Autophagy Modulates the Migration of Retinal Pericytes Induced by Advanced Glycation End Products.

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.

Effects of oral targeted treatments in pulmonary arterial hypertension: A systematic review and meta-analysis.

Background: Although pulmonary arterial hypertension (PAH) is a fatal disease, specific drugs have been used to treat PAH. These drugs predominantly target these three pathobiological pathways: Endothelin receptor antagonist (ERA), nitric oxide (NO), and prostanoids pathways. In this review, we aimed to analyze the efficacy and safety of oral targeted treatments for PAH. Methods: The national library of medicine (MEDLINE), excerpta medica database (EMBASE), and Cochrane Central Register of Controlled Trials databases were searched. Randomized controlled trials that compared the oral targeted drugs with placebos were selected. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) for variables with dichotomous outcomes, and standardized mean differences with continuous outcomes variables. Additionally, the mean of the differences for the 6-min walk distance (6MWD) was analyzed. Results: In total, 23 studies involving 7,121 patients were included in this study. These studies show that orally PAH-specific drugs could decrease the risk of clinical worsening events, with an OR of 0.55 (p < 0.001). Furthermore, these drugs could improve exercise capacity, showing a 21.74-m increase in 6MWD (95% CI: 17.53-25.95 m) and cause a greater amelioration of functional class (OR = 0.60, 95% CI: 0.47-0.76). Additionally, subgroup analysis indicated that compared with placebo, ERAs, and drugs in the NO pathway were most effective and safe, which are associated with an improvement in exercise capacity, 6MWD, and worsening events-free survival rate. Conclusion: Nitric oxide exhibited the most prominent clinical effect on exercise tolerance. However, in the subgroup analysis, oral targeted drugs of different pathways show applicability to different populations, which highlights the need for precise treatment in the clinical setting. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=297946], identifier [CRD 42022297946].

Liraglutide Alleviates Diabetic Atherosclerosis through Regulating Calcification of Vascular Smooth Muscle Cells.

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.

Exenatide Attenuates Non-Alcoholic Steatohepatitis by Inhibiting the Pyroptosis Signaling Pathway.

Background/Aims: Exenatide is a glucagon-like polypeptide-1 analog, whose main clinical use is to treat type 2 diabetes. However, the mechanism of exenatide in mitigating non-alcoholic steatohepatitis (NASH) remains unclear. This study aimed to investigate the in vitro and in vivo effect of exenatide on NASH. Methods: Leptin receptor-deficient C57BL/KsJ- db/db male mice were fed with methionine-choline-deficient (MCD) diet for 4 weeks to induce NASH, while oleic acid/LPS-treated HepG2 cells were used as an in vitro cell model. Exenatide (20 µg/kg/day, subcutaneous) and specific exenatide inhibitors (20 µg/kg/day, intraperitoneal) were used to determine the effects of exenatide on NASH. Results: Exenatide treatment inhibited the pyroptosis signaling pathway to attenuate NASH. Conclusion: To the best of our knowledge, this report provides the first evidence showing that exenatide attenuated NASH by inhibiting the pyroptosis signaling pathway. Exenatide thus has important pathophysiological functions in NASH and may represent a useful new therapeutic target.

Retinal microglia polarization in diabetic retinopathy.

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.

Circular RNAs: Novel target of diabetic retinopathy.

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.

Efficacy and Safety of Long-Term Oral Bosentan in Different Types of Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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 < 0.0001; functional benefits: 50.4%, 95% CI 43.7-57.1%), APAH-HIV (6MWD: SMD 0.83, 95% CI 0.36-1.30, p = 0.001; functional benefits: 80.4%), and IPAH (SMD 0.54, 95% CI 0.28-0.80, p < 0.0001; functional benefits: 61.4%, 95% CI 54.2-68.5%), but a non-significant change in APAH-CTD (6MWD: SMD 0.18, 95% CI - 0.60 to 0.95, p = 0.656; functional benefits: 27.5%). Furthermore, among the hemodynamic parameters, long-term bosentan led to a significant decrease in mean pulmonary artery pressure (SMD - 0.86, p < 0.0001) in APAH-CTD, and a decrease in pulmonary vascular resistance (SMD - 0.65, p < 0.0001) and elevated oxygen saturation (SMD 0.30, p = 0.006) in APAH-CHD. Importantly, in all pooled studies, the overall survival indicated 1-, 2-, and 3-year survival rates of 94.3%, 88.8%, and 81.7%, respectively, in all-cause PAH, and subgroup analysis demonstrated a relative decreasing trend in patients with HIV, from a 2-year survival of 89.8% to a 3-year survival of 66.1%. Adverse drug reactions were relatively mild. CONCLUSION: In this systematic review and meta-analysis, long-term administration of oral bosentan has been identified as a well-tolerated and effective agent in different types of PAH. In addition, we conclude that long-term oral bosentan should be considered for patients with CTD to achieve a satisfactory exercise capacity, and for those with APAH-HIV to improve survivals, where more attention on adverse events is required.

Neuroprotective Role of GLP-1 Analog for Retinal Ganglion Cells via PINK1/Parkin-Mediated Mitophagy in Diabetic Retinopathy.

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.

Potential Factors Affected Safety and Efficacy of Transcatheter Plug Closure for Pediatric Hemoptysis with Anomalous Bronchial Arteries.

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.

Associations Between Thyroid Hormones Within the Euthyroid Range and Indices of Obesity in Obese Chinese Women of Reproductive Age.

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 obesity and parameters of obesity in women of childbearing age remains controversial. The purpose of this study was to examine serum levels of thyroid hormones within the normal range in obese Chinese women of reproductive age and to investigate the relationship between concentration of thyroid hormones and indices of obesity, including body mass index (BMI), waist-to-hip ratio (WHR), insulin resistance, blood glucose, blood lipids, and blood pressure. Methods: One hundred fifty-one obese women of reproductive age and 160 nonobese women of reproductive age were enrolled in this study. Serum levels of thyroid-stimulating hormone (TSH) of all subjects were within the normal reference range (0.35-4.94 mIU/L). The serum levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSH, height, body weight, BMI, waist and hip circumferences, WHR, fasting blood glucose (FBG), fasting insulin (FI), homeostasis model assessment of insulin resistance (HOMA-IR), total triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured in all subjects. Quantile regression analysis was used to analyze the associations of serum levels of FT3, FT4, and TSH with values of BMI, WHR, FBG, FI, HOMA-IR, TG, TC, LDL-C, HDL-C, SBP, and DBP. Results: In the group of obese women, serum levels of FT4 were lower (P < 0.001) and serum levels of TSH were higher (P < 0.001) compared with nonobese controls. After adjusting for covariables, quantile regression analysis showed that serum levels of FT4 were inversely associated with BMI values between the quantile levels of 0.29 and 0.60 of BMI (i.e., BMI level of 22.49 and 28.31 kg/m2, respectively). Meanwhile, we found that serum levels of TSH positively correlated with BMI values after the quantile level of 0.51 (i.e., BMI level of 27.06 kg/m2), positively associated with TC after the quantile level of 0.6 (i.e., TC level of 4.86 mM), and positively associated with LDL-C after the quantile level of 0.39 (i.e., LDL level of 1.96 mM). No significant associations were found between serum levels of thyroid hormones and values of WHR, FBG, FI, HOMA-IR, TG, HDL-C, SBP, and DBP. Conclusions: FT4 and TSH play an important role in regulating the weight in women with normal thyroid function during their reproductive years. Women with decreased serum FT4 or increased serum TSH levels have a higher risk of developing obesity. Besides, TSH has a significant influence on metabolism of blood lipids. Women with higher serum levels of TSH have a higher risk of incidence of lipid metabolism disorders.

What is the position of pulmonary arterial hypertension-specific drug therapy in patients with Eisenmenger syndrome: A systematic review and meta-analysis.

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) (I = 60.5%; WMD: 53.86 m, 95% CI [36.59, 71.13], P < .001), functional class (FC) (WMD = -0.71, 95% CI [-0.98, -0.44], P < .001) and Borg dyspnea index (WMD = -1.28, 95% CI [-1.86, -0.70], P < .001), in addition to hemodynamics, especially mean pulmonary arterial pressure by 5.70 mmHg (WMD = -5.70 mmHg, 95% CI [-8.19, -3.22], P < .001) and pulmonary vascular resistance by 4.20 wood U (WMD: -4.20, 95% CI [-7.32, -1.09], P = .008), but unsatisfactory effects in oxygen saturation at exercise (P = .747). In a prolonged medication, bosentan, a dual ERA, has been proved acting an important role in improving exercise tolerance of patients with ES (6MWD: I = 47.5%; WMD: 88.68 m, 95% CI [54.05, 123.3], P < .001; FC: I = 0.0%; WMD = -0.65, 95% CI [-1.10, -0.19], P = .006). While a nonsignificant change of 6MWD was noted in a long-term therapy of ambrisentan (P = .385). There existed rare evidence about the efficacy and safety of macitentan, phosphodiesterase-5 inhibitors (PDE5i), and prostanoids in a prolonged medication. Most AEs were recorded as mild to moderate with PAH-SDT, but about 4.3% individuals treated with endothelin receptor antagonists (ERAs) suffered from serious ones, and 3.9% suffered from death. CONCLUSIONS: This systematic review and meta-analysis proved PAH-SDT as a safe and effective role in ES in an early stage. However, in a long-term treatment, bosentan has been supported for a lasting effect on exercise tolerance. A further multicenter research with a large sample about pharmacotherapy of ES is necessary.

Exenatide Delays the Progression of Nonalcoholic Fatty Liver Disease in C57BL/6 Mice, Which May Involve Inhibition of the NLRP3 Inflammasome through the Mitophagy Pathway.

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-1ß 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.

Astragaloside IV protects RGC-5 cells against oxidative stress.

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.

Liraglutide attenuates the migration of retinal pericytes induced by advanced glycation end products.

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.

The efficiency of endothelin receptor antagonist bosentan for pulmonary arterial hypertension associated with congenital heart disease: A systematic review and meta-analysis.

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.

Obestatin prevents H2O2-induced damage through activation of TrkB in RGC-5 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.

Protective treatments and their target retinal ganglion cells in diabetic retinopathy.

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.

Function of obestatin in the digestive system.

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.

Acupuncture inhibits Notch1 and Hes1 protein expression in the basal ganglia of rats with cerebral hemorrhage.

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.