Life-Cycle Environmental Impacts of Additive-Related Chemicals in Polyvinyl Chloride Plastics and the Mitigation Potential.

Plastic additive-related chemicals, particularly in polyvinyl chloride (PVC) plastics, have become a key issue in plastic pollution. Although addressing plastic pollution through the life-cycle approach is crucial, the environmental impacts of typical plastic additive-related chemicals in PVC plastics during the cradle-to-gate stage remain unexplored. Consequently, managing the life-cycle environmental impacts of these additives remains challenging. Herein, the environmental impacts of 23 typical plastic additive-related chemicals and six PVC plastic products were evaluated throughout the cradle-to-gate life-cycle stage using a life cycle assessment-material flow analysis (LCA-MFA) coupled model. The results indicate that plastic additives significantly contribute to the environmental impacts of PVC plastic products across various end point indicators, ranging from 8.7 to 40.6%. Additionally, scenario analysis (SA) reveals that conventional strategies for addressing plastic pollution may not be highly effective in mitigating the environmental impacts associated with plastic additives. Specifically, compared to primary polymers, these additives exhibit 4 to 13% lower mitigation potential under the same policy scenarios. However, technical adjustment strategies targeting additives show a mitigation potential of 12 to 39%, suggesting that guiding the plastic additive industry toward green transformation is a key strategy for reducing environmental impacts.

Glucose fluctuations aggravate cardiomyocyte apoptosis by enhancing the interaction between Txnip and Akt.

BACKGROUND: Glucose fluctuations may be involved in the pathophysiological process of cardiomyocyte apoptosis, but the exact mechanism remains elusive. This study focused on exploring the mechanisms related to glucose fluctuation-induced cardiomyocyte apoptosis. METHODS: Diabetic rats established via an injection of streptozotocin were randomized to five groups: the controlled diabetic (CD) group, the uncontrolled diabetic (UD) group, the glucose fluctuated diabetic (GFD) group, the GFD group rats with the injection of 0.9% sodium chloride (NaCl) (GFD + NaCl) and the GFD group rats with the injection of N-acetyl-L-cysteine (NAC) (GFD + NAC). Twelve weeks later, cardiac function and apoptosis related protein expressions were tested. Proteomic analysis was performed to further analyze the differential protein expression pattern of CD and GFD. RESULTS: The left ventricular ejection fraction levels and fractional shortening levels were decreased in the GFD group, compared with those in the CD and UD groups. Positive cells tested by DAB-TUNEL were increased in the GFD group, compared with those in the CD group. The expression of Bcl-2 was decreased, but the expressions of Bax, cleaved caspase-3 and cleaved caspase-9 were increased in response to glucose fluctuations. Compared with CD, there were 527 upregulated and 152 downregulated proteins in GFD group. Txnip was one of the differentially expressed proteins related to oxidative stress response. The Txnip expression was increased in the GFD group, while the Akt phosphorylation level was decreased. The interaction between Txnip and Akt was enhanced when blood glucose fluctuated. Moreover, the application of NAC partially reversed glucose fluctuations-induced cardiomyocyte apoptosis. CONCLUSIONS: Glucose fluctuations lead to cardiomyocyte apoptosis by up-regulating Txnip expression and enhancing Txnip-Akt interaction.

Acute skin toxicity and self-management ability among Chinese breast cancer radiotherapy patients: a qualitative study.

OBJECTIVES: Radiation dermatitis is the most common reaction to radiotherapy, almost all breast cancer patients receive radiotherapy on an outpatient basis. Currently, there are no studies on the experience of radiation dermatitis and the ability to self-manage it. Therefore, we aimed to use qualitative approaches to gain a deeper understanding of the actual experiences and self-management ability in order to provide a reference for further improving the effectiveness of self-management and to optimize symptom management strategies. METHODS: A descriptive qualitative study was conducted using purposive sampling to select 17 breast cancer patients undergoing radiotherapy. Semi-structured interviews were conducted from September to November 2023. The Colaizzi seven-step analysis method was used to classify the data into summarized themes. RESULTS: Four themes were identified from the interview responses: (1) multiple self-reported skin symptoms in breast cancer patients with radiation dermatitis; (2) the multidimensional impact on patient's quality of life, especially pruritus, ulceration; (3) the ability to self-manage radiation dermatitis: strong mental toughness, positive response, and self-doubt; (4) challenges faced: concerns about radiotherapy side effects and recurrence, targeted symptom management and continuity of care after the radiotherapy. CONCLUSIONS: Healthcare professionals should consider patients' self-reported symptoms when assessing radiation dermatitis. For pruritus and pain, we can enhance precision symptom management to improve patients' quality of life. By utilizing information technology tools, we can increase breast cancer patients' ability and confidence in managing radiation dermatitis effectively while enhancing accurate symptom management during radiotherapy.

Calcineurin/NFATc3 pathway mediates myocardial fibrosis in diabetes by impairing enhancer of zeste homolog 2 of cardiac fibroblasts.

BACKGROUND: Diabetes is associated with myocardial fibrosis, while the underlying mechanisms remain elusive. The aim of this study is to investigate the underlying role of calcineurin/nuclear factor of activated T cell 3 (CaN/NFATc3) pathway and the Enhancer of zeste homolog 2 (EZH2) in diabetes-related myocardial fibrosis. METHODS: Streptozotocin (STZ)-injected diabetic rats were randomized to two groups: the controlled glucose (Con) group and the diabetes mellitus (DM) group. Eight weeks later, transthoracic echocardiography was used for cardiac function evaluation, and myocardial fibrosis was visualized by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with high-glucose medium with or without cyclosporine A or GSK126. The expression of proteins involved in the pathway was examined by western blotting. The nuclear translocation of target proteins was assessed by immunofluorescence. RESULTS: The results indicated that high glucose treatment increased the expression of CaN, NFATc3, EZH2 and trimethylates lysine 27 on histone 3 (H3K27me3) in vitro and in vivo. The inhibition of the CaN/NFATc3 pathway alleviated myocardial fibrosis. Notably, inhibition of CaN can inhibit the nuclear translocation of NFATc3, and the expression of EZH2 and H3K27me3 protein induced by high glucose. Moreover, treatment with GSK126 also ameliorated myocardial fibrosis. CONCLUSION: Diabetes can possibly promote myocardial fibrosis by activating of CaN/NFATc3/EZH2 pathway.

Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain.

BACKGROUND: Peripheral nerve damage causes neuroinflammation, which plays a critical role in establishing and maintaining neuropathic pain (NeP). The mechanisms contributing to neuroinflammation remain poorly elucidated, and pharmacological strategies for NeP are limited. Thus, in this study, we planned to explore the possible link between astrocyte senescence and NeP disorders following chronic sciatic nerve injury. METHODS: An NeP animal model was established by inducing chronic constrictive injury (CCI) to the sciatic nerve in adult rats. A senolytic drug combination of dasatinib and quercetin was gavaged daily from the first postoperative day until the end of the study. Paw mechanical withdrawal threshold (PMWT) and paw thermal withdrawal latency (PTWL) were evaluated to assess behaviors in response to pain in the experimental rats. Senescence-associated ß-galactosidase staining, western blot analysis, and immunofluorescence were applied to examine the levels of proinflammatory factors and severity of the senescence-like response in the spinal cord. Lipopolysaccharide (LPS) was administered to induce senescence of spinal astrocytes in primary cultures in vitro, to explore the potential impacts of senescence on the secretion of proinflammatory factors. Furthermore, single-cell RNA sequencing (scRNA-seq) was conducted to identify senescence-related molecular responses in spinal astrocytes under neuropathic pain. RESULTS: Following sciatic nerve CCI, rats exhibited reduced PMWT and PTWL, increased levels of spinal proinflammatory factors, and an enhanced degree of senescence in spinal astrocytes. Treatment with dasatinib and quercetin effectively attenuated spinal neuroinflammation and mitigated the hypersensitivities of the rats subjected to sciatic nerve CCI. Mechanistically, the dasatinib-quercetin combination reversed senescence in LPS-stimulated primary cultured astrocytes and decreased the levels of proinflammatory factors. The scRNA-seq data revealed four potential senescence-related genes in the spinal astrocyte population, and the expression of clusterin (CLU) protein was validated via in vitro experiments. CONCLUSION: The findings indicate the potential role of astrocyte senescence in neuroinflammation following peripheral nerve injury, and suggest that targeting CLU activation in astrocytes might provide a novel therapeutic strategy to treat NeP.

Achieving artificial carbon cycle via integrated system of high-emitting industries and CCU technology: Case of China.

Process-related carbon emissions, which cannot be completely eliminated by the improvement of processes and energy structure, are recognized as an enormous challenge for in-depth decarbonization. To accelerate the achievement of carbon neutrality, the concept of 'artificial carbon cycle' is proposed based on the integrated system of process-related carbon emissions from high-emitting industries and CCU technology as a potential pathway towards a sustainable future. This paper conducts a systematic review on the integrated system with the case of China, which is the largest carbon-emitting and manufacturing country, to provide a clearer and more meaningful analysis. Multi-index assessment was used to organize the literature and draw the useful conclusion. Based on literature review, the high-quality carbon sources, reasonable carbon capture approaches and promising chemical products were identified and analyzed. Then the potential and practicability of the integrated system was further summarized and analyzed. Finally, key factors of future development including technology improvement, green hydrogen, clean energy and industrial cooperation were stressed to provide a theoretical reference for future researchers and policy makers.

A Formal and Visual Data-Mining Model for Complex Ship Behaviors and Patterns.

The successful emergence of real-time positioning systems in the maritime domain has favored the development of data infrastructures that provide valuable monitoring and decision-aided systems. However, there is still a need for the development of data mining approaches oriented to the detection of specific patterns such as unusual ship behaviors and collision risks. This research introduces a CSBP (complex ship behavioral pattern) mining model aiming at the detection of ship patterns. The modeling approach first integrates ship trajectories from automatic identification system (AIS) historical data, then categorizes different vessels' navigation behaviors, and introduces a visual-oriented framework to characterize and highlight such patterns. The potential of the model is illustrated by a case study applied to the Jiangsu and Zhejiang waters in China. The results show that the CSBP mining model can highlight complex ships' behavioral patterns over long periods, thus providing a valuable environment for supporting ship traffic management and preventing maritime accidents.

His-Purkinje conduction system pacing: A systematic review and network meta-analysis in bradycardia and conduction disorders.

BACKGROUND: His-Purkinje conduction system pacing (HPCSP) has emerged as an effective alternative to overcome the limitations of right ventricular pacing (RVP) via physiological left ventricular activation, but there remains a paucity of comparative information for His bundle pacing (HBP) and left bundle branch pacing (LBBP). METHODS: A Bayesian random-effects network analysis was conducted to compare the relative effects of HBP, LBBP, and RVP in patients with bradycardia and conduction disorders. PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from database inception until September 21, 2021. RESULTS: Twenty-eight studies involving 4160 patients were included in this meta-analysis. LBBP significantly improved success rate, pacing threshold, pacing impedance, and R-wave amplitude compared with HBP. LBBP also demonstrated a nonsignificant trend towards superior outcomes of lead complications, heart failure hospitalization, atrial fibrillation, and all-cause death. However, HBP was associated with significantly shorter paced QRS duration relative to LBBP. Despite higher success rates, shorter procedure/fluoroscopy duration, and fewer lead complications, patients receiving RVP were more likely to experience reduced left ventricular ejection fraction, longer paced QRS duration, and higher rates of heart failure hospitalization than those receiving HPCSP. No statistical differences were observed in the remaining outcome measures. CONCLUSIONS: This network meta-analysis demonstrates the efficacy and safety of HPCSP for the treatment of bradycardia and conduction disorders, with differences in pacing parameters, electrophysiology characteristics, and clinical outcomes between HBP and LBBP. Larger-scale, long-term comparative studies are warranted for further verification.

A method to screen left ventricular dysfunction through ECG based on convolutional neural network.

OBJECTIVE: This study aims to develop an artificial intelligence-based method to screen patients with left ventricular ejection fraction (LVEF) of 50% or lesser using electrocardiogram (ECG) data alone. METHODS: Convolutional neural network (CNN) is a class of deep neural networks, which has been widely used in medical image recognition. We collected standard 12-lead ECG and transthoracic echocardiogram (TTE) data including the LVEF value. Then, we paired the ECG and TTE data from the same individual. For multiple ECG-TTE pairs from a single individual, only the earliest data pair was included. All the ECG-TTE pairs were randomly divided into the training, validation, or testing data set in a ratio of 9:1:1 to create or evaluate the CNN model. Finally, we assessed the screening performance by overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: We retrospectively enrolled a total of 26 786 ECG-TTE pairs and randomly divided them into training (n = 21 732), validation (n = 2 530), and testing data set (n = 2 530). In the testing set, the CNN algorithm showed an overall accuracy of 73.9%, sensitivity of 69.2%, specificity of 70.5%, positive predictive value of 70.1%, and negative predictive value of 69.9%. CONCLUSION: Our results demonstrate that a well-trained CNN algorithm may be used as a low-cost and noninvasive method to identify patients with left ventricular dysfunction.

Glucose fluctuations promote vascular BK channels dysfunction via PKCα/NF-κB/MuRF1 signaling.

Glucose fluctuations may contribute to large conductance calcium activated potassium (BK) channel dysfunction. However, the underlying mechanisms remain elusive. The aim of this study was to investigate the molecular mechanisms involved in BK channel dysfunction as a result of glucose fluctuations. A rat diabetic model was established through the injection of streptozotocin. Glucose fluctuations in diabetic rats were induced via consumption and starvation. Rat coronary arteries were isolated and coronary vascular tensions were measured after three weeks. Rat coronary artery smooth muscle cells were isolated and whole-cell BK channel currents were recorded using a patch clamp technique. Human coronary artery smooth muscle cells in vitro were used to explore the underlying mechanisms. After incubation with iberiotoxin (IBTX), the Δ tensions (% Max) of rat coronary arteries in the controlled diabetes mellitus (C-DM), the uncontrolled DM (U-DM) and the DM with glucose fluctuation (GF-DM) groups were found to be 84.46 ± 5.75, 61.89 ± 10.20 and 14.77 ± 5.90, respectively (P < .05), while the current densities of the BK channels in the three groups were 43.09 ± 4.35 pA/pF, 34.23 ± 6.07 pA/pF and 17.87 ± 4.33 pA/pF, respectively (P < .05). The Δ tensions (% Max) of rat coronary arteries after applying IBTX in the GF-DM rats injected with 0.9% sodium chloride (NaCl) (GF-DM + NaCl) and the GF-DM rats injected with N-acetyl-L-cysteine (NAC) (GF-DM + NAC) groups were found to be 8.86 ± 1.09 and 48.90 ± 10.85, respectively (P < .05). Excessive oxidative stress and the activation of protein kinase C (PKC) α and nuclear factor (NF)-κB induced by glucose fluctuations promoted the decrease of BK-ß1 expression, while the inhibition of reactive oxygen species (ROS), PKCα, NF-κB and muscle ring finger protein 1 (MuRF1) reversed this effect. Glucose fluctuations aggravate BK channel dysfunction via the ROS overproduction and the PKCα/NF-κB/MuRF1 signaling pathway.

Glucose Fluctuations Promote Aortic Fibrosis through the ROS/p38 MAPK/Runx2 Signaling Pathway.

AIM: Glucose fluctuations may be responsible for, or further the onset of arterial hypertension, but the exact mechanisms remain unclear. The purpose of this study was to investigate the mechanisms behind and related to aortic fibrosis and aortic stiffening induced by glucose fluctuations. METHODS: Sprague-Dawley rats were injected with streptozotocin (STZ) and randomly divided into three treatment groups: controlled STZ-induced diabetes (C-STZ); uncontrolled STZ-induced diabetes (U-STZ); and STZ-induced diabetes with glucose fluctuations (STZ-GF). After 3 weeks, rat blood pressure (BP) was tested, and aortic fibrosis was detected by using the Masson trichrome staining technique. Levels of p38 mitogen-activated protein kinase (p38 MAPK), runt-related transcription factor 2 (Runx2), collagen type 1 (collagen I), and NADPH oxidases were determined by Western blot.Rat vascular smooth muscle cells in vitro were used to explore underlying mechanisms. RESULTS: The systolic BP of diabetic rats in the C-STZ, U-STZ, and STZ-GF groups was 127.67 ± 6.53, 150.03 ± 5.24, and 171.63 ± 3.53 mm Hg, respectively (p< 0.05). The mean BP of diabetic rats in the three groups was 91.20 ± 10.07, 117.29 ± 4.28, and 140.58 ± 2.14 mm Hg, respectively (p< 0.05). The diastolic BP of diabetic rats in the three groups was 73.20 ± 12.63, 101.93 ± 5.79, and 125.37 ± 4.62 mm Hg, respectively (p< 0.05). The ratios of fibrosis areas in the aortas of the three groups were 11.85 ± 1.23, 29.00 ± 0.87, and 48.36 ± 0.55, respectively (p< 0.05). The expressions of p38 MAPK, Runx2, and collagen I were significantly increased in the STZ-GF group. In vitro, applications of inhibitors of reactive oxygen species (ROS) and p38 MAPK successfully reversed glucose fluctuations that would have possibly induced aortic fibrosis. CONCLUSIONS: Blood glucose fluctuations aggravate aortic fibrosis via affecting the ROS/p38 MAPK /Runx2 signaling pathway.

The Role and Underlying Mechanisms of Exercise in Heart Failure.

Heart failure is a prevalent and life-threatening syndrome characterized by structural and/or functional abnormalities of the heart. As a global burden with high rates of morbidity and mortality, there is growing recognition of the beneficial effects of exercise on physical fitness and cardiovascular health. A substantial body of evidence supports the notion that exercise can play a protective role in the development and progression of heart failure and improve cardiac function through various mechanisms, such as attenuating cardiac fibrosis, reducing inflammation, and regulating mitochondrial metabolism. Further investigation into the role and underlying mechanisms of exercise in heart failure may uncover novel therapeutic targets for the prevention and treatment of heart failure.

Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway.

BACKGRUOUND: Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified. METHODS: In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed. RESULTS: In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation. CONCLUSION: Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis.

Gut microbiota changes in animal models of spinal cord injury: a preclinical systematic review and meta-analysis.

BACKGROUND: An increasing number of studies show that the intestinal flora is closely related to spinal cord injury. Many researchers are exploring the changes in the richness, diversity, and evenness of intestinal flora in spinal cord injury animal models to identify the characteristic bacteria. METHODS: A comprehensive literature search was conducted using three databases: PubMed, Embase, and Web of Science. A meta-analysis was performed using R 4.3.1 to evaluate the comparison of microbiota diversity, richness, and evenness and the relative abundance of intestinal microbiota in animals with spinal cord injury and blank controls. RESULTS: Fifteen studies were included in the meta-analysis, of which 12 involved gut microbiota distribution indicators and 11 included intestinal microflora relative abundance indicators. Meta-analysis of high-dimensional indicators describing the distribution of the gut microbiota identified a substantial decline in the evenness and richness of the intestinal flora. In addition, the Actinobacteria phylum and Erysipelotrichales and Clostridiales orders were significantly different between the spinal cord injury and sham groups; therefore, they may be the characteristic bacteria in spinal cord injury models. CONCLUSION: Our meta-analysis suggested that the gut microbiota in the spinal cord injury animal model group was altered compared with that in the control group, with varying degrees of changes in richness and evenness and potentially pathogenic characteristic flora. More rigorous methodological studies are needed because of the high heterogeneity and limited sample size. Further research is needed to clinically apply intestinal microbiota and potentially guide fecal microbiota transplantation therapy.

Our meta-analysis showed that spinal cord injury significantly decreased the richness and evenness of intestinal flora in experimental animals.No statistically significant changes in the phyla flora during spinal cord injury have been found.Erysipelotrichales and Clostridiales may be the characteristic flora of gut microbiota changes during spinal cord injury.

Bone marrow-derived mesenchymal stem cells attenuate complete Freund's adjuvant-induced inflammatory pain by inhibiting the expression of P2X3.

Bone marrow-derived mesenchymal stem cells (BMSCs) show a good property for pain treatment by modulating inflammatory response. However, the underlying therapeutic effect and related mechanism of BMSCs on inflammatory pain remain unclear. Therefore, we explored the function and potential mechanism of BMSCs performing in a complete Freund's adjuvant (CFA)-induced inflammatory pain model in this study. Here, BMSCs were injected into the CFA-treated rats, and we used behavioural tests to evaluate the changes in hypersensitivity. High-throughput sequencing was used to screen out the hub genes. Molecular biology experiments were performed to detect the level of P2X3 or inflammatory mediators in rats and observed the distribution of P2X3 in neural cells. Furthermore, the function of the P2X3 was explored via inhibitor and activator experiments. Finally, we found that BMSCs alleviated hyperalgesia and spinal levels of pro-inflammatory factors in CFA-treated rats. High-throughput sequencing showed that P2X3 and P2X7 were identified as hub genes, and only the expression level of P2X3 was significantly down-regulated after BMSCs treatment. Immunohistochemistry showed that P2X3 mainly colocalized with microglia and astrocytes. The levels of P2X3 and pro-inflammatory factors were all significantly reduced after BMSC injection. Moreover, similar attenuation was found in the CFA-treated rats after injecting the P2X3 inhibitor, and a P2X3 antagonist reversed the attenuation induced by the BMSCs. These findings suggest that BMSCs exerted a therapeutic effect on inflammatory pain by inhibiting the expression of P2X3 and the excessive production of inflammatory mediators was associated with an increased P2X3 level and BMSC therapy reverse these effects.

Higher glucose fluctuation is associated with a higher risk of cardiovascular disease: Insights from pooled results among patients with diabetes.

BACKGROUND: The relationship between glucose fluctuation and the risk of cardiovascular disease (CVD) in patients with diabetes remains elusive. Glycated hemoglobin (HbA1c) variability is a key parameter of glucose fluctuation. METHODS: PubMed, Cochrane Library, Web of Science, and Embase were searched up to 1 July 2022. Studies reporting associations of HbA1c variability (HbA1c-SD), coefficient of variation of HbA1c (HbA1c-CV), and HbA1c variability score [HVS] with the risk of CVD among patients with diabetes were included. We used three different insights (a high-low value meta-analysis, a study-specific meta-analysis, and a non-linear dose-response meta-analysis) to explore the relationship between HbA1c variability and CVD risk. A subgroup analysis was also performed to screen the potential confounding factors. RESULTS: A total of 14 studies with 254 017 patients with diabetes were eligible. The highest HbA1c variability was significantly associated with increased risks of CVD (HbA1c-SD, risk ratio [RR] 1.45; HbA1c-CV, RR 1.74; HVS, RR 2.46; all p < .001) compared to the lowest HbA1c variability. The RRs of CVD for per HbA1c variability were significantly >1 (all p < .001). The subgroup analysis for per HbA1c-SD found a significant exposure-covariate interaction in the types of diabetes (p = .003 for interaction). The dose-response analysis showed a positive association between HbA1c-CV and CVD risk (P for nonlinearity <.001). CONCLUSIONS: Our study suggests that the higher glucose fluctuation is significantly associated with the higher CVD risk in diabetes patients based on HbA1c variability. The CVD risk associated with per HbA1c-SD might be higher among patients type 1 diabetes than patients with type 2 diabetes.

Glucose fluctuations aggravate myocardial fibrosis via activating the CaMKII/Stat3 signaling in type 2 diabtetes.

BACKGROUND: Glucose fluctuations (GF) are a risk factor for cardiovascular complications associated with type 2 diabetes. However, there is a lack of adequate research on the effect of GF on myocardial fibrosis and the underlying mechanisms in type 2 diabetes. This study aimed to investigate the impact of glucose fluctuations on myocardial fibrosis and explore the potential mechanisms in type 2 diabetes. METHODS: Sprague Dawley (SD) rats were randomly divided into three groups: the control (Con) group, the type 2 diabetic (DM) group and the glucose fluctuations (GF) group. The type 2 diabetic rat model was established using a high-fat diet combined with low-dose streptozotocin injection and the GF model was induced by using staggered glucose and insulin injections daily. After eight weeks, echocardiography was used to assess the cardiac function of the three groups. Hematoxylin-eosin and Masson staining were utilized to evaluate the degree of pathological damage and fibrosis. Meanwhile, a neonatal rat cardiac fibroblast model with GF was established. Western and immunofluorescence were used to find the specific mechanism of myocardial fibrosis caused by GF. RESULTS: Compared with rats in the Con and the DM group, cardiac function in the GF group showed significant impairments. Additionally, the results showed that GF aggravated myocardial fibrosis in vitro and in vivo. Moreover, Ca2+/calmodulin­dependent protein kinase II (CaMKII) was activated by phosphorylation, prompting an increase in phosphorylation of signal transducer and activator of transcription 3 (Stat3) and induced nuclear translocation. Pretreatment with KN-93 (a CaMKII inhibitor) blocked GF-induced Stat3 activation and significantly suppressed myocardial fibrosis. CONCLUSIONS: Glucose fluctuations exacerbate myocardial fibrosis by triggering the CaMKII/Stat3 pathway in type 2 diabetes.

Identification of key immune-related genes in dilated cardiomyopathy using bioinformatics analysis.

Dilated cardiomyopathy (DCM) is characterized by the left ventricular dilatation and impaired myocardial systolic dysfunction with high mortality and morbidity. However, the underlying mechanisms remain elusive. We first identified the differentially expressed genes (DEGs) between the DCM and control group using two expression profiles from GSE3585 and GSE84796. Enrichment analysis was conducted to explore the potential mechanisms underlying DCM. A total of four algorithms, including key module of MCODE, degree, maximum neighborhood component (MNC), and maximal clique centrality (MCC), were used to identify the hub genes within Cytoscape. The correlation between hub genes and infiltrated immune cells was evaluated to determine potential immune-related genes. The expression analysis and diagnosis value analysis of potential immune-related genes were performed. Finally, the expression analysis with GSE57338 and relationship analysis with the comparative toxicogenomics database (CTD) were performed to identify the key immune-related genes in DCM. A total of 80 DEGs were screened for DCM. Enrichment analysis revealed that DEGs were involved in the immune-related pathological process. Immune infiltration analysis indicated a potentially abnormal immune response in DCM. Four up-regulated genes (COL1A2, COL3A1, CD53, and POSTN) were identified as potential immune-related genes. Finally, three genes (COL1A2, COL3A1, and POSTN) were determined as the key immune-related genes in DCM via expression analysis with a validation set (GSE57338) and relationship analysis with CTD. Our study suggested that the upregulated COL1A2, COL3A1, and POSTN might be the key immune-related genes for DCM. Further studies are needed to validate the underlying mechanisms.

Glucose fluctuations aggravated the late sodium current induced ventricular arrhythmias via the activation of ROS/CaMKII pathway.

BACKGROUND: Recent evidence revealed that glucose fluctuation might be more likely to cause arrhythmia than persistent hyperglycemia, whereas its mechanisms were elusive. We aimed to investigate the effect of glucose fluctuation on the occurrence of ventricular arrhythmia and its mechanism. METHODS: Streptozotocin (STZ) induced diabetic rats were randomized to five groups: the controlled blood glucose (C-STZ) group, uncontrolled blood glucose (U-STZ) group, fluctuated blood glucose (GF-STZ) group, and GF-STZ rats with 100 mg/kg Tempol (GF-STZ + Tempol) group or with 5 mg/kg KN93 (GF-STZ + KN93) group. Six weeks later, the susceptibility of ventricular arrhythmias and the electrophysiological dysfunctions of ventricular myocytes were evaluated using electrocardiogram and patch-clamp technique, respectively. The levels of reactive oxygen species (ROS) and oxidized CaMKII (ox-CaMKII) were determined by fluorescence assay and Western blot, respectively. Neonatal rat cardiomyocytes and H9C2 cells in vitro were used to explore the underlying mechanisms. RESULTS: The induction rate of ventricular arrhythmias was 10%, 55%, and 90% in C-STZ group, U-STZ group, and GF-STZ group, respectively (P < 0.05). The electrophysiological dysfunctions of ventricular myocytes, including action potential duration at repolarization of 90% (APD90), APD90 short-term variability (APD90-STV), late sodium current (INa-L), early after depolarization (EAD) and delayed after depolarizations (DAD), as well as the levels of ROS and ox-CaMKII, were significantly increased in GF-STZ group. In vivo and ex vivo, inhibition of ROS or ox-CaMKII reversed these effects. Inhibition of INa-L also significantly alleviated the electrophysiological dysfunctions. In vitro, inhibition of ROS increase could significantly decrease the ox-CaMKII activation induced by glucose fluctuations. CONCLUSIONS: Glucose fluctuations aggravated the INa-L induced ventricular arrhythmias though the activation of ROS/CaMKII pathway.

Glucose Fluctuations Aggravate Myocardial Fibrosis via the Nuclear Factor-κB-Mediated Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation.

Background: Glucose fluctuations may be associated with myocardial fibrosis. This study aimed to investigate the underlying mechanisms of glucose fluctuation-related myocardial fibrosis. Methods: Streptozotocin (STZ)-injected type 1 diabetic rats were randomized to five groups: the controlled blood glucose (CBG) group, uncontrolled blood glucose (UBG) group, fluctuated blood glucose (FBG) group, FBG rats injected with 0.9% sodium chloride (NaCl) (FBG + NaCl) group, and FBG rats injected with MCC950 (FBG + MCC950) group. Eight weeks later, left ventricular function was evaluated by echocardiography and myocardial fibrosis was observed by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with different concentrations of glucose in vitro. Results: The left ventricular function was impaired and myocardial fibrosis was aggravated most significantly in the FBG group compared with the CBG and UBG groups. The levels of interleukin (IL)-1ß, IL-18, transforming growth factor-ß1 (TGF-ß1), collagen type 1 (collagen I), nuclear factor (NF)-κB, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome were significantly increased in the FBG group. In vitro, the inhibition of NF-κB and inflammasome reversed these effects. In vivo, NLRP3 inhibition with MCC950 reversed left ventricular systolic dysfunction and myocardial fibrosis induced by glucose fluctuations. Conclusion: Glucose fluctuations promote diabetic myocardial fibrosis by the NF-κB-mediated inflammasome activation.