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Purpose: Corneal injury (CI) resulting in corneal opacity remains a clinical challenge. Exosomes (Exos) derived from bone marrow mesenchymal stem cells (BMSCs) have been proven effective in repairing various tissue injuries and are also considered excellent drug carriers due to their biological properties. Recently, microRNA-29b (miR-29b) was found to play an important role in the autophagy regulation which correlates with cell inflammation and fibrosis. However, the effects of miR-29b and autophagy on CI remain unclear. To find better treatments for CI, we used Exos to carry miR-29b and investigated its effects in the treatment of CI. Methods: BMSCs were transfected with miR-29b-3p agomir/antagomir and negative controls (NCs) to obtain Exos-29b-ago, Exos-29b-anta, and Exos-NC. C57BL/6J mice that underwent CI surgeries were treated with Exos-29b-ago, Exos-29b-anta, Exos-NC, or PBS. The autophagy, inflammation, and fibrosis of the cornea were estimated by slit-lamp, hematoxylin and eosin (H&E) staining, immunofluorescence, RTâqPCR, and Western blot. The effects of miR-29b-3p on autophagy and inflammation in immortalized human corneal epithelial cells (iHCECs) were also investigated. Results: Compared to PBS, Exos-29b-ago, Exos-29b-anta, and Exos-NC all could ameliorate corneal inflammation and fibrosis. However, Exos-29b-ago, which accumulated a large amount of miR-29b-3p, exerted excellent potency via autophagy activation by inhibiting the PI3K/AKT/mTOR pathway and further inhibited corneal inflammation via the mTOR/NF-κB/IL-1ß pathway. After Exos-29b-ago treatment, the expressions of collagen type III, α-smooth muscle actin, fibronectin, and vimentin were significantly decreased than in other groups. In addition, overexpression of miR-29b-3p prevented iHCECs from autophagy impairment and inflammatory injury. Conclusions: Exos from BMSCs carrying miR-29b-3p can significantly improve the therapeutic effect on CI via activating autophagy and further inhibiting corneal inflammation and fibrosis.
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Autofagia , Lesões da Córnea , Modelos Animais de Doenças , Exossomos , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , MicroRNAs , Animais , MicroRNAs/genética , Exossomos/metabolismo , Exossomos/transplante , Células-Tronco Mesenquimais/metabolismo , Camundongos , Lesões da Córnea/metabolismo , Lesões da Córnea/genética , Lesões da Córnea/terapia , Portadores de Fármacos , Inflamação/metabolismo , Masculino , Células Cultivadas , Humanos , Western BlottingRESUMO
BACKGROUND: Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored. METHODS: We studied the function of Hmbox1 in exercise-induced physiological cardiac growth in mice after 4 weeks of swimming exercise. Hmbox1 expression was then evaluated in human heart samples from deceased patients with myocardial infarction and in the animal cardiac I/R injury model. Its role in cardiac I/R injury was examined in mice with adeno-associated virus 9 (AAV9) vector-mediated Hmbox1 knockdown and in those with cardiac myocyte-specific Hmbox1 ablation. We performed RNA sequencing, promoter prediction, and binding assays and identified glucokinase (Gck) as a downstream effector of Hmbox1. The effects of Hmbox1 together with Gck were examined in cardiomyocytes to evaluate their cell size, proliferation, apoptosis, mitochondrial respiration, and glycolysis. The function of upstream regulator of Hmbox1, ETS1, was investigated through ETS1 overexpression in cardiac I/R mice in vivo. RESULTS: We demonstrated that Hmbox1 downregulation was required for exercise-induced physiological cardiac growth. Inhibition of Hmbox1 increased cardiomyocyte size in isolated neonatal rat cardiomyocytes and human embryonic stem cell-derived cardiomyocytes but did not affect cardiomyocyte proliferation. Under pathological conditions, Hmbox1 was upregulated in both human and animal postinfarct cardiac tissues. Furthermore, both cardiac myocyte-specific Hmbox1 knockout and AAV9-mediated Hmbox1 knockdown protected against cardiac I/R injury and heart failure. Therapeutic effects were observed when sh-Hmbox1 AAV9 was administered after I/R injury. Inhibition of Hmbox1 activated the Akt/mTOR/P70S6K pathway and transcriptionally upregulated Gck, leading to reduced apoptosis and improved mitochondrial respiration and glycolysis in cardiomyocytes. ETS1 functioned as an upstream negative regulator of Hmbox1 transcription, and its overexpression was protective against cardiac I/R injury. CONCLUSIONS: Our studies unravel a new role for the transcriptional repressor Hmbox1 in exercise-induced physiological cardiac growth. They also highlight the therapeutic potential of targeting Hmbox1 to improve myocardial survival and glucose metabolism after I/R injury.
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Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell-to-myeloid cell interactions remain largely unknown, we sought to investigate the cross-talk between NK cells and suppressive myeloid cells. Upon contact with tumor-experienced NK cells, monocytes and neutrophils displayed increased expression of MDSC-related suppressive factors along with increased capacities to suppress T cells. These changes were accompanied by impaired antigen presentation by monocytes and increased ER stress response by neutrophils. In a cohort of patients with sarcoma and breast cancer, the production of interleukin-6 (IL-6) by tumor-infiltrating NK cells correlated with S100A8/9 and arginase-1 expression by MDSCs. At the same time, NK cell-derived IL-6 was associated with tumors with higher major histocompatibility complex class I expression, which we further validated with b2m-knockout (KO) tumor mice models. Similarly in syngeneic wild-type and IL-6 KO mouse models, we then demonstrated that the accumulation of MDSCs was influenced by the presence of such regulatory NK cells. Inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) axis alleviated suppression of T cell responses, resulting in reduced tumor growth and metastatic dissemination. Together, these results characterize a critical NK cell-mediated mechanism that drives the development of MDSCs during tumor immune escape.
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Tolerância Imunológica , Interleucina-6 , Células Matadoras Naturais , Células Supressoras Mieloides , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Interleucina-6/metabolismo , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/imunologia , Animais , Humanos , Transdução de Sinais , Microambiente Tumoral/imunologia , Camundongos Knockout , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) ranks as the third most common cause of cancer related death globally, representing a substantial challenge to global healthcare systems. In China, the primary risk factor for HCC is the hepatitis B virus (HBV). Aberrant serum glycoconjugate levels have long been linked to the progression of HBV-associated HCC (HBV-HCC). Nevertheless, few study systematically explored the dysregulation of glycoconjugates in the progression of HBV-associated HCC and their potency as the diagnostic and prognostic biomarker. METHODS: An integrated strategy that combined transcriptomics, glycomics, and glycoproteomics was employed to comprehensively investigate the dynamic alterations in glyco-genes, N-glycans, and glycoproteins in the progression of HBV- HCC. RESULTS: Bioinformatic analysis of Gene Expression Omnibus (GEO) datasets uncovered dysregulation of fucosyltransferases (FUTs) in liver tissues from HCC patients compared to adjacent tissues. Glycomic analysis indicated an elevated level of fucosylated N-glycans, especially a progressive increase in fucosylation levels on IgA1 and IgG2 determined by glycoproteomic analysis. CONCLUSIONS: The findings indicate that the abnormal fucosylation plays a pivotal role in the progression of HBV-HCC. Systematic and integrative multi-omic analysis is anticipated to facilitate the discovery of aberrant glycoconjugates in tumor progression.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Glicômica , Glicoproteínas/genética , Perfilação da Expressão Gênica , PolissacarídeosRESUMO
OBJECTIVE: To evaluate the effect of recombinant human epidermal growth factor (rhEGF) on radiotherapy-related neuropathic pain in patients with head and neck malignancies, and to explore comprehensive nursing strategies. METHODS: In this retrospective study, a total of 80 patients diagnosed with head and neck malignancy and receiving radiotherapy were divided into 2 groups according to treatment. Patients in the control group received conventional radiation therapy and postoperative care, and those in the trial group received rhEGF in addition to conventional radiation therapy and care. Visual analogue scale (VAS) was used to evaluate the pain degree of patients before and after treatment, EORTC QLQ-C30 scale was used to evaluate the quality of life of patients before and after treatment, and the skin and mucosal reactions of patients after radiotherapy were observed. RESULTS: Baseline characteristics were similar between the two groups. VAS scores in the trial group were significantly lower than those in the control group during and after radiotherapy (p < 0.001), and skin and mucosal reactions were less severe (p < 0.05). In addition, compared with the control group, the quality of life and symptom scores of the trial group were significantly improved after treatment (p < 0.05). CONCLUSION: rhEGF can effectively alleviate neuropathic pain during and after radiotherapy in patients with head and neck malignancies, improve skin and mucosal response, and improve quality of life.
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Arabidopsis plants adapt to warm temperatures by promoting hypocotyl growth primarily through the basic helix-loop-helix transcription factor PIF4 and its downstream genes involved in auxin responses, which enhance cell division. In the current study, we discovered that cell wall-related calcium-binding protein 2 (CCaP2) and its paralogs CCaP1 and CCaP3 function as positive regulators of thermo-responsive hypocotyl growth by promoting cell elongation in Arabidopsis. Interestingly, mutations in CCaP1/CCaP2/CCaP3 do not affect the expression of PIF4-regulated classic downstream genes. However, they do noticeably reduce the expression of xyloglucan endotransglucosylase/hydrolase genes, which are involved in cell wall modification. We also found that CCaP1/CCaP2/CCaP3 are predominantly localized to the plasma membrane, where they interact with the plasma membrane H+-ATPases AHA1/AHA2. Furthermore, we observed that vanadate-sensitive H+-ATPase activity and cell wall pectin and hemicellulose contents are significantly increased in wild-type plants grown at warm temperatures compared with those grown at normal growth temperatures, but these changes are not evident in the ccap1-1 ccap2-1 ccap3-1 triple mutant. Overall, our findings demonstrate that CCaP1/CCaP2/CCaP3 play an important role in controlling thermo-responsive hypocotyl growth and provide new insights into the alternative pathway regulating hypocotyl growth at warm temperatures through cell wall modification mediated by CCaP1/CCaP2/CCaP3.
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Proteínas de Arabidopsis , Arabidopsis , Membrana Celular , Parede Celular , ATPases Translocadoras de Prótons , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Parede Celular/metabolismo , Parede Celular/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Membrana Celular/metabolismo , ATPases Translocadoras de Prótons/metabolismo , ATPases Translocadoras de Prótons/genética , Regulação da Expressão Gênica de Plantas , Hipocótilo/crescimento & desenvolvimento , Hipocótilo/genética , Hipocótilo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genéticaRESUMO
Objective: To validate whether a residual mass demonstrated on early postoperative MR after percutaneous endoscopic lumbar discectomy (PELD) is indeed an intraoperatively retained annulus fibrosus, and explore the correlation between imaging changes in the residual mass and clinical prognosis of patients. Methods: A prospective study of 118 patients were included. During surgery, a contrast medium, Gadopentetate Dimeglumine, was injected around the ruptured annulus fibrosus. The intensity of the T2 signal, the size of the remaining mass (SR), and the cross-sectional area of the spinal canal (SCSA), VAS, and ODI were assessed at preoperative, 1-h (7-day), 6-month, and 12-month postoperative intervals. Based on VAS at 7 days post-surgery, patients were classified into either a non-remission group (Group A, VAS > 3) or a remission group (Group B, VAS ≤ 3). Results: Six patients who developed recurrent LDH were excluded. A residual mass was detected on MRI 1 h after surgery in 94.6% (106/112). During one year of follow-up, 90.1% (101/112) of the patients displayed fibrous annulus remodeling, although 68.7% (77/112) still exhibited herniation. Significant differences were found in the ODI between Groups A and B one week after surgery (p < 0.001). However, no significant differences were observed in T2 signal intensity, SR, and SCSA at 1-h, 6-month and 12-month post-surgery (p > 0.05) between the two groups. In a multiple linear regression analysis, early postoperative ODI changes were associated with T2 signal (B = -10.22, sig < 0.05), long-term changes were associated with alterations in SR (B = 5.63, sig < 0.05) and SCSA (B = -0.13, sig < 0.05). Conclusion: The residual mass observed in early postoperative MR images after PELD was the retained annulus fibrosus intraoperatively. Short-term changes in clinical symptoms after PELD were linked to T2 signal intensity, while long-term changes were associated with changes in SR and SCSA.
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Central nervous system (CNS) diseases are one of the diseases that threaten human health. The delivery of drugs targeting the CNS has always been a significant challenge; the blood-brain barrier (BBB) is the main obstacle that must be overcome. The rise of bone marrow mesenchymal stem cell (BMSC) therapy has brought hope for the treatment of CNS diseases. However, the problems of low homing rate, susceptibility differentiation into astrocytes, immune rejection, and formation of iatrogenic tumors of transplanted BMSCs limit their clinical application. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have become a hot research topic in the treatment of CNS diseases in recent years because of their excellent histocompatibility, low immunogenicity, ease of crossing the BBB, and their ability to serve as natural carriers for treatment. This article reviews the mechanisms of BMSC-Exos in CNS diseases and provides direction for further research.
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Purpose: This study aimed to explore the effects of elevated KDM4D expression and potential therapeutic effects of Lycium barbarum polysaccharide (LBP) on pterygium. Methods: The expression levels of KDM4D in the primary pterygium (n = 29) and normal conjunctiva (n = 14) were detected by immunohistochemistry. The effects of KDM4D on pterygium fibroblasts were detected by the CCK-8 assay, liquid chromatography-mass spectrometry assay, flow cytometry, and scratch wound healing assay. The relative expression of KDM4D in pterygium fibroblasts stimulated by interleukin (IL)-1ß, IL-6, IL-8, and LBP was detected by quantitative real-time PCR and Western blot. The effects of LBP on pterygium fibroblasts were detected using flow cytometry and scratch wound healing assays. Results: The expression level of KDM4D in pterygium was higher than that in normal conjunctiva. KDM4D increased the cell viability of pterygium fibroblasts. The differentially expressed genes identified in the LM-MS assay enriched in "actin filament organization" and "apoptosis." KDM4D promoted migration and inhibited apoptosis of pterygium fibroblasts in vitro. Inflammatory cytokines, including IL-1ß, IL-6, and IL-8, enhanced the expression of KDM4D in pterygium fibroblasts. LBP inhibited the expression of KDM4D in pterygium fibroblasts and decreased their cell viability. Moreover, LBP attenuated the KDM4D effects on migration and apoptosis of pterygium fibroblasts. Conclusions: Elevated KDM4D expression is a risk factor for pterygium formation. LBP inhibits the expression of KDM4D in pterygium fibroblasts and may be a potential drug for delaying pterygium development.
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Túnica Conjuntiva/anormalidades , Medicamentos de Ervas Chinesas , Pterígio , Humanos , Pterígio/tratamento farmacológico , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismoRESUMO
DNA cytosine methylation plays a vital role in repressing retrotransposons, and such derepression is linked with developmental failure, tumorigenesis and aging. DNA methylation patterns are formed by precisely regulated actions of DNA methylation writers (DNA methyltransferases) and erasers (TET, ten-eleven translocation dioxygenases). However, the mechanisms underlying target-specific oxidation of 5mC by TET dioxygenases remain largely unexplored. Here we show that a large low-complexity domain (LCD), located in the catalytic part of Tet enzymes, negatively regulates the dioxygenase activity. Recombinant Tet3 lacking LCD is shown to be hyperactive in converting 5mC into oxidized species in vitro. Endogenous expression of the hyperactive Tet3 mutant in mouse oocytes results in genome-wide 5mC oxidation. Notably, the occurrence of aberrant 5mC oxidation correlates with a consequent loss of the repressive histone mark H3K9me3 at ERVK retrotransposons. The erosion of both 5mC and H3K9me3 causes ERVK derepression along with upregulation of their neighboring genes, potentially leading to the impairment of oocyte development. These findings suggest that Tet dioxygenases use an intrinsic auto-regulatory mechanism to tightly regulate their enzymatic activity, thus achieving spatiotemporal specificity of methylome reprogramming, and highlight the importance of methylome integrity for development.
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5-Metilcitosina , Dioxigenases , Animais , Camundongos , 5-Metilcitosina/metabolismo , Dioxigenases/genética , Dioxigenases/metabolismo , Retroelementos/genética , Metilação de DNA , Oócitos/metabolismo , DesmetilaçãoRESUMO
BACKGROUND: To explore the value of arterial spin labeled (ASL) and blood oxygen level dependent (BOLD) imaging in evaluating allogeneic kidney function after renal transplantation. METHODS: One hundred and thirty-five renal transplant patients were included. Demographic and imaging data were collected. Transplanted renal function, pathology, ASL and BOLD parameters were obtained. The patients were divided into normal, mild and severe injury group. The correlation between BOLD/ASL parameters and clinical data were evaluated. The prediction models were based on ASL and BOLD parameters using multivariate logistic analysis. Cox proportional hazards regression model was used to analyze the effects of gender, age, ASL and BOLD on the survival of renal transplant patients. RESULTS: ASL and BOLD parameters were independently associated with renal function injury and renal allograft positive pathology. The AUC of prediction model for renal allograft function based on ASL and BOLD parameters was 0.85, while the AUC based on BOLD parameters was 0.70. Renal transplantation time showed a positive correlation with age, BOLD parameters and SCrï¼while a negative correlation with ASL parameters and eGFR. ASL parameter was positively correlated with eGFR and negatively correlated with Scr. BOLD parameter was negatively correlated with eGFR, ASL and positively correlated with Scr. Cox proportional hazards regression model showed that the increase of age could reduce the risk of renal function injury and positive pathology. CONCLUSIONS: ASL and BOLD were associated with renal function injury and renal allograft positive pathology. ASL and BOLD had some value in predicting renal allograft function.
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Transplante de Rim , Humanos , Imageamento por Ressonância Magnética/métodos , Rim/diagnóstico por imagem , Artérias , AloenxertosRESUMO
Kidney renal clear cell carcinoma (KIRC) is the most prevalent type of kidney cancer and causes thousands of deaths each year. The prognosis for KIRC is poor. One critical factor is that the mechanism beneath KIRC is unclear. ORM1 is a reactant to acute inflammation. In this study, we demonstrated that methylation of ORM1 promoter was low and ORM1 was expressed significantly higher in KIRC. KIRC with higher ORM1 expression exhibited worse survival probability. Meanwhile, ORM1 was expressed higher in KIRC cell lines. When ORM1 was knocked down, cell proliferation ability was inhibited potently compared to the NC control. Cell migration as well as invasion ability were also suppressed dramatically. At molecular level, the expression of active caspase-3 and Bax was upregulated in ORM1-KD group while Bcl-2 downregulated. Moreover, CALR decreased following ORM1-KD and rescued expression of CALR increased Bcl-2 level but reduced the level of cleaved caspase-3 and Bax. Consistently, the apoptotic rate of 786-O and Caki-2 cells was upregulated in ORM1-KD but downregulated after CALR overexpression. The activity of caspase-3 was also regulated by ORM1-KD. In addition, the inhibition rate of sorafenib was enhanced in ORM1 KD group but reduced after overexpression of ORM1. Conclusively, ORM1 is clinically associated with progression of KIRC and regulates cell proliferation, migration, invasion, and apoptosis in KIRC. Moreover, ORM1 affects the efficiency of sorafenib in KIRC and regulates caspase-3 mediated cascades response through CALR molecule. This study provides us a new way to recognize the development and progression in KIRC.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Sorafenibe , Caspase 3/genética , Proteína X Associada a bcl-2 , Carcinoma de Células Renais/genética , Processos Neoplásicos , Neoplasias Renais/genética , Apoptose/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , RimRESUMO
The results of environmental epidemiological studies regarding the relationship between human exposure to nickel and the risk of diabetes remain controversial. Therefore, we performed a meta-analysis to investigate the relationship between nickel exposure and diabetes. PubMed, Web of Science, and Embase electronic databases were thoroughly searched from their inception to May 2023 to obtain relevant studies. The random-effects model was employed to determine pooled odds ratios (ORs) and 95% confidence intervals (CIs). Stratified and sensitivity analyses were also performed. Cochran Q test and I2 statistic were employed to assess heterogeneity between studies. Begg's and Egger's tests were employed to evaluate publication bias. The indicated studies were evaluated using the ROBINS-E risk of bias tool. The dose-response relationship between nickel in urine and diabetes risk was estimated by restricted cubic spline. A total of 12 studies with 30,018 participants were included in this study. In this meta-analysis, comparing the highest vs. lowest levels of nickel exposure, the pooled ORs for diabetes were 1.42 (95% confidence interval 1.14-1.78) for urine and 1.03 (0.57-1.86) for blood, respectively. A linear relationship between urinary nickel and diabetes risk was discovered in the dose-response analysis (P nonlinearity = 0.6198). Each 1 µg/L increase of urinary nickel, the risk of diabetes increased by 7% (OR = 1.07, 95% CI 1.04-1.10). The risk of diabetes was positively correlated with urine nickel exposure, whereas the risk was not significantly correlated with blood nickel. In the future, more high-quality prospective studies are needed to validate this conclusion.
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Líquidos Corporais , Diabetes Mellitus , Humanos , Níquel , Diabetes Mellitus/epidemiologia , Estudos Prospectivos , Razão de ChancesRESUMO
BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction. Despite the potential benefits of higher physical activity and lower sedentary behavior in MG patients, evidence from observational studies for the effect of physical activity on the risk of MG is limited and inconclusive. METHODS: We employed linkage disequilibrium score (LDSC) regression, two-sample Mendelian randomization (MR), and its multivariable extension analyses (MVMR) to assess the relationship between leisure screen time (LST), moderate-to-vigorous intensity physical activity during leisure time (MVPA) and the risk of MG using genome-wide association studies (GWAS) summary datasets. MR analyses were performed using the inverse-variance-weighted (IVW), weighted-median, and MR-Egger regression. Sensitivity analyses were further performed using alternative instruments to test the robustness of our findings. RESULTS: We found evidence of genetic overlap between LST (rg = 0.113, P = 0.023) and MG, as well as between MVPA (rg=-0.220, P = 0.0001) and MG, using LDSC method. The results of the MR suggested an association between genetic liability to LST and increased risk of MG (IVW OR = 1.609, 95% CI = 1.153 to 2.244; P = 0.005). This association was particularly notable for late-onset MG (IVW OR = 1.698, 95% CI = 1.145 to 2.518; P = 0.008), but not for early-onset MG. Consistent findings were obtained in the MVMR analysis using BMI as covariate (IVW OR = 1.593, 95% CI 1.167 to 2.173, P = 0.003). However, the MR analysis does not support a substantial causal effect of MVPA on the risk of MG. CONCLUSION: Our findings support a causal effect of sedentary behavior as measured by LST on MG, indicating that lack of exercise may play a role in the development of MG. Longitudinal and interventional studies of this association are warranted.
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Miastenia Gravis , Comportamento Sedentário , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Miastenia Gravis/epidemiologia , Miastenia Gravis/genética , Exercício Físico , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
This study aimed to investigate the effects of different levels of autophagy induced by transient serum starvation on the metabolism, lipid metabolism, and differentiation of porcine skeletal muscle satellite cells (SMSCs) to preliminary elucidate the role and function of autophagy in the regulatory network of skeletal muscle development. Different levels of autophagy were induced by controlling the serum concentration in the culture system for 24 h. Apoptosis, membrane potential, reactive oxygen species (ROS), ATP, and myogenic and lipogenic differentiation markers were monitored to determine if autophagy affected the metabolism and differentiation of SMSCs. Autophagy was induced in SMSCs via serum starvation (5%, 15%), as evidenced by decreased p62 and mTOR phosphorylation levels and increased LC3B lipidation and AMPK phosphorylation levels. Transmission electron microscopy revealed the presence of autophagosomes, and the rates of morphologically abnormal nuclei and mitochondria gradually increased with the decrease in serum concentration, the number of autophagic lysosomes also increased, indicating that 5% serum starvation induced severe autophagy, while 15% serum starvation induced mild autophagy. Compared with the control group and 15% serum-starved SMSCs, SMSCs undergoing 5% serum starvation had the highest intracellular ATP and ROS levels, the highest percentage of apoptotic cells, and the lowest membrane potential. The 15% serum-starved SMSCs had the highest membrane potential, but the percentage of apoptotic cells did not change significantly compared with the control group. The levels of the myogenic markers MyoD1 and MHC were significantly higher in 15% serum-starved SMSCs than in serum-sufficient SMSCs and the lowest in the 5% serum-starved SMSCs. The lipid contents (measured by Oil Red O staining and quantification of triglycerides) and lipogenic markers Peroxisome Proliferators-activated Receptors γ and Lipoprotein Lipase were also significantly higher in SMSCs undergoing 15% serum starvation than in the control group, and the lowest in the 5% serum-starved SMSCs. Different levels of starvation stress induce different levels of autophagy. Mild autophagy induced by moderate serum starvation promotes the metabolism and differentiation of SMSCs, while severe autophagy renders SMSCs more apoptotic, abnormal metabolism and suppresses SMSC differentiation into adipocytes or myocytes, and reduces lipid metabolisms. Our study suggests that autophagy plays a role in skeletal muscle development and may help design strategies for improving meat production traits in domestic pigs.
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Células Satélites de Músculo Esquelético , Inanição , Animais , Suínos , Espécies Reativas de Oxigênio/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Diferenciação Celular , Autofagia , Inanição/metabolismo , Lipídeos/farmacologia , Trifosfato de Adenosina/metabolismo , Músculo Esquelético/metabolismoRESUMO
PURPOSE: Aspirin has been suggested to reduce the risk of cancer. However, previous studies have been inconsistent regarding the relationship between aspirin use and the risk of occurrence of prostate cancer (PCa). The purpose of this study was to assess the effect of aspirin on clinical outcomes in patients with PCa in a meta-analysis and to explore the possible dose-response relationship. METHODS: A systematic literature search was conducted in 10 electronic databases and 4 registries. The combined relative risks (RRs) were calculated using a random-effects model with 95% confidence interval (CIs) to assess the effect of aspirin on the risk of PCa. Relevant subgroup analyses and sensitivity analyses were performed. RESULTS: The across studies results show that aspirin use associated with lower incidence of PCa (RR: 0.96, 95% CI: 0.95-0.98), and reduced mortality (RR: 0.88, 95% CI: 0.82-0.95). The results of the subgroup analysis indicated that both cohort and population studies in the Americas showed a reduction in PCa incidence and mortality with aspirin use. A linear correlation was observed between dosage/duration of aspirin use and its protective effect. Additionally, post-diagnosis aspirin use was associated with decreased risk of PCa mortality. CONCLUSIONS: This meta-analysis revealed an independent correlation between the use of aspirin and reductions in both the incidence and mortality rates of PCa. However, randomized controlled trials did not find any association between aspirin use and PCa. Furthermore, the impact of aspirin on PCa occurrence was found to be dependent on both dosage and duration.
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Aspirina , Neoplasias da Próstata , Masculino , Humanos , Aspirina/uso terapêutico , Incidência , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/induzido quimicamente , RiscoRESUMO
The association between sugar-sweetened beverages intake and colorectal cancer (CRC) remains controversial. A metaanalysis was performed to clarify the correlation between sugar-sweetened beverages and CRC risk/mortality. A systematic literature search was conducted in PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Sinomed (CBM), Wanfang Data Knowledge Service Platform, and China Science and Technology Journal VIP database. Articles were restricted to be available in any language until March 31, 2022. The highest exposed categories were used to calculate the pooled relative risks (RR) values. Pooled relative risks (RR) and 95% confidence intervals (CI) were used to estimate the association of sugar-sweetened beverages with CRC risk and mortality. Heterogeneity was assessed with the Cochran Q statistic and quantified with the I2 statistic. A total of 17 studies (6 case-control and 11 cohort) involving 557,391 subjects were included in this meta-analysis. The pooled RRs for CRC incidence and mortality among people taking sugar-sweetened beverages were 1.17 (95% CI: 1.07-1.28) and 1.13 (95% CI: 0.99-1.29), respectively. In subgroup analysis, a correlation was found in the distal colon with a pooled RR of 1.41 (95% CI: 1.10-1.80). There was no correlation in the proximal colon with a pooled RR of 1.58 (95% CI: 0.79-3.17). We found statistically significant associations between CRC incidence and sugar-sweetened beverages intake in North America and Oceania, with pooled RRs of 1.16 (95% CI: 1.00-1.33) and 1.32 (95% CI: 1.13-1.55), respectively. In sensitivity analysis, after excluding each study and calculating heterogeneity and effect sizes, there was still a correlation between sugar-sweetened beverages intake and CRC risk. This meta-analysis suggests that sugar-sweetened beverages intake may increase CRC risk, independent of CRC mortality. Whether CRC risk increases with increased sugar-sweetened beverage intake needs further investigation in the future. This meta-analysis aimed to indicate the relationship between sugar-sweetened beverages intake and the risk and mortality of colorectal cancer. A total of 17 studies involving 557,391 subjects were included. The results showed that sugar-sweetened beverages may increase the risk of colorectal cancer but may not be associated with colorectal cancer mortality.
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Inflammation is a key factor in the pathogenesis of dry eye disease (DED). We aimed to investigate the role of microRNA-146a (miR-146a) in regulating corneal inflammation in a mouse model of benzalkonium chloride (BAC)-induced dry eye and the TNF-α-induced NF-κB signaling pathway in human corneal epithelial cells (HCECs). A mouse model of dry eye was established by administering with BAC to BALB/c mice, and the expression of TNF-α, IL-1ß, IL-6, IL-8, cyclooxygenase 2 (COX2), interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) in the corneas of dry eye model mice was significantly increased; this was accompanied by the upregulation of miR-146a and activation of the NF-κB pathway. In vitro, TNF-α induced miR-146a expression in HCECs, while the NF-κB inhibitor SC-514 reduced the expression of miR-146a. Overexpression of miR-146a decreased the expression of IRAK1 and TRAF6, which have been identified as targets of miR-146a. Furthermore, overexpression of miR-146a suppressed NF-κB p65 translocation from the cytoplasm to the nucleus. Moreover, overexpression of miR-146a attenuated the TNF-α-induced expression of IL-6, IL-8, COX2 and intercellular adhesion molecule 1 (ICAM1), while inhibition of miR-146a exerted the opposite effect. Our results suggest that miR-146a mediates the inflammatory response in DED. MiR-146a negatively regulates inflammation in HCECs through the IRAK1/TRAF6/NF-κB pathway, and this may serve as a potential therapeutic approach for the treatment of DED.
Assuntos
Síndromes do Olho Seco , MicroRNAs , Animais , Humanos , Camundongos , Compostos de Benzalcônio , Ciclo-Oxigenase 2/genética , Modelos Animais de Doenças , Inflamação/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Interleucina-6 , Interleucina-8 , MicroRNAs/genética , NF-kappa B , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/genética , Fator de Necrose Tumoral alfaRESUMO
Defining reliable surrogate markers and overcoming drug resistance are the most challenging issues for improving therapeutic outcomes of antiangiogenic drugs (AADs) in cancer patients. At the time of this writing, no biomarkers are clinically available to predict AAD therapeutic benefits and drug resistance. Here, we uncovered a unique mechanism of AAD resistance in epithelial carcinomas with KRAS mutations that targeted angiopoietin 2 (ANG2) to circumvent antivascular endothelial growth factor (anti-VEGF) responses. Mechanistically, KRAS mutations up-regulated the FOXC2 transcription factor that directly elevated ANG2 expression at the transcriptional level. ANG2 bestowed anti-VEGF resistance as an alternative pathway to augment VEGF-independent tumor angiogenesis. Most colorectal and pancreatic cancers with KRAS mutations were intrinsically resistant to monotherapies of anti-VEGF or anti-ANG2 drugs. However, combination therapy with anti-VEGF and anti-ANG2 drugs produced synergistic and potent anticancer effects in KRAS-mutated cancers. Together, these data demonstrate that KRAS mutations in tumors serve as a predictive marker for anti-VEGF resistance and are susceptible to combination therapy with anti-VEGF and anti-ANG2 drugs.