Protein disulfide isomerase is essential for spermatogenesis in mice.

Spermatogenesis requires precise posttranslational control in the endoplasmic reticulum (ER), but the mechanism remains largely unknown. The protein disulfide isomerase (PDI) family is a group of thiol oxidoreductases responsible for catalyzing the disulfide bond formation of nascent proteins. In this study, we generated 14 strains of KO mice lacking the PDI family enzymes and found that only PDI deficiency caused spermatogenesis defects. Both inducible whole-body PDI-KO (UBC-Cre/Pdifl/fl) mice and premeiotic PDI-KO (Stra8-Cre/Pdifl/fl) mice experienced a significant decrease in germ cells, testicular atrophy, oligospermia, and complete male infertility. Stra8-Cre/Pdifl/fl spermatocytes had significantly upregulated ER stress-related proteins (GRP78 and XBP1) and apoptosis-related proteins (Cleaved caspase-3 and BAX), together with cell apoptosis. PDI deletion led to delayed DNA double-strand break repair and improper crossover at the pachytene spermatocytes. Quantitative mass spectrometry indicated that PDI deficiency downregulated vital proteins in spermatogenesis such as HSPA4L, SHCBP1L, and DDX4, consistent with the proteins' physical association with PDI in normal testes tissue. Furthermore, PDI served as a thiol oxidase for disulfide bond formation of SHCBP1L. Thus, PDI plays an essential role in protein quality control for spermatogenesis in mice.

Real-world effectiveness of GLP-1 receptor agonist-based treatment strategies on "time in range" in patients with type 2 diabetes.

Background: Diabetes affects millions of people worldwide annually, and several methods, including medications, are used for its management; glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one such class of medications. The efficacy and safety of GLP-1RAs in treating type 2 diabetes mellitus (T2DM) have been assessed and have been shown to significantly improve time in range (TIR) in several clinical trials. However, presently, there is a lack of real-world evidence on the efficacy of GLP-1RAs in improving TIR. To address this, we investigated the effect of GLP-1RA-based treatment strategies on TIR among patients with T2DM in real-world clinical practice. Methods: This multicenter, retrospective, real-world study included patients with T2DM who had previously used a continuous glucose monitoring (CGM) system and received treatment with GLP-1RAs or oral antidiabetic drugs (OADs). Patients who received OADs served as controls and were matched in a 1:1 ratio to their GLP-1RA counterparts by propensity score matching. The primary endpoint was the TIR after 3-6 months of treatment. Results: According to propensity score matching, 202 patients were equally divided between the GLP-1RA and OAD groups. After 3-6 months of treatment, the TIR values for the GLP-1RA and OAD groups were 76.0% and 65.7%, respectively (p < 0.001). The GLP-1RA group displayed significantly lower time above range (TAR) and mean glucose values than the OAD group (p < 0.001). Subgroup analysis revealed that, compared with the administration of liraglutide, the administration of semaglutide and polyethylene glycol loxenatide (PEG-Loxe) significantly improved TIR over 3-6 months of treatment (p < 0.05). Conclusion: These real-world findings indicate that GLP-1RA-based treatment strategies could be superior to oral treatment strategies for improving TIR among patients with T2DM and that once-weekly GLP-1RA may be more effective than a once-daily GLP-1RA. Clinical trial registration: http://www.chinadrugtrials.org.cn/index.html, identifier number ChiCTR2300073697.

Clinical efficacy of plasma exchange in systemic lupus erythematosus during pregnancy.

OBJECTIVE: To investigate the clinical efficacy of plasma exchange (PE) with or without prednisone and hydroxychloroquine (HCQ) for the treatment of systemic lupus erythematosus (SLE) during pregnancy. METHODS: The clinical characteristics of 14 pregnant women with SLE admitted to our hospital were retrospectively analyzed, including 7 only treated with prednisone and HCQ (non-PE group) as well as 7 combined PE (PE group). The delivery situations of 14 patients were recorded. Data like erythrocyte sedimentation rate (ESR), urine protein, platelet count, and SLEDAI scores were compared between two groups before treatment and 3, 6, and 12 months after delivery. RESULTS: Three patients in the non-PE group ended in miscarriage while all patients in the PE group were delivered successfully. Eleven successfully delivered fetuses in the two groups were healthy, and the Apgar scores were over 8. The ESR of the PE group was significantly lower than that of the non-PE group at 6 and 12 months after delivery, while there was no statistical difference in ESR between the two groups before treatment and 3 months after delivery. The ESR and urine protein were significantly higher in the non-PE group at months 3, 6, and 12 postpartum. There was a significant decrease in disease activity postpartum in the PE group compared to predelivery disease activity. The change in platelet counts between the two groups significantly increased over time in the PE group, while SLEDAI scores decreased. CONCLUSIONS: The combination of PE and oral prednisone and HCQ is possibly a more effective treatment than oral prednisone and HCQ alone for patients with active SLE during pregnancy. This treatment option reduces pregnancy loss and promotes the patients' postpartum condition to a certain extent.

The global, regional and national burden of type 2 diabetes mellitus in the past, present and future: a systematic analysis of the Global Burden of Disease Study 2019.

Aim: To report the global, regional, and national burden of type 2 diabetes mellitus (T2DM) in 2019, assess its trends in the past, and forecast its trends in the future. Methods: The main data source was the Global Burden of Disease 2019 database. We assessed the changes in T2DM burden from 1990 to 2019 with joinpoint regression analysis. Age-period-cohort analysis was used to forecast the T2DM incidence and mortality rate from 2020 to 2034. Results: The burden of T2DM has increased from 1990 to 2019 generally. The low-middle socio-demographic index (SDI) region had the highest increase in age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR), age-standardized mortality rate (ASMR), and age-standardized disability-adjusted life years (ASDR) due to T2DM. Nationally, the increase in ASIR (r=0.151, p=0.046) and the decrease in ASMR (r=0.355, p<0.001) were positively correlated with SDIs. In 2019, the global ASIR, ASPR, ASMR, ASDR due to T2DM were 259.9 (95% UI 240.3-281.4), 5282.9 (95% UI 4853.6-5752.1), 18.5 (95% UI 17.2-19.7), and 801.5 (95% UI 55477000-79005200) per 100,000 population, respectively. Additionally, the ASIR (r=0.153, p=0.030) and ASPR (r=0.159, p=0.024) of T2DM were positively correlated with SDIs, while ASMR (r=-0.226, p=0.001) and ASDR (r=-0.171, p=0.015) due to T2DM were negatively correlated with SDIs. The ASIR was estimated to increase to 284.42, and ASMR was estimated to increase to 19.1 from 2030 to 2034, per 100,000 population. Conclusion: Globally, the burden of T2DM has increased in the past and was forecast to continue increasing. Greater investment in T2DM prevention is needed.

Efficacy of polyethylene glycol loxenatide versus insulin glargine on glycemic control in patients with type 2 diabetes: a randomized, open-label, parallel-group trial.

Objective: This trial aimed to evaluate the glycemic control of polyethylene glycol loxenatide measured with continuous glucose monitoring (CGM) in patients with type 2 diabetes mellitus (T2DM), with the hypothesis that participants given PEG-Loxe would spend more time in time-in-range (TIR) than participants were given insulin glargine after 24 weeks of treatment. Methods: This 24-week, randomized, open-label, parallel-group study was conducted in the Department of Endocrine and Metabolic Diseases, Longhu Hospital, Shantou, China. Participants with T2DM, who were ≥45 years of age, HbA1c of 7.0%-11.0%, and treated at least 3 months with metformin were randomized (1:1) to receive PEG-Loxe or insulin glargine. The primary endpoint was TIR (blood glucose range: 3.9-10.0 mmol/L) during the last 2 weeks of treatment (weeks 22-24). Results: From March 2020 to April 2022, a total of 107 participants with T2DM were screened, of whom 78 were enrolled into the trial (n = 39 per group). At the end of treatment (weeks 22-24), participants given PEG-Loxe had a greater proportion of time in TIR compared with participants given insulin glargine [estimated treatment difference (ETD) of 13.4% (95% CI, 6.8 to 20.0, p < 0.001)]. The tight TIR (3.9-7.8 mmol/L) was greater with PEG-Loxe versus insulin glargine, with an ETD of 15.6% (95% CI, 8.9 to 22.4, p < 0.001). The time above range (TAR) was significantly lower with PEG-Loxe versus insulin glargine [ETD for level 1: -10.5% (95% CI: -14.9 to -6.0), p < 0.001; ETD for level 2: -4.7% (95% CI: -7.9 to -1.5), p = 0.004]. The time below range (TBR) was similar between the two groups. The mean glucose was lower with PEG-Loxe versus insulin glargine, with an ETD of -1.2 mmol/L (95% CI, -1.9 to -0.5, p = 0.001). The SD of CGM glucose levels was 1.88 mmol/L for PEG-Loxe and 2.22 mmol/L for insulin glargine [ETD -0.34 mmol/L (95% CI: -0.55 to -0.12), p = 0.002], with a similar CV between the two groups. Conclusion: The addition of once-weekly GLP-1RA PEG-Loxe to metformin was superior to insulin glargine in improving glycemic control and glycemic variability evaluated by CGM in middle-aged and elderly patients with T2DM.

Pharmacoeconomic analysis (CER) of Dulaglutide and Liraglutide in the treatment of patients with type 2 diabetes.

Aim: To evaluate the treatment effect Fand pharmacoeconomic value of Dugaglutide in women with type 2 diabetes. Methods: Women (n=96) with type 2 diabetes recruited from June 2019 to December 2021 were randomized into two equal groups. The control group was treated with Liraglutide, and the observation group was treated with Dulaglutide, both for 24 weeks. The blood glucose levels, biochemical index, insulin resistance index (HOMA-IR), cost-effect ratio (CER), and drug safety were determined and compared between the two groups. Results: Blood glucose levels, the biochemical index, and HOMA-IR were lower in both groups after the treatment (P < 0.05), and there was no statistical difference in the blood glucose levels, biochemical index and HOMA-IR between the two groups (P > 0.05). The CER levels did not differ statistically between the two groups (P > 0.05). Both the cost and the incidence of drug side effects during solution injection were lower in the observation group than in the control group after 24 weeks of treatment (P < 0.05). Conclusion: Both Dulaglutide and Liraglutide can reduce blood glucose levels, improve biochemical index, and HOMA-IR levels in women with type 2 diabetes. Dulaglutide is more cost-effective and safe. Clinical trial registration: https://www.chictr.org.cn/index.aspx, identifier ChiCTR1900026514.

The effect of guar gum consumption on the lipid profile in type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

Dyslipidemia is a common encounter in type 2 diabetes mellitus (T2DM) and the current strategies to manage it are still suboptimal. Subsequently, identifying newer molecules with lipid-lowering effects is necessary. A great deal of attention has been given in recent years to fiber supplements, e.g., guar gum. Thus, we screened and evaluated the quality of the evidence regarding the benefits of guar gum supplementation in T2DM and conducted a meta-analysis to assess the effects of this compound on serum lipids in T2DM. We conducted a comprehensive search in PubMed/Medline, Web of Science, Scopus, Google Scholar and Embase, from the inception of these databases until January 2021. In total, 11 papers were included based on the eligible criteria in our meta-analysis. The meta-analysis of the eligible trials demonstrated a significant reduction of total cholesterol (TC) (WMD: -20.32 mg/dL, 95% CI: -27.02, -13.62, P < 0.001) and low-density lipoprotein cholesterol (LDL-C) (WMD: -14.52 mg/dL, 95% CI: -20.69, -8.35, P < 0.001) following guar gum supplementation in T2DM patients. The subgroup analysis based on the dosage (g/day) of this compound revealed that ≥20 g/day of guar gum led to a notable decrease in triglyceride (TG) levels (WMD: -12.55 mg/dL, 95% CI: -23.72, -1.37, P = 0.02) versus < 20 g/day (WMD: -1.84 mg/dL, 95% CI: -32.18, 28.49, P = 0.90). Guar gum supplementation had no effects on high-density lipoprotein cholesterol (HDL-C) (WMD: 0.66 mg/dL, 95% CI: -0.95, 2.28, P = 0.42). Guar gum consumption has lipid-lowering effects when administered to patients with type 2 diabetes mellitus and it is particularly able to reduce TC, LDL-C and TG levels. Further research is however needed to confirm our findings.

Fecal microbiota transplantation treatment of autoimmune-mediated type 1 diabetes: A systematic review.

There is a strong link between fecal microbiota and the development of type 1 diabetes. As an emerging therapeutic modality, fecal microbiota transplantation has been shown to be safe and effective in the treatment of many intestinal and extraintestinal diseases. Various studies have found that fecal microbiota transplantation can treat diseases by correcting patients' immune disorders. Besides, many studies have found that fecal microbiota transplantation can improve glycemic control and insulin resistance in diabetic patients. Therefore, this paper reviews the mechanism of action of fecal microbiota transplantation on autoimmune-mediated T1DM and the current research progress, feasibility, and issues that need to be addressed in the future development of fecal microbiota transplantation in the treatment of autoimmune-mediated T1DM.

Gut microbiota diversity in middle-aged and elderly patients with end-stage diabetic kidney disease.

Background: Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD), but the mechanism between DKD and ESRD remains unclear. Some experts have put forward the "microbial-centered ESRD development theory", believing that the bacterial load caused by gut microecological imbalance and uremia toxin transfer are the core pathogenic links. The purpose of this study was to analyze the genomic characteristics of gut microbiota in patients with ESRD, specifically DKD or non-diabetic kidney disease (NDKD). Methods: In this cross-sectional study, patients with ESRD were recruited in a community, including 22 DKD patients and 22 NDKD patients matched using gender and age. Fecal samples of patients were collected for 16S rDNA sequencing and gut microbiota analysis. The distribution structure, diversity, and abundance of microflora in DKD patients were analyzed by constructing species evolutionary trees and analyzing alpha diversity, beta diversity, and linear discriminant analysis effect size (LEfSe). Results: The results of our study showed that there were statistically significant differences in the richness and species of gut microbiota at the total level between DKD patients and NDKD patients. The analysis of genus level between the two groups showed significant differences in 16 bacterial genera. Among them, Oscillibacter, Bilophila, UBA1819, Ruminococcaceae UCG-004, Anaerotruncus, Ruminococcaceae, and Ruminococcaceae NK4A214 bacteria in DKD patients were higher than those in NDKD patients. Conclusions: 16S rDNA sequencing technology was used in this study to analyze the characteristics of intestinal flora in ESRD patients with or without diabetes. We found that there was a significant difference in the intestinal flora of ESRD patients caused by DKD and NDKD, suggesting that these may be potential causative bacteria for the development of ERSD in DKD patients.

Fecal microbiota transplantation treatment of autoimmune-mediated type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is an autoimmune-mediated disease characterized by a reduced or absolute lack of insulin secretion and often associated with a range of vascular and neurological complications for which there is a lack of effective treatment other than lifestyle interventions and pharmacological treatments such as insulin injections. Studies have shown that the gut microbiota is involved in mediating the onset and development of many fecal and extrafecal diseases, including autoimmune T1DM. In recent years, many cases of gut microbiota transplantation for diseases of the bowel and beyond have been reported worldwide, and this approach has been shown to be safe and effective. Here, we conducted an experimental treatment study in two adolescent patients diagnosed with autoimmune T1DM for one year. Patients received one to three rounds of normal fecal microbiota transplants (FMT) and were followed for up to 30 weeks. Clinical outcomes were measured, including biochemical indices, medication regimen, and dosage adjustment. Fecal microbiota metagenomic sequencing after transplantation provides a reference for more reasonable and effective microbiota transplantation protocols to treat autoimmune T1DM. Our results suggest that FMT is an effective treatment for autoimmune T1DM. Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR2100045789.

Polyethylene Glycol Loxenatide Injection (GLP-1) Protects Vascular Endothelial Cell Function in Middle-Aged and Elderly Patients With Type 2 Diabetes by Regulating Gut Microbiota.

Objective: To evaluate the protective effect of Polyethylene Glycol Loxenatide Injection (Glucagon-like peptide-1, GLP-1) on endothelial cells from middle-aged and elderly patients with newly diagnosed or poorly controlled type 2 diabetes mellitus (T2DM). GLP-1 weekly formulation was analyzed for cardiovascular disease protection and correlated with intestinal flora. Design: Stool samples were collected from middle-aged and elderly patients with new-onset or poorly controlled type 2 diabetes in Longhu People's Hospital and Shantou Central Hospital from June 2019 to November 2019. Samples were collected at week 0, 4, and 8 of treatment with GLP-1 weekly formulations. Samples were analyzed for metagenomic sequencing. Analysis was performed to compare the characteristics of the gut microbiota at week 0, 4, and 8 of GLP-1 treatment and to correlate different microbiota with characteristic clinical parameters. Results: Statistical differences were found in blood glucose lowering, cardiovascular endothelial, and inflammation-related indices between week 0 and W4 and in blood glucose lowering and cardiovascular endothelial indices from week 0 to 8 in the newly diagnosed or poorly controlled type 2 diabetic patients treated with GLP-1. Changes in gut microbiota at week 0, 4, and 8 after using GLP-1 were not statistically different, but had an overall trend of rising and then falling, and with different bacteria, that were correlated with different clinical indicators. Conclusion: GLP-1 improves endothelial cell function indicators in middle-aged and elderly diabetic patients, which may be related to its alteration of the population numbers of gut microbiota such as Acinetobacter, Eubacterium ramulus ATCC 29099, and Bacteroides_faecis. This study provides a guidance for the treatment of type 2 diabetic patients.

Reconstruction of intestinal microecology of type 2 diabetes by fecal microbiota transplantation: Why and how.

Type 2 diabetes (T2D) is a chronic metabolic disease characterized by hyperglycemia due to insulin resistance. Mounting evidence has correlated T2D to alterations in the composition of gut microbiota. Accordingly, targeting the gut microbiota has become an emerging strategy for T2D management. The aim of this article is to get a better insight into the rationale for targeting gut microbiota in T2D treatment. Thus, we herein reviewed the change of gut microbiota composition in T2D, factors shaping gut microbiota, and potential mechanisms behind the contribution of gut microbiota to T2D pathogenesis. At present, it has become possible to use intestinal microorganism capsules, bacteria liquid, and other preparations to carry out fecal microbiota transplantation for the treatment and intervention of T2D with insulin resistance and immune-mediated type 1 diabetes (T1D).

Fecal microbiota transplantation reverses insulin resistance in type 2 diabetes: A randomized, controlled, prospective study.

Objectives: Recent studies have shown that fecal microbiota transplantation (FMT) improved the metabolic profiles of patients with type 2 diabetes mellitus (T2DM), yet the effectiveness in reversing insulin resistance and increasing metformin sensitivity in T2DM patients have not been reported. In this study, we evaluated the improvements of T2DM patients and their gut microbiota by FMT alone and FMT plus metformin. Methods: A total of 31 patients with newly diagnosed T2DM were randomized to intervention by metformin, FMT, or FMT plus metformin in the study. Patients were followed up at baseline and week 4 after treatment. Blood and stool samples were collected and subject to analyze clinical parameters and microbial communities by metagenomic sequencing, respectively. Results: FMT alone and FMT plus metformin significantly improved the clinical indicators HOMA-IR and BMI in T2DM, besides fasting blood glucose, postprandial blood glucose, and hemoglobin A1c that were also controlled by metformin. Donor microbiota effectively colonized in T2DM with slightly higher colonization ration in FMT than FMT plus metformin within 4 weeks, resulting in increased microbial diversity and community changes from baseline after treatment. A total of 227 species and 441 species were significantly alerted after FMT and FMT plus metformin, respectively. FMT were significantly associated with the clinical parameters. Among them, Chlorobium phaeovibrioides, Bifidibacterium adolescentis and Synechococcus sp.WH8103 were potential due to their significantly negative correlations with HOMA-IR. Conclusions: FMT with or without metformin significantly improve insulin resistance and body mass index and gut microbial communities of T2DM patients by colonization of donor-derived microbiota.

The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion.

BACKGROUND: Type 3 von Willebrand disease (VWD) exhibits severe hemorrhagic tendency with complicated pathogenesis. The C-terminal cystine knot (CTCK) domain plays an important role in the dimerization and secretion of von Willebrand factor (VWF). The CTCK domain has four intrachain disulfide bonds including Cys2724-Cys2774, Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806, and the single cysteine mutation in Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806 result in type 3 VWD, demonstrating the crucial role of these three disulfide bonds in VWF biosynthesis, however, the role of the remaining disulfide bond Cys2724-Cys2774 remains unclear. METHOD AND RESULTS: In this study, by the next-generation sequencing we found a missense mutation a c.8171G>A (C2724Y) in the CTCK domain of VWF allele in a patient family with type 3 VWD. In vitro, VWF C2724Y protein was expressed normally in HEK-293T cells but did not form a dimer or secrete into cell culture medium, suggesting that C2724 is critical for the VWF dimerization, and thus for VWF multimerization and secretion. CONCLUSIONS: Our findings provide the first genetic evidence for the important role of Cys2724-Cys2774 in VWF biosynthesis and secretion. Therefore, all of the four intrachain disulfide bonds in CTCK monomer contribute to VWF dimerization and secretion.

Gut Bacterial Characteristics of Patients With Type 2 Diabetes Mellitus and the Application Potential.

Type 2 diabetes mellitus (T2DM) is a complex disorder comprehensively influenced by genetic and environmental risk, and research increasingly has indicated the role of microbial dysbiosis in T2DM pathogenesis. However, studies comparing the microbiome characteristics between T2DM and healthy controls have reported inconsistent results. To further identify and describe the characteristics of the intestinal flora of T2DM patients, we performed a systematic review and meta-analysis of stool microbial profiles to discern and describe microbial dysbiosis in T2DM and to explore heterogeneity among 7 studies (600 T2DM cases, 543 controls, 1143 samples in total). Using a random effects model and a fixed effects model, we observed significant differences in beta diversity, but not alpha diversity, between individuals with T2DM and controls. We identified various operational taxonomic unit (OTUs) and bacterial genera with significant odds ratios for T2DM. The T2DM signatures derived from a single study by stepwise feature selection could be applied in other studies. By training on multiple studies, we improved the detection accuracy and disease specificity for T2DM. We also discuss the relationship between T2DM-enriched or T2DM-depleted genera and probiotics and provide new ideas for diabetes prevention and improvement.

Vitamin D and Lipid Profiles in Postmenopausal Women: A Meta-Analysis and Systematic Review of Randomized Controlled Trials.

Background and Aim: It is known that hyperlipidemia and low vitamin D level are risk factors associated with cardiovascular disease (CVD). However, the effect of vitamin D administration on lipid profiles in postmenopausal women remains unclear. This study aims to evaluate the effect of vitamin D on lipid profiles in postmenopausal women based on meta-analysis and systemic review. Methods: The literature search was performed in multiple databases (Scopus, PubMed/Medline, Web of Science, and Embase) from 1997 to 2021. The statistical analysis was performed using the Stata software version 14 (Stata Corp. College Station, Texas, United States). The effects of vitamin D administration of the lipid profiles, including Triacylglycerol (TG), LDL-Cholesterol (LDL-C), HDL-Cholesterol (HDL-C), and Total Cholesterol (TC) were evaluated by the Der Simonian and Laird random effects model. The weighted mean difference (WMD) and 95% confidence intervals (CI) were calculated. Results: The level of TG changed significantly by -3.76 mg/dl (CI: -6.12 to -1.39, p = 0.004) and HDL-C by 0.48 mg/dl (CI: -0.80 to -0.15, p = 0.004) in vitamin D administration group [11 eligible trials (placebo = 505 participants, vitamin D intervention = 604 participants)] compared to the control group in the postmenopausal women. Taking into account this comparison between groups, in contrast, the level of LDL-Cholesterol (LDL-C) (WMD: 0.73 mg/dl, 95% CI: -1.88, 3.36, p = 0.583) and TC (WMD: 0.689 mg/dl, CI: -3.059 to 4.438, p = 0.719) did not change significantly. Conclusion: In conclusion, the vitamin D administration in postmenopausal women, decreased the concentrations of TG, and HDL-C, but have no effects on LDL-C and TC.

Curcumin inhibits high glucose oxidative stress and apoptosis in pancreatic beta cells via CHOP/PCG-1a and pERK1/2.

Loss of pancreatic beta-cells by apoptosis appears to play an important role in the development of insulin deficiency and the onset and/or progression of the diabetes mellitus. To this end, we report that curcumin prevents high glucose (HG) induced oxidative stress and apoptosis in mouse pancreatic beta cells. Moreover, curcumin prevents HG induced increase in expression of CHOP, decrease in PCG-1a and phosphorylation of ERK1/2 (pERK1/2) without any effect on the phosphorylation levels of p38 and JNK. Moreover, similar to curcumin, blockade of pERK1/2 reduced the HG induced apoptosis in pancreatic beta cells. Overexpression of CHOP or siRNA knockdown of PCG-1a counteracted the effect of curcumin on HG induced apoptosis and oxidative stress. These results suggest that curcumin acts through CHOP/PCG-1a and ERK1/2 signaling to block the HG induced oxidative stress and apoptosis.

Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets.

BACKGROUND: Branched-chain amino acids (BCAAs), essential nutrients including leucine, isoleucine, and valine, serve as a resource for energy production and the regulator of important nutrient and metabolic signals. Recent studies have suggested that dysfunction of BCAA catabolism is associated with the risk of cardiovascular disease. Platelets play an important role in cardiovascular disease, but the functions of BCAA catabolism in platelets remain unknown. METHODS: The activity of human platelets from healthy subjects before and after ingestion of BCAAs was measured. Protein phosphatase 2Cm specifically dephosphorylates branched-chain α-keto acid dehydrogenase and thereby activates BCAA catabolism. Protein phosphatase 2Cm-deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation. RESULTS: We found that ingestion of BCAAs significantly promoted human platelet activity (n=5; P<0.001) and arterial thrombosis formation in mice (n=9; P<0.05). We also found that the valine catabolite α-ketoisovaleric acid and the ultimate oxidation product propionyl-coenzyme A showed the strongest promotion effects on platelet activation, suggesting that the valine/α-ketoisovaleric acid catabolic pathway plays a major role in BCAA-facilitated platelet activation. Protein phosphatase 2Cm deficiency significantly suppresses the activity of platelets in response to agonists (n=5; P<0.05). Our results also suggested that BCAA metabolic pathways may be involved in the integrin αIIbß3-mediated bidirectional signaling pathway that regulates platelet activation. Mass spectrometry identification and immunoblotting revealed that BCAAs enhanced propionylation of tropomodulin-3 at K255 in platelets or Chinese hamster ovary cells expressing integrin αIIbß3. The tropomodulin-3 K255A mutation abolished propionylation and attenuated the promotion effects of BCAAs on integrin-mediated cell spreading, suggesting that K255 propionylation of tropomodulin-3 is an important mechanism underlying integrin αIIbß3-mediated BCAA-facilitated platelet activation and thrombosis formation. In addition, the increased levels of BCAAs and the expression of positive regulators of BCAA catabolism in platelets from patients with type 2 diabetes mellitus are significantly correlated with platelet hyperreactivity. Lowering dietary BCAA intake significantly reduced platelet activity in ob/ob mice (n=4; P<0.05). CONCLUSIONS: BCAA catabolism is an important regulator of platelet activation and is associated with arterial thrombosis risk. Targeting the BCAA catabolism pathway or lowering dietary BCAA intake may serve as a novel therapeutic strategy for metabolic syndrome-associated thrombophilia.

Plasma kallikrein contributes to ambient particulate matter-induced lung injury.

Particulate matter (PM) is a key component of air pollutants and is associated with mortality of cardiovascular and respiratory diseases. PM-induced tissue injury involves inflammation and coagulation. Plasma prekallikrein (pKal), along with coagulation factor XII (FXII) and high-molecular-weight kininogen (HK), form the plasma kallikrein-kinin system (KKS), a component of the innate immune response that generates proinflammatory products in response to injury. When the KKS proteins contact with activation surface such as negatively charged molecules, this system becomes activated. Activated kallikrein (Kal) activates FXII to initiate the intrinsic coagulation pathway, and cleaves HK to release bradykinin to enhance vascular permeability and systemic inflammation. In his study we determined the role of plasma pKal in the PM2.5-induced lung injury. Using TALEN technology, we generated a new mouse strain lacking the gene for pKal. In PM2.5-induced lung injury model, Klkb1-/- mice exhibited a decrease in total protein, cells numbers in bronchoalveolar lavage fluid (BALF) and histologic lung injury score. The TNF-α and IL-6 levels in BALF were significantly decreased in PM2.5-treated Klkb1-/- mice. Plasma thrombin-antithrombin (TAT) complex levels were significantly decreased in PM2.5-treated Klkb1-/- mice. PM2.5 induces pKal activation, HK cleavage and bradykinin production. PM2.5-induced HK cleavage in plasma was completely blocked by a Kal inhibitor, as well as in pKal-deficient plasma. PM2.5 markedly induced thrombin generation in human plasma and wild-type mouse plasma, which was inhibited by both blockade and deficiency of pKal. Taken together, plasma pKal is activated by PM2.5 and the activated Kal plays an important role in PM2.5-induced lung injury.