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Hippo/YAP signaling pathway: a new therapeutic target for diabetes mellitus and vascular complications.
Wei, L, Gao, J, Wang, L, Tao, Q, Tu, C
Therapeutic advances in endocrinology and metabolism. 2023;:20420188231220134
Abstract
Diabetic angiopathy, which includes diabetic kidney disease (DKD), cardio-cerebrovascular disease, and diabetic retinopathy (DR) among other diseases, is one of the most common complications affecting diabetic patients. Among these, DKD, which is a major cause of morbidity and mortality, affects about 40% of diabetic patients. Similarly, DR involves retinal neovascularization and neurodegeneration as a result of chronic hyperglycemia and is the main cause of visual impairment and blindness. In addition, inflammation also promotes atherosclerosis and diabetes, with atherosclerosis-related cardiovascular diseases being often a main cause of disability or death in diabetic patients. Given that vascular diseases caused by diabetes negatively impact human health, it is therefore important to identify appropriate treatments. In this context, some studies have found that the Hippo/Yes-associated protein (YAP) pathway is a highly evolutionarily conserved protein kinase signal pathway that regulates organ growth and size through its effector signaling pathway Transcriptional co-Activator with PDZ-binding motif (TAZ) and its YAP. YAP is a key factor in the Hippo pathway. The activation of YAP regulates gluconeogenesis, thereby regulating glucose tolerance levels; silencing the YAP gene thereby prevents the formation of glomerular fibrosis. YAP can combine with TEA domain family members to regulate the proliferation and migration of retinal vascular endothelial cells (ECs), so YAP plays a prominent role in the formation and pathology of retinal vessels. In addition, YAP/TAZ activation and translocation to the nucleus promote endothelial inflammation and monocyte-EC attachment, which can increase diabetes-induced cardiovascular atherosclerosis. Hippo/YAP signaling pathway provides a potential therapeutic target for diabetic angiopathy, which can prevent the progression of diabetes to DR and improve renal fibrosis and cardio-vascular atherosclerosis.
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Remediation technologies for neonicotinoids in contaminated environments: Current state and future prospects.
Wei, J, Wang, X, Tu, C, Long, T, Bu, Y, Wang, H, Jeyakumar, P, Jiang, J, Deng, S
Environment international. 2023;:108044
Abstract
Neonicotinoids (NEOs) are synthetic insecticides with broad-spectrum insecticidal activity and outstanding efficacy. However, their extensive use and persistence in the environment have resulted in the accumulation and biomagnification of NEOs, posing significant risks to non-target organisms and humans. This review provides a summary of research history, advancements, and highlighted topics in NEOs remediation technologies and mechanisms. Various remediation approaches have been developed, including physiochemical, microbial, and phytoremediation, with microbial and physicochemical remediation being the most extensively studied. Recent advances in physiochemical remediation have led to the development of innovative adsorbents, photocatalysts, and optimized treatment processes. High-efficiency degrading strains with well-characterized metabolic pathways have been successfully isolated and cultured for microbial remediation, while many plant species have shown great potential for phytoremediation. However, significant challenges and gaps remain in this field. Future research should prioritize isolating, domesticating or engineering high efficiency, broad-spectrum microbial strains for NEO degradation, as well as developing synergistic remediation techniques to enhance removal efficiency on multiple NEOs with varying concentrations in different environmental media. Furthermore, a shift from pipe-end treatment to pollution prevention strategies is needed, including the development of green and economically efficient alternatives such as biological insecticides. Integrated remediation technologies and case-specific strategies that can be applied to practical remediation projects need to be developed, along with clarifying NEO degradation mechanisms to improve remediation efficiency. The successful implementation of these strategies will help reduce the negative impact of NEOs on the environment and human health.
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The Role of PKM2 in Diabetic Microangiopathy.
Tu, C, Wang, L, Wei, L
Diabetes, metabolic syndrome and obesity : targets and therapy. 2022;:1405-1412
Abstract
Diabetic microangiopathy is among the most common complications affecting patients with diabetes, and includes both diabetic retinopathy (DR) and diabetic nephropathy (DKD). Diabetic microangiopathy remains a persistent threat to the health and quality of life of affected patients. Mechanistically, the severity of DR and DKD is tied to mitochondrial and glucose metabolism abnormalities, with the activation of the glycolytic enzyme pyruvate kinase M2 (PKM2) contributing to mitochondrial and glomerular dysfunction, abnormal renal hemodynamics, and retinopathy. PKM2 can activate inflammatory bodies in macrophages to promote the release of inflammatory mediators, and serves as a key regulator of inflammatory factors, chemokines and adhesion molecules. As such, there is sufficient evidence that PKM2 can be used as a biomarker for the diagnosis of diabetes and diabetic microangiopathy. Here, we survey the mechanisms whereby PKM2 contributes to diabetes-related microvascular diseases, associated regulatory roles, post-translational modifications, and the potential utility of PKM2 as a therapeutic target. Through this literature review, we have determined that PKM2 offers promise as both a diagnostic marker and therapeutic target with direct relevance to research pertaining to diabetic microangiopathy.
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RNA-binding proteins in diabetic microangiopathy.
Tu, C, Wang, L, Wei, L
Journal of clinical laboratory analysis. 2022;(5):e24407
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Abstract
BACKGROUND As the most common complication of diabetes, the diabetic microangiopathy characterizes diabetic retinopathy (DR) and nephropathy (DN). Diabetic microangiopathy has always been a serious clinical problem. A wide variety of nucleic acid interacting factors called the RNA binding proteins (RBPS) take part in several crucial cellular processes. METHODS Over the past decade, studies have shown that RBPs have crucial part in both malignant tumors and diabetes, especially in diabetic microangiopathy. This review examined the research history of RBPS in DR and DN. RESULTS We reviewed the literature and found that RBPS is potentially useful as therapeutic targets, diagnostic markers, or predict disease progression. CONCLUSION HuR acts as a vital therapeutic targeting protein in diabetic microangiopathy. IGF2BP2, P311, TTP, YBX1, and MBNL1 have a potential role in the treatment of DN.
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Risk factors for gastric cancer: A comprehensive analysis of observational studies.
Hui, Y, Tu, C, Liu, D, Zhang, H, Gong, X
Frontiers in public health. 2022;:892468
Abstract
BACKGROUND Multifarious factors have a causal relationship with gastric cancer (GC) development. We conducted a comprehensive analysis to evaluate the strength of the evidence examining non-genetic risk factors for gastric cancer. METHODS PubMed, Web of Science, and the Cochrane Library were searched from inception to November 10, 2021 to identify meta-analyses of observational studies examining the association between environmental factors and GC risk. For each meta-analysis, the random effect size, 95% confidence interval, heterogeneity among studies, and evidence of publication bias were assessed; moreover, the evidence was graded using predefined criteria, and the methodological quality was evaluated using AMSTAR 2. RESULTS A total of 137 associations were examined in 76 articles. Among these meta-analyses, 93 associations yielded significant estimates (p < 0.05). Only 10 associations had strong epidemiologic evidence, including 2 risk factors (waist circumference and bacon), and 8 protective factors (dietary total antioxidant capacity, vegetable fat, cruciferous vegetable, cabbage, total vitamin, vitamin A, vitamin C, and years of fertility); 26 associations had moderate quality of evidence; and the remaining 57 associations were rated as weak. Ninety-four (68.61%) associations showed significant heterogeneity. Twenty-five (18.25%) associations demonstrated publication bias. CONCLUSIONS In this comprehensive analysis, multiple associations were found between environmental factors and GC with varying levels of evidence. Healthy dietary habits and lifestyle patterns could reduce the risk for GC. However, further high-quality prospective studies are still necessary to draw more definitive conclusions.
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Patients' risk factors for periprosthetic joint infection in primary total hip arthroplasty: a meta-analysis of 40 studies.
Ren, X, Ling, L, Qi, L, Liu, Z, Zhang, W, Yang, Z, Wang, W, Tu, C, Li, Z
BMC musculoskeletal disorders. 2021;(1):776
Abstract
BACKGROUND Periprosthetic joint infection (PJI) is a catastrophic complication after total hip arthroplasty (THA). Our meta-analysis aimed to identify the individual-related risk factors that predispose patients to PJI following primary THA. METHODS Comprehensive literature retrieval from Pubmed, Web of Science, and the Cochrane Library was performed from inception to Feb 20th, 2021. Patient-related risk factors were compared as per the modifiable factors (BMI, smoke and alcohol abuse), non-modifiable factors (gender, age), and medical history characteristics, such as diabetes mellitus (DM), avascular necrosis (AVN) of femoral head, femoral neck fracture, rheumatoid arthritis (RA), cardiovascular disease (CVD), and osteoarthritis (OA) etc. The meta-analysis was applied by using risk ratios with 95% corresponding intervals. Sensitivity analysis and publication bias were performed to further assess the credibility of the results. RESULTS Overall, 40 studies with 3,561,446 hips were enrolled in our study. By implementing cumulative meta-analysis, higher BMI was found associated with markedly increased PJI risk after primary THA [2.40 (2.01-2.85)]. Meanwhile, medical characteristics including DM [1.64 (1.25-2.21)], AVN [1.65 (1.07-2.56)], femoral neck fracture [1.75 (1.39-2.20)], RA [1.37 (1.23-1.54)], CVD [1.34 (1.03-1.74)], chronic pulmonary disease (CPD) [1.22 (1.08-1.37)], neurological disease [1.19 (1.05-1.35)], opioid use [1.53 (1.35-1.73)] and iron-deficiency anemia (IDA) [1.15 (1.13-1.17)] were also significantly correlated with higher rate of PJI. Conversely, dysplasia or dislocation [0.65 (0.45-0.93)], and OA [0.70 (0.62-0.79)] were protective factors. Of Note, female gender was protective for PJI only after longer follow-up. Besides, age, smoking, alcohol abuse, previous joint surgery, renal disease, hypertension, cancer, steroid use and liver disease were not closely related with PJI risk. CONCLUSION Our finding suggested that the individual-related risk factors for PJI after primary THA included high BMI, DM, AVN, femoral neck fracture, RA, CVD, CPD, neurological disease, opioid use and IDA, while protective factors were female gender, dysplasia/ dislocation and OA.
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Association of prior metabolic and bariatric surgery with severity of coronavirus disease 2019 (COVID-19) in patients with obesity.
Aminian, A, Fathalizadeh, A, Tu, C, Butsch, WS, Pantalone, KM, Griebeler, ML, Kashyap, SR, Rosenthal, RJ, Burguera, B, Nissen, SE
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2021;17(1):208-214
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A growing body of evidence indicates that patients with obesity are disproportionately affected with a severe form of SARS-CoV-2 infection and may experience resultant higher mortality. The aim of this study was to determine the association of prior metabolic surgery with severity of SARSCoV-2 infection in patients with severe obesity. This study is a retrospective, matched-cohort analysis of a prospective, observational, institutional review board–approved clinical registry of all patients tested for SARS-CoV-2 infection. The study population included a total of 363 patients, including 33 individuals who had metabolic surgery and 330 matched patients who tested positive. Results indicate that a history of metabolic surgery is associated with lower severity of SARSCoV-2 infection in patients with severe obesity, as manifested by lower risks of hospital and ICU admission. Authors conclude that prior metabolic surgery with subsequent weight loss and improvement of metabolic abnormalities could potentially reduce morbidity from SARS-CoV-2 infection.
Abstract
BACKGROUND Obesity is a risk factor for poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). OBJECTIVES To investigate the relationship between prior metabolic surgery and the severity of COVID-19 in patients with severe obesity. SETTING Cleveland Clinic Health System in the United States. METHODS Among 4365 patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between March 8, 2020 and July 22, 2020 in the Cleveland Clinic Health System, 33 patients were identified who had a prior history of metabolic surgery. The surgical patients were propensity matched 1:10 to nonsurgical patients to assemble a cohort of control patients (n = 330) with a body mass index (BMI) ≥ 40 kg/m2 at the time of SARS-CoV-2 testing. The primary endpoint was the rate of hospital admission. The exploratory endpoints included admission to the intensive care unit (ICU), need for mechanical ventilation and dialysis during index hospitalization, and mortality. After propensity score matching, outcomes were compared in univariate and multivariate regression models. RESULTS The average BMI of the surgical group was 49.1 ± 8.8 kg/m2 before metabolic surgery and was down to 37.2 ± 7.1 at the time of SARS-CoV-2 testing, compared with the control group's BMI of 46.7 ± 6.4 kg/m2. In the univariate analysis, 6 (18.2%) patients in the metabolic surgery group and 139 (42.1%) patients in the control group were admitted to the hospital (P = .013). In the multivariate analysis, a prior history of metabolic surgery was associated with a lower hospital admission rate compared with control patients with obesity (odds ratio, 0.31; 95% confidence interval, 0.11-0.88; P = .028). While none of the 4 exploratory outcomes occurred in the metabolic surgery group, 43 (13.0%) patients in the control group required ICU admission (P = .021), 22 (6.7%) required mechanical ventilation, 5 (1.5%) required dialysis, and 8 (2.4%) patients died. CONCLUSION Prior metabolic surgery with subsequent weight loss and improvement of metabolic abnormalities was associated with lower rates of hospital and ICU admission in patients with obesity who became infected with SARS-CoV-2. Confirmation of these findings will require larger studies.
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Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection.
Tang, F, Tie, Y, Hong, W, Wei, Y, Tu, C, Wei, X
Annals of surgical oncology. 2021;(7):4030-4048
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Abstract
Surgical resection is a common therapeutic option for primary solid tumors. However, high cancer recurrence and metastatic rates after resection are the main cause of cancer related mortalities. This implies the existence of a "fertile soil" following surgery that facilitates colonization by circulating cancer cells. Myeloid-derived suppressor cells (MDSCs) are essential for premetastatic niche formation, and may persist in distant organs for up to 2 weeks after surgery. These postsurgical persistent lung MDSCs exhibit stronger immunosuppression compared with presurgical MDSCs, suggesting that surgery enhances MDSC function. Surgical stress and trauma trigger the secretion of systemic inflammatory cytokines, which enhance MDSC mobilization and proliferation. Additionally, damage associated molecular patterns (DAMPs) directly activate MDSCs through pattern recognition receptor-mediated signals. Surgery also increases vascular permeability, induces an increase in lysyl oxidase and extracellular matrix remodeling in lungs, that enhances MDSC mobilization. Postsurgical therapies that inhibit the induction of premetastatic niches by MDSCs promote the long-term survival of patients. Cyclooxygenase-2 inhibitors and β-blockade, or their combination, may minimize the impact of surgical stress on MDSCs. Anti-DAMPs and associated inflammatory signaling inhibitors also are potential therapies. Existing therapies under tumor-bearing conditions, such as MDSCs depletion with low-dose chemotherapy or tyrosine kinase inhibitors, MDSCs differentiation using all-trans retinoic acid, and STAT3 inhibition merit clinical evaluation during the perioperative period. In addition, combining low-dose epigenetic drugs with chemokine receptors, reversing immunosuppression through the Enhanced Recovery After Surgery protocol, repairing vascular leakage, or inhibiting extracellular matrix remodeling also may enhance the long-term survival of curative resection patients.
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The addition of topical calcipotriol to phototherapy enhance the efficacy of treatment in patients with vitiligo: A systematic review and meta-analysis.
Hu, M, Liao, K, Lei, W, Zhang, R, Tu, C
International immunopharmacology. 2021;:107910
Abstract
BACKGROUND Treatment of vitiligo has several challenges. Phototherapy and topical calcipotriol have been reported to be effective in combination with other therapies, but there is no consensus on the combination use. OBJECTIVE To perform a systematic review and meta-analysis that elucidates the efficacy of the combination of phototherapy and topical calcipotriol. METHODS This systematic review was performed by searching PubMed, EMBASE, Web of Science, Cochrane Library databases, Chinese National Knowledge Infrastructure (CNKI), WanFang and VIP databases for relevant publications till February 28, 2021. Relative risk (RR) and its 95% confidence interval (CI) were used to evaluate the data. Bias assessment, heterogeneity and sensitivity analysis were conducted in this meta-analysis. RESULTS After screening, nine studies with 700 participants were included. The meta-analysis indicated that the combination of phototherapy and topical calcipotriol showed significantly higher effective rate (RR 1.11, 95% CI 1.02-1.22; p < 0.05) and apparent effective rate (RR 1.35, 95% CI 1.15-1.59; p < 0.01) than phototherapy monotherapy in the treatment of vitiligo. In addition, the side effects were minor, transient and tolerable. CONCLUSIONS This meta-analysis provides evidence supporting phototherapy combined with topical calcipotriol as a valuable treatment modality for patients with vitiligo, which has better efficacy than monotherapy.
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Identification of DNAH6 mutations in infertile men with multiple morphological abnormalities of the sperm flagella.
Tu, C, Nie, H, Meng, L, Yuan, S, He, W, Luo, A, Li, H, Li, W, Du, J, Lu, G, et al
Scientific reports. 2019;(1):15864
Abstract
Male infertility due to spermatogenesis defects affects millions of men worldwide. However, the genetic etiology of the vast majority remains unclear. Here we describe three men with primary infertility due to multiple morphological abnormalities of the sperm flagella (MMAF) from two unrelated Han Chinese families. We performed whole-exome sequencing (WES) and Sanger sequencing on the proband of family 1, and found that he carried novel compound heterozygous missense mutations in dynein axonemal heavy chain 6 (DNAH6) that resulted in the substitution of a conserved amino acid residue and co-segregated with the MMAF phenotype in this family. Papanicolaou staining and transmission electron microscopy analysis revealed morphological and ultrastructural abnormalities in the sperm flagella in carriers of these genetic variants. Immunostaining experiments showed that DNAH6 was localized in the sperm tail. This is the first report identifying novel recessive mutations in DNAH6 as a cause of MMAF. These findings expand the spectrum of known MMAF mutations and phenotypes and provide information that can be useful for genetic and reproductive counseling of MMAF patients.