, anthropometric parameters, blood pressure, biochemical parameters and fundus photography results.Results: In both men and women, a one standard deviation (SD) increase in NC、CVAI and PWNC was not associated with the prevalence of DR (P>0.05). However, in both men and women, a one SD increase in NC、CVAI and PWNC was significantly associated with the prevalence of MetS (P0.05).Conclusions: NC, CVAI and PWNC are associated with the prevalence of MetS. NC in men and CVAI in women had the largest area under the ROC curve compared to the other induces, which may be convenient and valuable anthropometric measurements for early prevention of MetS. However, these induces had no association with DR and there is no relationship between DR and MetS.

Background: A number of researches have reported that thyroid hormones are associated with obesity. However, the relationship of serum levels of thyroid hormones in the normal range with o...

Objective We investigated the prevalence of abnormal thyroid function and depression in centrally obese participants, and to analyze the relationship of thyroid hormones and depression with components of central obesity. Methods We randomly selected 858 centrally obese participants and 500 non-obese controls in this study. For all participants, we measured serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), body mass index (BMI), waist–hip ratio (WHR), fasting blood glucose and insulin, homeostasis model assessment of insulin resistance (HOMA-IR), lipid concentrations, and blood pressure. Depression was assessed using the Center for Epidemiological Studies-Depression (CES-D) scale. Results Centrally obese participants had a higher prevalence of hypothyroidism and depression than non-obese controls. Serum FT4 levels negatively correlated with BMI and serum TSH levels and positively correlated with BMI, WHR, total triglycerides (TG), total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C). After excluding participants with hypothyroidism and hyperthyroidism, serum FT4 levels showed negative correlation and serum TSH levels showed positive correlation with BMI in the remaining centrally obese participants. CES-D scores positively correlated with BMI. Conclusion We found high prevalences of hypothyroidism and depression among centrally obese participants. FT4 and TSH are important in weight regulation. Depression positively correlated with obesity.

Objective. To evaluate the safety and efficacy of interventional care in pediatric hemoptysis for anomalous bronchial arteries (BAs) and to identify the potential factors resulting in hemoptysis recurrence. Methods. 20 children complained of hemoptysis were diagnosed with anomalous BAs. All patients received transcatheter plug occlusion in Department of Cardiology, Children’s Hospital of Chongqing Medical University. The safety and efficacy were evaluated according to clinical symptoms and images monitoring of enrolled subjects grouped as recurrence group and nonrecurrence group. The potential factors causing hemoptysis recurrence were reviewed and summarized. Results. No deaths were recorded in a follow-up. Otherwise, hemoptysis recurrence was found in 8 subjects for 14 times, accounting for about 40%. Compared with nonrecurrence group, it indicated a statistical significance in hemoglobin levels (P=0.049), mycoplasma pneumonia particle assays (MP-PA) titers (P=0.030), and number of anomalous BAs (P=0.020). Meanwhile, 50% recurrent scenarios were associated with a respiratory infection by microbiological assessment before transcatheter plug occlusion. The repeat occlusion was applied for unclosed BAs leading to visual recurrent hemoptysis, the average interval time of which was 5.4 ± 3.6 mon. Conclusion. The data from this retrospective study have shown that transcatheter plug occlusion is a relatively safe procedure with a low mortality. The number of abnormal BAs has been identified as a highly significant predictor of recurrence, and the role of MP and other potential factors should be verified in a multicenter, larger sample size, and randomized controlled trial.

Microglia, the main immune cell of the central nervous system (CNS), categorized into M1-like phenotype and M2-like phenotype, play important roles in phagocytosis, cell migration, antigen presentation, and cytokine production. As a part of CNS, retinal microglial cells (RMC) play an important role in retinal diseases. Diabetic retinopathy (DR) is one of the most common complications of diabetes. Recent studies have demonstrated that DR is not only a microvascular disease but also retinal neurodegeneration. RMC was regarded as a central role in neurodegeneration and neuroinflammation. Therefore, in this review, we will discuss RMC polarization and its possible regulatory factors in early DR, which will provide new targets and insights for early intervention of DR.

GLP-1 analogs have been widely used to treat patients with type 2 diabetes in recent years and studies have found that GLP-1 analogs have multiple organ benefits. However, the role of GLP-1 analogs in diabetic retinopathy (DR), a common complication of diabetes mellitus (DM), remains controversial. Retinal ganglion cells (RGCs) are the only afferent neurons responsible for transmitting visual information to the visual center and are vulnerable in the early stage of DR. Protection of RGC is vital for visual function. The incretin glucagon-like peptide-1 (GLP-1), which is secreted by L-cells after food ingestion, could lower blood glucose level through stimulating the release of insulin. In the present study, we evaluated the effects of GLP-1 analog on RGCs both in vitro and in vivo. We established diabetic rat models in vivo and applied an RGC-5 cell line in vitro. The results showed that in high glucose conditions, GLP-1 analog alleviated the damage of RGCs. In addition, GLP-1 analog prevented mitophagy through the PINK1/Parkin pathway. Here we demonstrated the neuroprotective effect of GLP-1 analog, which may be beneficial for retinal function, and we further elucidated a novel mechanism in GLP-1 analog-regulated protection of the retina. These findings may expand the multi-organ benefits of GLP-1 analogs and provide new insights for the prevention of DR.

Background. Diabetic retinopathy (DR) is the most important manifestation of diabetic microangiopathy. It is essential to explore the gene regulatory relationship and genomic variation disturbance of biological networks in DR progression. Methods. In this study, we constructed a comprehensive lncRNA-mRNA ceRNA network of DR procession (CLMN) and explored its topological characteristics. Results. Modular and functional analysis indicated that the organization of CLMN performed fundamental and specific functions in diabetes and DR pathology. The differential expression of hub ceRNA nodes and positive correlation reveals the highly connected ceRNA regulation and important roles in the regulating of DR pathology. A large proportion of SNPs in the TFBS, DHS, and enhancer regions of lncRNAs will affect lncRNA transcription and further cause expression variation. Some SNPs were found to disrupt the lncRNA functional elements such as miRNA target binding sites. These results indicate the complex nature of genotypic effects in the disturbing of CLMN and further contribute to gene expression variation and different disease phenotypes. Conclusion. The identification of individual genomic variations and analysis of biological network disturbance by these genomic variations will help provide more personalized treatment plans and promote the development of precision medicine for DR.

Hepatic gluconeogenesis plays an important role in maintaining the body’s glucose metabolism homeostasis. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases, when combined with type 2 diabetes mellitus (T2DM), it can cause severe glucose metabolism disorders. Studies have confirmed that chronic liver inflammatory lesions are the basis of T2DM combined with NAFLD (T2DM–NAFLD), inhibiting liver inflammation can improve glucose metabolism disorders. It is essential to explore safe and effective drugs to inhibit liver inflammation to improve the body’s glucose metabolism disorders. Bicyclol is a biphenyl derivative that has anti-oxidative and anti-inflammatory properties. In the present study, the hepatoprotective effects and underlying mechanisms of bicyclol in T2DM–NAFLD were investigated, and T2DM–NAFLD with/without bicyclol treatment models were established. The results revealed that bicyclol alleviated fasting blood glucose, serum transaminase levels, insulin resistance, hepatic adipogenesis, lipid accumulation and markedly reduced T2DM–NAFLD rat histological alterations of livers. Not only that, bicyclol markedly attenuated T2DM–NAFLD induced production of inflammation factors (IL-1β and TNF-α). Moreover, bicyclol suppressed the expression of insulin/gluconeogenesis signaling pathway (Akt, PGC-1α and PEPCK). These findings suggested that bicyclol might be a potentially effective drug for the treatment of T2DM–NAFLD and other metabolic disorders.

Introduction: P2X7R excitation-interrelated NLRP3 inflammasome activation induced by high glucose contributes to the pathogenesis of diabetic retinopathy (DR). Relaxin-3 is a bioactive peptide with a structure similar to insulin, which has been reported to be effective in diabetic cardiomyopathy models in vivo and in vitro. However, it is not known whether relaxin-3 has a beneficial impact on DR, and the underlying mechanisms of the effect are also remain unknown.Methods and Results: The retinas of male streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats were characterized. Human retinal microvascular endothelial cells (HRMECs) were used to evaluate the anti-inflammatory, antiapoptotic, antipyroptotic and anti-migration effects of H3 relaxin by transmission electron microscopy, wound-healing assay, transwell assay, flow cytometry, cytokine assays and western-blot analysis. After H3 relaxin treatment, changes of the ultrastructure and expression of NLRP3 inflammasome related proteins in the retinas of rats were compared with those in the diabetic group. In vitro, H3 relaxin played a beneficial role that decreased cell inflammation, apoptosis, pyroptosis and migration stimulated by advanced glycation end products (AGEs). Moreover, inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury that similar to the effects of H3 relaxin. H3 relaxin suppressed the stimulation of apoptosis, pyroptosis and migration of HRMECs in response to AGEs mediated by P2X7R activation of the NLRP3 inflammasome.Conclusion: Our findings provide new insights into the mechanisms of the inhibitory effect of H3 relaxin on AGE-induced retinal injury, including migration, apoptosis and pyroptosis, mediated by P2X7R-dependent activation of the NLRP3 inflammasome in HRMECs.

Retinal pericyte migration represents a novel mechanism of pericyte loss in diabetic retinopathy (DR), which plays a crucial role in the early impairment of the blood-retinal barrier (BRB). Glucagon-like peptide-1 (GLP-1) has been shown to protect the diabetic retina in the early stage of DR; however, the relationship between GLP-1 and retinal pericytes has not been discussed. In this study, advanced glycation end products (AGEs) significantly increased the migration of primary bovine retinal pericytes without influencing cell viability. AGEs also significantly enhanced phosphatidylinositol 3-kinase (PI3K)/Akt activation, and changed the expressions of migration-related proteins, including phosphorylated focal adhesion kinase (p-FAK), matrix metalloproteinase (MMP)-2 and vinculin. PI3K inhibition significantly attenuated the AGEs-induced migration of retinal pericytes and reversed the overexpression of MMP-2. Glucagon-like peptide-1 receptor (Glp1r) was expressed in retinal pericytes, and liraglutide, a GLP-1 analog, significantly attenuated the migration of pericytes by Glp1r and reversed the changes in p-Akt/Akt, p-FAK/FAK, vinculin and MMP-2 levels induced by AGEs, indicating that the protective effect of liraglutide was associated with the PI3K/Akt pathway. These results provided new insights into the mechanism underlying retinal pericyte migration. The early use of liraglutide exerts a potential bebefical effect on regulating pericyte migration, which might contribute to mechanisms that maintain the integrity of vascular barrier and delay the development of DR.

For a long time, diabetic retinopathy (DR) has been one of the most severe complications of diabetes. The early treatment of DR is not clearly recognized. The additional benefit of hypoglycemic agents for DR has become a new research field. Glucagon-like peptide-1 receptor (GLP-1R) has been shown to be widely expressed in tissues including retina. Glucagon-like peptide-1 receptor agonists (GLP-1RA) have been generally used in the treatment of diabetic patients. Studies shows that GLP-1RA could inhibit nerve damage by decrease apoptosis of nerve cells and activation of glial cells. In addition, GLP-1RA plays a protective role for tight junction (TJ) and cells of blood retinal barrier (BRB). It also protects retina from BRB damage. In this review, we discuss the potential protective mechanisms of GLP-1RA for DR beyond the hypoglycemic effects.

Astragaloside IV is the main active compound of Astragalus membranaceus. Astragaloside IV has strong anti-oxidative activities and protective effects against progression of peripheral neuropathy. In this study, we determined whether astragaloside IV protects retinal ganglion cells (RGC) from oxidative stress injury using the rat RGC-5 cell line. Hydrogen peroxide (H2O2) was used to induce oxidative stress injury, with the protective effect of astragaloside IV examined. Cell Counting Kit-8 and 4′,6-diamidino-2-phenylindole staining showed that astragaloside IV increased cell survival rate and decreased apoptotic cell number. Flow cytometry showed that astragaloside IV decreased H2O2-induced reactive oxygen species levels. While laser confocal microscopy showed that astragaloside IV inhibited the H2O2-induced decrease of mitochondrial membrane potential. Western blot assay showed that astragaloside IV reduced cytochrome c release induced by H2O2, inhibited Bax and caspase-3 expression, and increased Bcl-2 expression. Altogether, these results indicate that astragaloside IV has potential protective effects against H2O2-induced oxidative stress in retinal ganglion cells.

Backgroud In the early stage of diabetic retinopathy, the damage of retinal ganglion cells already exists, promoting the development of the disease. The aim of this study was to investigate the protective role and the mechanisms of obestatin against H2O2-induced damage in RGC-5 cells. Methods RGC-5 cells were incubated with various concentrations of obestatin for 24h before H2O2 added. The survival rates of RGC-5 were measured by MTT assay. The expression of apoptosis-related proteins and TrkB pathway-related proteins were detected by Western blot analysis. Results Our data showed that H2O2 evidently decreased the survival rate of RGC-5 cells. However, obestatin pretreatment reversed the decreased activity. Moreover, obestatin effectively increased the expression of Bcl-2 and decreased the expression of Bax. In addition, obestatin potentially plays a role in protecting RGC-5 by activating of TrkB. Obestatin notablely increased the phosphorylation of TrkB, AKT and ERK1/2. All these effects of obestatin can be inhibited by GLP-1R antagonist exendin (9-39). Conclusions Obestatin prevents H2O2-induced damage in RGC-5 cells by activating TrkB pathway. Moreover, GLP-1R is closely related to the function of obestatin in RGC-5 cells.

Retinal ganglion cells (RGCs), which exist in the inner retina, are the retinal neurons which can be damaged in the early stage of diabetic retinopathy (DR). Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, exerts biological functions by binding the receptor (GLP-1R), the expression of which in RGC-5 cells was first shown by our team in 2012. It was reported that liraglutide prevented retinal neurodegeneration in diabetic subjects. However, the involvement of mechanisms such as autophagy and mitochondrial balance in liraglutide-induced retinal protection is unknown. Here, we aimed to investigate the protective effects of liraglutide and explore the potential mechanisms of liraglutide-induced retinal RGC protection. RGC-5 cells were treated with H2O2 and/or liraglutide. Cell viability was detected with the CCK-8 kit. The axon marker GAP43, autophagy and mitophagy indicators LC3A/B, Beclin-1, p62, Parkin, BCL2/Adenovirus E1B 19kDa protein-interacting protein 3-like (BNIP3L) and the key regulator of mitochondrial biogenesis PGC-1α were examined via western blot analysis. Autophagy was also evaluated using the ImageXpress Micro XLS system and transmission electron microscopy (TEM). Reactive oxygen species (ROS), mitochondrial membrane potential and fluorescent staining for mitochondria were also measured using the ImageXpress Micro XLS system. Our results showed that pretreatment with liraglutide significantly prevented H2O2-induced cell viability decline, mitochondrial morphological deterioration and induction of autophagy, which appeared as increased expression of LC3 II/I and Beclin-1, along with p62 degradation. Moreover, liraglutide suppressed the H2O2-induced decline in GAP43 expression, thus protecting cells. However, rapamycin induced autophagy and blocked the protective process. Liraglutide also provided mitochondrial protection and appeared to alleviate H2O2-induced ROS overproduction and a decline in mitochondrial membrane potential, partially by promoting mitochondrial generation and attenuating mitophagy. In conclusion, liraglutide attenuates H2O2 induced RGC-5 cell injury by inhibiting autophagy through maintaining a balance between mitochondrial biogenesis and mitophagy.

Diabetic retinopathy(DR)is one of the complications of diabetes which could cause severe vision loss. Retinal ganglion cell(RGC)injury has been confirmed prior to micro-vascular damage. Over the past few decades, a number of animal and clinical studies have confirmed that RGC impairment leads to an early deterioration of vision in DR. Inhibition of aldose reductase (AR), advanced glycation end product (AGE), oxidative stress, glutamate toxicity, and an inflammatory response may play important roles in protecting RGCs in DR. Furthermore, nicotinamide mononucleotide adenylyl transferase-1 (Nmnat1), neurotrophins and neurotrophic factors may become new therapeutic targets. Photobiomodulation (PBM) may be used as adjunctive therapy in protective treatment of RGCs. In this review, we highlight and discuss protective treatments and their targets which have shown great promise for treatment of RGC injury in DR.

Physical health has a direct relationship with digestive function. Any abnormalities in the link may cause malnutrition, endocrine disorders, and the decline of organ functions. Obestatin, a biologically active peptide, is encoded by the ghrelin gene. Most studies suggest that obestatin is a pleiotropic peptide, which acts by suppressing the motility of the gastrointestinal tract, regulating the secretion of insulin, reducing inflammation and apoptosis, and promoting proliferation. These characteristics suggest that obestatin may represent an efficient way to prevent the occurrence and development of some digestive diseases. However, the functions of obestatin are not clear, and even appear to be contradictory. The aim of this review was to discuss the close relationship between obestatin and the digestive system, and to provide a unique perspective for the future development of obestatin relative to digestive diseases.

Non-alcoholic steatohepatitis (NASH) is a key step in the progression of non-alcoholic fatty liver disease (NAFLD), which causes serious health problems worldwide. The nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor-containing pyrin domain 3 (NLRP3) inflammasome and pyroptosis play crucial roles in the progression of NASH. Our team has provided clinical evidence of the effects of glucagon-like peptide-1 (GLP-1) on the improvement in liver function and histological resolution of NAFLD. Preliminary work has demonstrated that GLP-1 inhibited NLRP3 inflammasome activation in a mouse model of NAFLD. We further explored the potential molecular mechanisms underlying the anti-inflammatory effect of liraglutide, a long-acting GLP-1 analog, in the treatment of NASH. We established a HepG2 cell model of NASH using double stimulation with palmitic acid and lipopolysaccharide to assess NLRP3 inflammasome and pyroptotic cell activity and to evaluate mitochondrial function and mitophagy. Liraglutide reduced lipid accumulation, inhibited NLRP3 inflammasome and pyroptosis activation, attenuated mitochondrial dysfunction and reactive oxygen species generation, augmented mitophagy in hepatocytes. Mitophagy inhibition with 3-methyladenine/PINK1-directed siRNA weakened the liraglutide-mediated suppression of inflammatory injury. We propose that liraglutide suppresses NLRP3 inflammasome-induced hepatocyte pyroptosis via mitophagy to slow the progression of NASH.

Background: It is commonly reported a limitation of therapeutic strategy in Eisenmenger syndrome (ES) historically. This qualitative systematic review is conducted to evaluate the safety and efficacy of pulmonary arterial hypertension-specific drug therapy (PAH-SDT) for ES patients for a clinical therapeutic strategy based on evidence. Methods: PubMed, EMBASE, and the Cochrane Library databases have been systematically reviewed up to January 2019. Two reviewers independently conducted a literature search, quality evaluation, and data extraction. The occurrence of death, deterioration, and adverse events (AEs) has respectively been described as a count or percentage. Meta-analysis was conducted by Stata 15.1, and weighted mean differences (WMD) with 95% confidence intervals (CI) were recorded for continuous data. Randomized-effect model or fixed-effect model was applied according to the heterogeneity test. Results: Fifteen citations recruiting 456 patients associated with ES were eventually pooled, which involved 4 RCTs, 6 prospective studies, and 5 retrospective studies. Within the first year, it indicated PAH-SDT significantly ameliorated exercise capacity in 6-minute walk distance (6MWD) (I2 = 60.5%; WMD: 53.86 m, 95% CI [36.59, 71.13], P

Diabetic retinopathy (DR) is the leading cause of visual impairment and acquired blindness among adults worldwide. Retinal microvascular pericyte deficiency is one of the earliest pathological changes associated with DR, and long noncoding RNA myocardial infarction-associated transcript (MIAT) has been implicated as a crucial regulator of microvascular dysfunction in DR. Pyroptosis is a caspase-1-dependent proinflammatory form of cell death, and in the present study, we investigated the potential pyroptosis of primary human retinal pericytes (HRPCs) and the mechanism by which MIAT is involved in this process. We applied advanced glycation end product modified bovine serum albumin (AGE-BSA) to simulate the DR environment. The results suggested that AGE-BSA induced the active cleavage of caspase-1 and gasdermin D, the release of IL-1β, IL-18 and LDH, and reduced cell viability, which was prevented by the inhibition of caspase-1, indicating the occurrence of caspase-1-mediated pyroptosis in HRPCs. Immunofluorescence images revealed the phenotypic characteristics of pyroptosis, including pyknosis, swelling and hyperpermeability in plasmolemma. MIAT and CASP1 expression were substantially increased, while that of miR-342-3p was decreased in AGE-BSA-treated HRPCs. MIAT knockdown inhibited pyroptosis in HRPCs, which was reinforced by cotreatment with miR-342-3p mimic but relieved by cotreatment with miR-342-3p inhibitor. Furthermore, HRPC pyroptosis was inhibited by treatment with the miR-342-3p mimic alone but enhanced by the miR-342-3p inhibitor. Luciferase reporter assay results demonstrated binding between MIAT and miR-342-3p, as well as between miR-342-3p and CASP1. MIAT antagonized the effect of miR-342-3p on the depression of its target CASP1 and promoted AGE-BSA-induced pericyte pyroptosis. These findings may promote a better understanding of retinal pericyte depletion pathogenesis and the development of new therapeutic strategies for the treatment of diabetic retinopathy.

Supplemental Digital Content is available in the text, Background: Oral bosentan has been widely applied in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). A systemic review and meta-analysis was conducted for a therapeutic evaluation of oral bosentan in both adult and pediatric patients with PAH-CHD. The acute responses and a long-term effect were respectively assessed in a comparison with baseline characteristics, and the improvement of exercise tolerance was analyzed. Methods: PubMed, Medline, Embase, and Cochrane Central Register of clinical controlled trails or observational studies have been searched for a recording of bosentan effects on the PAH-CHD participants. For mortality and rate of adverse events (AEs), it was described in detail. Randomized-effects model or fixed-effects model was used to calculate different effective values with a sensitivity analysis. Results: Seventeen studies were pooled in this review, and 3 studies enrolled the pediatric patients. Among all studies, 456 patients were diagnosed with PAH-CHD, and 91.7% were treated with oral bosentan. With a term less than 6 months of bosentan therapy, there existed a significant improvement in 6-minute walk distance (6MWD) and the World Health Organization functional class (WHO-FC), but no such differences in Borg dyspnea index scores (BDIs) and the resting oxygen saturation (SpO2). Although with a prolonged treatment, not only 6MWD and FC, but also the resting SpO2 and heart rate were changed for a better exercise capability. Additionally, compared with the basic cardiopulmonary hemodynamics, it showed a statistically significant difference in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRi). Although a limitation of pooled studies with comparative outcomes of different terms, outcomes presented a lower WHO-FC which contributes to a success in a prolonged treatment. Conclusions: Bosentan in PAH-CHD is well established and still requires clinical trials for an identification of its efficiency on CHD patients for an optimized period lessening a serious complication and the common AEs.

Notch pathway activation maintains neural stem cells in a proliferating state and increases nerve repair capacity. To date, studies have rarely focused on changes or damage to signal transduction pathways during cerebral hemorrhage. Here, we examined the effect of acupuncture in a rat model of cerebral hemorrhage. We examined four groups: in the control group, rats received no treatment. In the model group, cerebral hemorrhage models were established by infusing non-heparinized blood into the brain. In the acupuncture group, modeled rats had Baihui (DU20) and Qubin (GB7) acupoints treated once a day for 30 minutes. In the DAPT group, modeled rats had 0.15 μg/mL DAPT solution (10 mL) infused into the brain. Immunohistochemistry and western blot results showed that acupuncture effectively inhibits Notch1 and Hes1 protein expression in rat basal ganglia. These inhibitory effects were identical to DAPT, a Notch signaling pathway inhibitor. Our results suggest that acupuncture has a neuroprotective effect on cerebral hemorrhage by inhibiting Notch-Hes signaling pathway transduction in rat basal ganglia after cerebral hemorrhage.

In the early stage of diabetic retinopathy, the damage of retinal ganglion cells already exists, promoting the development of the disease. The aim of this study was to investigate the protective role and the mechanisms of obestatin against HRGC-5 cells were incubated with various concentrations of obestatin for 24h before HOur data showed that HObestatin prevents H

Objective. This study is aimed at investigating whether exenatide (Exe) delays the progression of nonalcoholic fatty liver disease (NAFLD) in C57BL/6 mice by targeting the NLRP3 inflammasome through the autophagy/mitophagy pathway. Methods. Thirty male C57BL/6 mice were randomly divided into three groups: control group (n=10), model group (n=10), and Exe (exenatide) group (n=10). Mouse models of NAFLD and diabetes were established using a high-fat diet and streptozocin. Results. The levels of fasting blood glucose (FBG), total cholesterol (TC), and triglyceride (TG) in the serum were significantly reduced after Exe treatment. The body weight, liver weight/body weight, and number of lipid droplets in the liver significantly decreased in Exe-treated mice. Treatment with Exe markedly reduced the levels of liver lipids, malondialdehyde (MDA), and alanine aminotransferase (ALT) in serum and livers. The number of autophagosomes increased significantly in the Exe group. The expression of LC3A/B-II/I, Beclin-1, Parkin, and BNIP3L increased significantly, whereas NLRP3 and IL-1β proteins were suppressed after Exe treatment. Conclusion. We successfully established a mouse model of NAFLD and diabetes. Exe may reduce oxidative stress injury and inhibit the NLRP3 inflammasome by enhancing the autophagy/mitophagy pathway in liver, which has a protective effect on the liver in NAFLD and diabetes in C57BL/6 mice.

Background The purpose of this study was to evaluate the advantages of exenatide treatment on obesity and non-alcoholic fatty liver disease (NAFLD) with elevated liver enzymes in patients with type 2 diabetes (T2D). Methods A total of 60 newly diagnosed patients with obesity, NAFLD with elevated liver enzymes and T2D were included in the study. The patients were randomly divided into two groups. The exenatide treatment group (n = 30) were treated with exenatide and insulin glargine, and the intensive insulin therapy group (n = 30) were treated with insulin aspart and insulin glargine for 12 weeks. Selected clinical characteristics were determined, and ultrasonography was performed at both baseline and 12 weeks following treatment. Results At baseline, the clinical characteristics were matched between the two groups. After 12 weeks, fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG) and total bilirubin levels were significantly decreased in the two groups (p

Retinal ganglion cells (RGCs) are the only afferent neurons that can transmit visual information to the brain. The death of RGCs occurs in the early stages of glaucoma, diabetic retinopathy, and many other retinal diseases. Autophagy is a highly conserved lysosomal pathway, which is crucial for maintaining cellular homeostasis and cell survival under stressful conditions. Research has established that autophagy exists in RGCs after increasing intraocular pressure (IOP), retinal ischemia, optic nerve transection (ONT), axotomy, or optic nerve crush. However, the mechanism responsible for defining how autophagy is induced in RGCs has not been elucidated. Accumulating data has pointed to an essential role of reactive oxygen species (ROS) in the activation of autophagy. RGCs have long axons with comparatively high densities of mitochondria. This makes them more sensitive to energy deficiency and vulnerable to oxidative stress. In this review, we explore the role of oxidative stress in the activation of autophagy in RGCs, and discuss the possible mechanisms that are involved in this process. We aim to provide a more theoretical basis of oxidative stress-induced autophagy, and provide innovative targets for therapeutic intervention in retinopathy.

Exendin-4 is a peptide resembling glucagon-like peptide-1 (GLP-1), which has protective effects on nerve cells. However, the effects of Exendin-4 on retinal ganglion cells (RGC) are still under clear. The purpose of the present study is to demonstrate that exenatide prevents high- or low-glucose-induced retinal ganglion cell impairment. We observed the expression of GLP-1R in RGC-5 cells by immunofluorescence and Western blot. To investigate the effect of exenatide on RGC-5 cells incubated different glucose concentrations, CCK-8 measured the survival rates and electron microscopy detected cellular injury. The expression levels of Bcl-2 and Bax were analyzed by immunocytochemistry and Western blot. Exenatide protects RGC-5 from high- or low-glucose-induced cellular injury and the optimum concentration was 0.5μg/ml. Exenatide can inhibit high- or low-glucose-induced mitochondrial changes. Exenatide protects RGC-5 from high- or low-glucose-induced Bax increased and Bcl-2 decreased. Furthermore, the protective effect of exenatide could be inhibited by Exendin (9-39). These findings indicate that exenatide shows a neuroprotective effect for different glucose concentrations-induced RGC-5 cells injury. Exenatide could protect RGC-5 cells from degeneration or death, which may protect retinal function and have a potential value for patients with diabetic retinopathy.

Exenatide (exendin-4 analogue) is widely used in clinics and shows a neuroprotective effect. The main objectives of the present study were to prove that retinal ganglion cells (RGC-5) express GLP-1R, to ascertain whether exenatide prevents a high-glucose-induced RGC-5 impairment, to determine the appropriate concentration of exenatide to protect RGC-5 cells, and to explore the neuroprotective mechanisms of exenatide. Immunofluorescence and Western blot analyses demonstrated that RGC-5 cells express GLP-1R. We incubated RGC-5 cells with 25 mM glucose prior to incubation with either 25 mM glucose, 55 mM glucose (high), high glucose plus exenatide or high glucose plus a GLP-1R antagonist. The survival rates of the cells were measured by CCK-8, and cellular injury was detected by electron microscopy. There were statistical differences between the high-glucose group and the control group (P

Rationale Familial hypercholesterolemia (FH) is a common inherited cause of coronary heart disease (CHD) and premature death in an early age. Nevertheless, an ischemic heart failure (IHF) associated with FH seems to be rare, and an early diagnosis and therapy could influence the prognosis. Patient concerns In this 13-year-old girl, multiple xanthomas began to develop from the first day of birth. Until June, 2017, she was admitted to our center due to edema, oliguria, and dyspnea during exertion, which was attributed to a recent respiratory infection. Diagnosis Homozygous FH (HoFH), CHD, and IHF. Interventions The patient has been treated with statin, ezetimibe, aspirin, and traditional heart failure (HF) medications. In addition, the beta-blocker was simultaneously administered. Outcomes Genotypes of this proband indicated homozygous mutations of low-density lipoprotein receptor (LDLR) and some co-segregated mutations, such as von Willebrand factor (VWF) and fibroblast growth factor receptors. At 6-month follow-up, we found a decreased level of plasma lipid profile, in addition to a significant improvement in 6-minute walk distance and functional class. Echocardiography indicated nonsignificant improvements in the structure and function of the heart. Lessons This case report indicates that HoFH can lead to dramatically progressive endothelial damages and ventricular remodeling, severe atherosclerosis, even IHF. Genetic outcomes indicate IHF with HoFH could possibly result from LDLR mutations and some co-segregated mutations influencing endothelial function and cardiovascular remodeling. In a short-term follow-up, a combination of statins, ezetimibe, aspirin, and traditional HF agents is safe and effective for IHF with HoFH, and there is a need for further identification of drugs to ameliorate endothelial function and cardiovascular remodeling which may play an important role in long-term treatment.

Men with type 2 diabetes (T2D) and obesity are often characterised by low testosterone (T). We aimed to determine whether exenatide (EXE) combined metformin (MET) treatment has a better effect on serum total testosterone (TT) levels than glimepiride (GLI) combined MET treatment in men with T2D and obesity. In a multicentre, 12-week observational study, 176 obese T2D men with failed glycaemic control were included in the study: ninety men (mean age, 43.00 ± 8.50 years) in EXE + MET group and 86 men (mean age, 44.00 ± 7.00 years) in GLI + MET group. Serum TT levels were more significantly increased in EXE + MET group than GLI + MET group (121.72 ± 56.73 ng/dl versus 34.67 ± 16.30 ng/dl). The increasement of TT levels in those patients who lost body weight ≥5% was significantly greater than those who lost weight

Obestatin is a recently discovered gastrointestinal hormone. It might play a role in the pathophysiology of obesity. We tried to investigate the expression of obestatin in gastric body mucosa in overweight (BMI>or=24 kg/m(2))/obese (BMI>or=28 kg/m(2)) patients. Thirty overweight/obese patients and 20 healthy controls were included in the study. Biopsy specimens of gastric mucosa were obtained from the middle body of the greater curvature. Obestatin expression in gastric mucosa was evaluated by immunohistochemistry. Fasting plasma obestatin levels were measured by radioimmunoassay. The number of obestatin-positive cells in gastric body mucosa was significantly lower in overweight and obese patients than that in healthy subjects. The plasma concentrations of obestatin were also decreased in overweight and obese patients. There was a positive correlation between the numbers of obestatin-positive cells in the gastric body mucosa and circulating obestatin levels. The results indicate that overweight and obese subjects have a reduction in the number of obestatin-positive cells in gastric body mucosa.

Objective Ghrelin is a peptide hormone involved in human energy homeostasis. Obestatin is a recently discovered active peptide derived from preproghrelin. It seemed that obestatin was a physiologic opponent of ghrelin. Helicobacter pylori infection may be associated with appetite and nutrition. We compared the plasma ghrelin/obestatin ratio in H. pylori –positive and -negative groups. Methods People undergoing an annual health checkup were included. Helicobacter pylori status was based on serologic and carbon-13 urea breath findings. Fifty adults with H. pylori infection and 50 adults matched by age and body mass index without H. pylori infection were enrolled in this study. Plasma ghrelin and obestatin levels were measured by radioimmunoassay. Results Ghrelin concentrations and ghrelin/obestatin ratios were lower in the H. pylori –positive group than in the H. pylori –negative group. There was no significant difference in circulating obestatin between those with and without H. pylori infection. In all subjects, the ghrelin/obestatin ratio was negatively correlated with body mass index, the homeostasis model of assessment for insulin resistance, and serum levels of triacylglycerol. There was a positive correlation between circulating obestatin and ghrelin levels. Conclusion Helicobacter pylori infection was associated with a reduction in the circulating ghrelin/obestatin ratio in Chinese adults.

Adipokines contribute to the atherosclerotic process, connecting obesity and diabetes to cardiovascular disease. Vaspin is a recently discovered adipokine, so data about the relationship of vaspin to coronary artery disease in type-2 diabetes mellitus (T2DM) is limited. The current study was designed to evaluate the association of vaspin with the presence of coronary artery disease in T2DM.We enrolled 228 patients with T2DM, with or without CAD, between March 2010 and July 2011, and 120 healthy control participants. Serum vaspin, homeostasis model assessment of insulin resistance (HOMA-IR) and other cardiovascular risk factors were assayed.Vaspin levels were significantly increased in patients with T2DM compared to healthy individuals, and were further increased in patients with both T2DM and CAD compared to those with T2DM but without CAD. Moreover, vaspin correlated positively with body mass index, fasting plasma glucose, insulin and HOMA-IR in all patients with T2DM (P0.05). Furthermore, in multivariate logistic regression analysis, vaspin level was associated with the presence of CAD in patients with T2DM.Vaspin correlates with CAD in T2DM.

This study investigated the effect of different insulin concentrations on the activity of vascular endothelial cells (VECs), and the role of PPARγ activator rosiglitazone (RGZ) on the expression of the chemerin receptor, ChemR23, in insulin-treated human umbilical vein endothelial cells (HUVECs).Cell viability was determined in HUVECs treated with different insulin concentrations. Immunofluorescence staining was used to detect ChemR23 expression in insulin-treated HUVECs. Western blot assays were used to evaluate ChemR23 and PPARγ protein expression in insulin-treated HUVECs after pretreatment with PPARγ activator (RGZ) or inhibitor (GW9662).High insulin concentrations significantly inhibited HUVEC cell viability compared to low insulin concentrations, and this inhibition was attenuated by pretreatment with RGZ. High concentrations of insulin caused a significant upregulation of ChemR23 and a significant downregulation of PPARγ. These effects were attenuated by RGZ pretreatment, while PPARγ antagonist, GW9662 reversed this attenuation.ChemR23 upregulation may play a role in VEC damage caused by high concentrations of insulin. The protective effect of PPARγ activation in VECs may be mediated via ChemR23 downregulation.

Summary Benign prostatic hyperplasia (BPH) is a prevalent disease globally, and accumulating evidence has indicated an association between BPH, insulin resistance (IR) and diabetes. Exendin-4 is widely used in clinics, which could enhance the proliferation of pancreatic β cells. The ability of exendin-4 to promote tumorigenesis has been of concern, and whether exendin-4 would enhance the propagation of BPH is not fully understood. We aimed to determine whether glucagon-like peptide-1 receptors (GLP-1Rs) were expressed in rat prostate and to determine the effect of exendin-4 on prostate of BPH. Male Wistar rats were used and assigned to six groups: normal diet (ND), high-fat diet (HFD), HFD + exendin-4, HFD + BPH, HFD + BPH + exendin-4 and HFD + BPH + rosiglitazone group. After castration, steroids were injected subcutaneously for 4 weeks to induce BPH. Rats were kept on high-fat diet to induce IR. Treatment groups were treated with exendin-4 and rosiglitazone. Prostatic index and HOMA-IR index were used to evaluate the prostatic hyperplasia status and the degree of IR respectively. The expression of GLP-1R was indicated not only by immunohistochemistry, but also by Western blot analysis. The expression of GLP-1R was significantly higher, and HOMA-IR index and body weight significantly decreased after administration of exendin-4. However, no significant differences in the prostatic index were observed between exendin-4 treatment groups and non-exendin-4 treatment groups. Prostatic index was not influenced by exendin-4 maybe by improving IR and weight loss.

Diabetic retinopathy (DR) is a leading cause of acquired blindness in adults. Previous research has shown that the apoptosis of retinal ganglion cells(RGCs) plays an important role in the initiation and development of diabetic retinopathy. The positive effect of estrogen on the nervous system is currently attracting increasing attention. In this study, we investigated whether17β-estradiolum (E2) has protective effects on RGCs in a high-glucose environment.The cell survival rates were measured by Cell Counting Kit-8, the apoptosis was detected by flow cytometry, the intracellular reactive oxygen species (ROS) levels were examined by immunofluorescence method, and the intracellular mitochondrial membrane potential was examined by confocal microscopy. The expression levels of cytochrome C, Bcl-2, and Bax were analyzed by Western blot method. The effect of estrogen receptor blocker tamoxifen on the RGCs was also evaluated.It was found that E2 stabilizes the mitochondrial membrane potential, reduces intracellular ROS levels, up-regulates Bcl-2 expression, inhibits Bax expression, decreases the generation of cytochrome C, and finally reduces the apoptosis of RGC-5 cells in a high-glucose environment. These protective functions could be attributed to E2 receptors, which make E2 a prospective patent application candidate in the treatment of DR. Furthermore, when cells were pre-cultured with tamoxifen, we found that tamoxifen inhibited the shielding effects of E2.E2 has a broad application prospect in the treatment of DR.

The purpose of this study was to evaluate the advantages of exenatide treatment on obesity and non-alcoholic fatty liver disease (NAFLD) with elevated liver enzymes in patients with type 2 diabetes (T2D).A total of 60 newly diagnosed patients with obesity, NAFLD with elevated liver enzymes and T2D were included in the study. The patients were randomly divided into two groups. The exenatide treatment group (n = 30) were treated with exenatide and insulin glargine, and the intensive insulin therapy group (n = 30) were treated with insulin aspart and insulin glargine for 12 weeks. Selected clinical characteristics were determined, and ultrasonography was performed at both baseline and 12 weeks following treatment.At baseline, the clinical characteristics were matched between the two groups. After 12 weeks, fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG) and total bilirubin levels were significantly decreased in the two groups (p 0.001). Body weight and waist circumference were significantly decreased in the exenatide group but increased in the intensive insulin group (p 0.001). The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transpeptidase (γGGT) in the exenatide group were significantly lower than in the intensive insulin group (p 0.001). The mean body weight change correlated with the levels of ALT, AST and γGGT change (ALT, r = 0.761; AST, r = 0.733; γGGT, r = 0.752; p 0.001). Moreover, the reversal rate of fatty liver was significantly higher in the exenatide group (93.3%) than the intensive insulin group (66.7%) (p 0.01).Exenatide has a better hepatic-protective effect than intensive insulin therapy and perhaps represents a unique option for adjunctive therapy for patients with obesity, non-alcoholic fatty liver disease with elevated liver enzymes and T2D.