ABSTRACT
BACKGROUND: Erectile dysfunction (ED) is a prevalent condition that is thought to be significantly impacted by oxidative stress. The oxidative balance score (OBS) has been built to characterize the state of antioxidant/pro-oxidant balance. There is less known regarding the relationship of OBS with ED. METHODS: This study conducted cross-sectional analyses on 1860 males who participated in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2004. OBS was constructed by the 16 dietary components and 4 lifestyle factors. Self-reported ED was defined as men who indicated that they "never" or "sometimes" could achieve or keeping an erection adequate for satisfactory intercourse. Multivariate logistic regression models were applied to examine the association between OBS and the risk of ED. RESULTS: Among 1860 participants, the median OBS was 20 (IQR 15-26), and OBS was lower in males with ED vs. those without ED (P = 0.001). The results of our analyses indicated a negative correlation between OBS and ED among male subjects. Specifically, each one-unit increase in the continuous OBS was relate to 3% reduction in the odds of ED after full adjustment. Moreover, when extreme OBS quartiles were compared, the adjusted odds ratio (95% confidence interval) for the 4th OBS category was 0.53 (0.32 to 0.88) after full adjustment (P for trend < 0.05). There was also statistical significance in the relationships between dietary/lifestyle OBS with ED, and the association between lifestyle OBS and ED may be even tighter. For each unit increase in lifestyle OBS, the odds of ED decreased by 11% after full adjustment. CONCLUSION: Higher OBS was associated with reduced risk of ED in U.S. males. These findings suggested that adopting an antioxidant-rich diet and engaging in antioxidant-promoting lifestyle behaviors may contribute to a lower incidence of ED. These results provided recommendations for a comprehensive dietary and lifestyle antioxidants for ED patients.
Subject(s)
Erectile Dysfunction , Nutrition Surveys , Oxidative Stress , Humans , Male , Erectile Dysfunction/epidemiology , Cross-Sectional Studies , Middle Aged , Nutrition Surveys/methods , Nutrition Surveys/statistics & numerical data , Adult , Diet/methods , Diet/statistics & numerical data , Life Style , Risk Factors , Antioxidants/administration & dosage , Antioxidants/analysis , Logistic Models , Aged , Odds RatioABSTRACT
Microplastics (MPs) are pervasive pollutants in the natural environment and contribute to increased levels of illness in both animals and humans. However, thespecific impacts of MPs on skin damage and alopeciaare not yet well understood. In this study, we have examined the effects of two types of polystyrene MPs (pristine and aged) on skin and hair follicle damage in mice. UV irradiation changed the chemical and physical properties of the aged MPs, including functional groups, surface roughness, and contact angles. In both in vivo and in vitro experiments, skin and cell injuries related to oxidative stress, apoptosis, tight junctions (TJs), alopecia, mitochondrial dysfunction, and other damages were observed. Mechanistically, MPs and aged MPs can induce TJs damage via the oxidative stress pathway and inhibition of antioxidant-related proteins, and this can lead to alopecia. The regulation of cell apoptosis was also observed, and this is involved in the ROS-mediated mitochondrial signaling pathway. Importantly, aged MPs showed exacerbated toxicity, which may be due to their elevated surface irregularities and altered chemical compositions. Collectively, this study suggests a potential therapeutic approach for alopecia and hair follicle damage caused by MPs pollution.
Subject(s)
Alopecia , Apoptosis , Microplastics , Oxidative Stress , Polystyrenes , Skin , Tight Junctions , Alopecia/chemically induced , Microplastics/toxicity , Oxidative Stress/drug effects , Apoptosis/drug effects , Animals , Mice , Polystyrenes/toxicity , Tight Junctions/drug effects , Tight Junctions/metabolism , Skin/drug effects , Skin/pathology , Hair Follicle/drug effects , Reactive Oxygen Species/metabolismABSTRACT
The Golgi apparatus plays a crucial role in intracellular protein transportation, processing, and sorting. Dysfunctions of the Golgi apparatus have been implicated in tumorigenesis and drug resistance. This study aimed to investigate the prognostic and treatment response assessment value of Golgi apparatus-related gene (GARGs) features in gastric cancer patients. Transcriptome data and clinical information of gastric cancer patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Cox regression analysis was employed to assess the prognostic significance of GARGs and construct risk features. The immune landscape, drug sensitivity, immune therapy response, gene expression patterns, and somatic mutation characteristics were analyzed between different risk groups. A nomogram model for predicting gastric cancer prognosis was developed and evaluated. Among 1643 GARGs examined, 365 showed significant associations with gastric cancer prognosis. Five independent prognostic GARGs (NGF, ABCG1, CHAC1, GBA2, PCSK7) were selected to construct risk features for gastric cancer patients. These risk features effectively stratified patients into high-risk and low-risk groups, with the former exhibiting worse prognosis than the latter. Patients in the high-risk group displayed higher levels of immune cell infiltration, while the expression levels of NGF, CHAC1, GBA2, PCSK7 were significantly correlated with immune cell infiltration. Notably, the low-risk group exhibited higher sensitivity to epothilone.B, metformin, and tipifarnib compared to the high-risk group. Moreover, patients in the low-risk group demonstrated greater responsiveness to immune therapy than those in the high-risk group. In terms of biological processes and KEGG pathways related to immunity regulation, significant suppression was observed in the high-risk group compared to the low-risk group; meanwhile cell cycle pathways exhibited significant activation in the high-risk group. Furthermore, the low-risk group exhibited a higher tumor mutation burden compared to the high-risk group. The risk features derived from GARGs, in conjunction with age, were identified as independent risk factors for gastric cancer. The nomogram incorporating these factors demonstrated improved performance in predicting gastric cancer prognosis. Our study established risk features derived from GARGs that hold potential clinical utility in prognostic assessment and immune therapy response evaluation of gastric cancer patients.
Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Prognosis , Immunotherapy , Golgi Apparatus , SubtilisinsABSTRACT
OBJECTIVE: Difficult-to-heal wound is a prevalent and significant complication of diabetes, characterized by impaired functionality of epithelial cells such as fibroblasts. This study aims to investigate the potential mechanism of ADSC-Exos promoting diabetic wound healing by regulating fibroblast function. MATERIALS AND METHODS: ADSC-Exos were confirmed through TEM, NTA, and Western Blot techniques. The study conducted on rat skin fibroblasts (RSFs) exposed to 33 mmol/L glucose in vitro. We used cck-8, EDU, transwell, and scratch assays to verify the proliferation and migration of RSFs. Furthermore, levels of TGF-ß1 and α-SMA proteins were determined by immunofluorescence and Western Blot. RSFs were transfected with miR-128-1-5p mimics and inhibitors, followed by quantification of TGF-ß1, α-SMA, Col I and Smad2/3 protein levels using Western Blot. In vivo, the effects of ADSC-Exos on diabetic wounds were assessed using digital imaging, histological staining, as well as Western Blot analysis. RESULTS: In vitro, ADSC-Exos significantly enhanced proliferation and migration of RSFs while reducing the expression of TGF-ß1 and α-SMA. In vivo, ADSC-Exos effectively promoted diabetic wound healing and mitigated scar fibrosis. Additionally, ADSC-Exos exhibited elevated levels of miR-128-1-5p, which targets TGF-ß1, resulting in a notable reduction in TGF-ß1, α-SMA, Col I and smad2/3 phosphorylation in RSFs. CONCLUSION: In conclusion, our results demonstrated that ADSC-Exos promoted diabetic wound healing, and inhibited skin fibrosis by regulating miR-128-1-5p/TGF-ß1/Smad signaling pathway, which provides a promising innovative treatment for diabetic wound healing.
Subject(s)
Diabetes Mellitus, Experimental , Exosomes , Fibroblasts , Fibrosis , Mesenchymal Stem Cells , MicroRNAs , Rats, Sprague-Dawley , Signal Transduction , Transforming Growth Factor beta1 , Wound Healing , MicroRNAs/genetics , MicroRNAs/metabolism , Animals , Transforming Growth Factor beta1/metabolism , Mesenchymal Stem Cells/metabolism , Exosomes/metabolism , Rats , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/genetics , Fibroblasts/metabolism , Male , Cell Proliferation , Cell Movement , Smad2 Protein/metabolism , Adipose Tissue/metabolism , Adipose Tissue/cytology , Smad3 Protein/metabolism , Smad3 Protein/genetics , Smad Proteins/metabolismABSTRACT
Purpose: The incidence of gastroparesis is higher in individuals diagnosed with type 2 diabetes mellitus (T2DM) compared to the healthy individuals. Our study aimed to explore the risk factors for gastroparesis in T2DM and to establish a clinical prediction model (nomogram). Methods: Our study enlisted 694 patients with T2DM from two medical centers over a period of time. From January 2020 to December 2022, 347 and 149 patients were recruited from the Beilun branch of Zhejiang University's First Affiliated Hospital in the training and internal validation cohorts, respectively. The external validation cohort consisted of 198 patients who were enrolled at Nanchang University's First Affiliated Hospital from October 2020 to September 2021. We conducted univariate and multivariate logistic regression analyses to select the risk factors for gastroparesis in patients with T2DM; subsequently,we developed a nomogram model. The performance of the nomogram was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), calibration curve, and decision curve analysis(DCA). Results: Four clinical variables, including age, regular exercise, glycated hemoglobin level(HbA1c), and Helicobacter pylori (H. pylori) infection, were identified and included in the model. The model demonstrated excellent discrimination, with an AUC of 0.951 (95% CI = 0.925-0.978) in the training group, and 0.910 (95% CI = 0.859-0.961) and 0.875 (95% CI = 0.813-0.937) in the internal and external validation groups, respectively. The calibration curve showed good consistency between prediction of the model and observed gastroparesis. The DCA also demonstrated good clinical efficacy. Conclusion: The nomogram model developed in this study showed good performance in predicting gastroparesis in patients with T2DM.
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The prevalence of alopecia has increased recently. Hair loss is often accompanied by the resting phase of hair follicles (HFs). Dermal papilla (DP) plays a crucial role in HF development, growth, and regeneration. Activating DP can revive resting HFs. Augmenting WNT/ß-catenin signaling stimulates HF growth. However, the factors responsible for activating resting HFs effectively are unclear. In this study, we investigated epidermal cytokines that can activate resting HFs effectively. We overexpressed ß-catenin in both in vivo and in vitro models to observe its effects on resting HFs. Then, we screened potential epidermal cytokines from GEO DATASETs and assessed their functions using mice models and skin-derived precursors (SKPs). Finally, we explored the molecular mechanism underlying the action of the identified cytokine. The results showed that activation of WNT/ß-catenin in the epidermis prompted telogen-anagen transition. Keratinocytes infected with Ctnnb1-overexpressing lentivirus enhanced SKP expansion. Subsequently, we identified endothelin 1 (ET-1) expressed higher in hair-growing epidermis and induced the proliferation of DP cells and activates telogen-phase HFs in vivo. Moreover, ET-1 promotes the proliferation and stemness of SKPs. Western blot analysis and in vivo experiments revealed that ET-1 induces the transition from telogen-to-anagen phase by upregulating the PI3K/AKT pathway. These findings highlight the potential of ET-1 as a promising cytokine for HF activation and the treatment of hair loss.
Subject(s)
Hair Follicle , Proto-Oncogene Proteins c-akt , Animals , Mice , Hair Follicle/metabolism , Proto-Oncogene Proteins c-akt/metabolism , beta Catenin/genetics , beta Catenin/metabolism , Endothelin-1/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Cells, Cultured , Cell Proliferation , Epidermis/metabolism , Alopecia/metabolism , Wnt Signaling Pathway , Dermis/metabolism , Cytokines/metabolismABSTRACT
Norepinephrine (NA), a stress hormone, can accelerate hair graying by binding to ß2 adrenergic receptors (ß2AR) on melanocyte stem cells (McSCs). From this, NA-ß2AR axis could be a potential target for preventing the stress effect. However, identifying selective blockers for ß2AR has been a key challenge. Therefore, in this study, advanced computer-aided drug design (CADD) techniques were harnessed to screen natural molecules, leading to the discovery of rhynchophylline as a promising compound. Rhynchophylline exhibited strong and stable binding within the active site of ß2AR, as verified by molecular docking and dynamic simulation assays. When administered to cells, rhynchophylline effectively inhibited NA-ß2AR signaling. This intervention resulted in a significant reduction of hair graying in a stress-induced mouse model, from 28.5% to 8.2%. To gain a deeper understanding of the underlying mechanisms, transcriptome sequencing was employed, which revealed that NA might disrupt melanogenesis by affecting intracellular calcium balance and promoting cell apoptosis. Importantly, rhynchophylline acted as a potent inhibitor of these downstream pathways. In conclusion, the study demonstrated that rhynchophylline has the potential to mitigate the negative impact of NA on melanogenesis by targeting ß2AR, thus offering a promising solution for preventing stress-induced hair graying.
ABSTRACT
Knowledge gaps that limit the development of therapies for polycystic ovary syndrome (PCOS) concern various environmental factors that impact clinical characteristics. Circadian dysrhythmia contributes to glycometabolic and reproductive hallmarks of PCOS. Here, we illustrated the amelioration of Limosilactobacillus reuteri (L. reuteri) on biorhythm disorder-ignited dyslipidemia of PCOS via a microbiota-metabolite-liver axis. A rat model of long-term (8 weeks) darkness treatment was used to mimic circadian dysrhythmia-induced PCOS. Hepatic transcriptomics certified by in vitro experiments demonstrated that increased hepatic galanin receptor 1 (GALR1) due to darkness exposure functioned as a critical upstream factor in the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway to suppress nuclear receptors subfamily 1, group D, member 1 (NR1D1) and promoted sterol regulatory element binding protein 1 (SREBP1), inducing lipid accumulation in the liver. Further investigations figured out a restructured microbiome-metabolome network following L. reuteri administration to protect darkness rats against dyslipidemia. Notably, L. reuteri intervention resulted in the decrease of Clostridium sensu stricto 1 and Ruminococcaceae UCG-010 as well as gut microbiota-derived metabolite capric acid, which could further inhibit GALR1-NR1D1-SREBP1 pathway in the liver. In addition, GALR antagonist M40 reproduced similar ameliorative effects as L. reuteri to protect against dyslipidemia. While exogenous treatment of capric acid restrained the protective effects of L. reuteri in circadian disruption-induced PCOS through inhibiting GALR1-dependent hepatic lipid metabolism. These findings purport that L. reuteri could serve for circadian disruption-associated dyslipidemia. Manipulation of L. reuteri-capric acid-GALR1 axis paves way for clinical therapeutic strategies to prevent biorhythm disorder-ignited dyslipidemia in PCOS women.
Subject(s)
Dyslipidemias , Limosilactobacillus reuteri , Polycystic Ovary Syndrome , Humans , Rats , Female , Animals , Receptor, Galanin, Type 1 , Phosphatidylinositol 3-Kinases , Dyslipidemias/etiology , Dyslipidemias/prevention & controlABSTRACT
Activation of endogenous neural stem cells (NSCs) is greatly significant for the adult neurogenesis; however, it is extremely limited in the spinal cord after injury. Recent evidence suggests that accumulation of protein aggregates impairs the ability of quiescent NSCs to activate. Ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, plays critical roles in protein aggregations clearance, but its effects on NSC activation remains unknown. Here, we show that UCHL1 promotes NSC activation by clearing protein aggregates through ubiquitin-proteasome approach. Upregulation of UCHL1 facilitated the proliferation of spinal cord NSCs after spinal cord injury (SCI). Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3+ neurotoxic reactive astrocytes negatively regulated UCHL1 and proteasome activity via C3/C3aR signaling, led to increased abundances of protein aggregations and decreased NSC proliferation. Furthermore, blockade of reactive astrocytes or C3/C3aR pathway enhanced NSC activation post-SCI by reserving UCHL1 and proteasome functions. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, which may provide potential molecular targets and new insights for NSC fate regulation.
Subject(s)
Neural Stem Cells , Spinal Cord Injuries , Humans , Protein Aggregates , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism , Cell Differentiation/physiology , Proteasome Endopeptidase Complex/metabolism , Neural Stem Cells/metabolism , Spinal Cord Injuries/metabolism , Spinal Cord/metabolismABSTRACT
The skin is a multi-layered structure composed of the epidermis, dermis and hypodermis. The epidermis originates entirely from the ectoderm, whereas the dermis originates from various germ layers depending on its anatomical location; thus, there are different developmental patterns of the skin. Although the regulatory mechanisms of epidermal formation are well understood, mechanisms regulating dermis development are not clear owing to the complex origin. It has been shown that several morphogenetic pathways regulate dermis development. Of these, transforming growth factor-ß (TGF-ß) and fibroblast growth factor (FGF) signalling pathways are the main modulators regulating skin cell induction, fate decision, migration and differentiation. Recently, the successful generation of human skin by modulating TGF-ß and FGF signals further demonstrated the irreplaceable roles of these pathways in skin regeneration. This review provides evidence of the role of TGF-ß and FGF signalling pathways in the development of different skin layers, especially the disparate dermis of different body regions. This review also provides new perspectives on the distinct developmental patterns of skin and explores new ideas for clinical applications in the future.
Subject(s)
Skin , Transforming Growth Factor beta , Humans , Transforming Growth Factor beta/metabolism , Skin/metabolism , Cell Differentiation , Epidermis/metabolism , Signal Transduction , Fibroblast Growth Factors/metabolismABSTRACT
Purpose: Constipation is a common complication of diabetic patients, which has a negative impact on their own health. This study aims to establish and internally validate the risk nomogram of constipation in patients with type 2 diabetes mellitus (T2DM) and to test its predictive ability. Patients and Methods: This retrospective study included 746 patients with T2DM at two medical centers. Among the 746 patients with T2DM, 382 and 163 patients in the Beilun branch of the First Affiliated Hospital of Zhejiang University were enrolled in the training cohort and the validation cohort, respectively. A total of 201 patients in the First Affiliated Hospital of Nanchang University were enrolled in external validation cohorts. The nomogram was established by optimizing the predictive factors through univariate and multivariable logistic regression analysis. The prediction performance of the nomogram was measured by the area under the receiver operating characteristic curve (AUROC), the calibration curve, and the decision curve analysis (DCA). Furthermore, its applicability was internally and independently validated. Results: Among the 16 clinicopathological features, five variables were selected to develop the prediction nomogram, including age, glycated hemoglobin (HbA1c), calcium, anxiety, and regular exercise. The nomogram revealed good discrimination with an area under the receiver operating characteristic curve (AUROC) of 0.908 (95% CI = 0.865-0.950) in the training cohort, and 0.867 (95% CI = 0.790-0.944) and 0.816 (95% CI = 0.751-0.881) in the internal and external validation cohorts, respectively. The calibration curve presented a good agreement between the prediction by the nomogram and the actual observation. The DCA revealed that the nomogram had a high clinical application value. Conclusion: In this study, the nomogram for pretreatment risk management of constipation in patients with T2DM was developed which could help in making timely personalized clinical decisions for different risk populations.
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BACKGROUND: The hair follicles (HFs) are barely regenerated after loss in injuries in mammals as well as in human beings. Recent studies have shown that the regenerative ability of HFs is age-related; however, the relationship between this phenomenon and the stem cell niche remains unclear. This study aimed to find a key secretory protein that promotes the HFs regeneration in the regenerative microenvironment. METHODS: To explore why age affects HFs de novo regeneration, we established an age-dependent HFs regeneration model in leucine-rich repeat G protein-coupled receptor 5 (Lgr5) + /mTmG mice. Proteins in tissue fluids were analyzed by high-throughput sequencing. The role and mechanism of candidate proteins in HFs de novo regeneration and hair follicle stem cells (HFSCs) activation were investigated through in vivo experiments. The effects of candidate proteins on skin cell populations were investigated by cellular experiments. RESULTS: Mice under 3-week-old (3W) could regenerate HFs and Lgr5 HFSCs, which were highly correlated with the immune cells, cytokines, IL-17 signaling pathway, and IL-1α level in the regeneration microenvironment. Additionally, IL-1α injection induced de novo regeneration of HFs and Lgr5 HFSCs in 3W mouse model with a 5 mm wound, as well as promoted activation and proliferation of Lgr5 HFSCs in 7-week-old (7W) mice without wound. Dexamethasone and TEMPOL inhibited the effects of IL-1α. Moreover, IL-1α increased skin thickness and promoted the proliferation of human epidermal keratinocyte line (HaCaT) and skin-derived precursors (SKPs) in vivo and in vitro, respectively. CONCLUSIONS: In conclusion, injury-induced IL-1α promotes HFs regeneration by modulating inflammatory cells and oxidative stress-induced Lgr5 HFSCs regeneration as well as promoting skin cell populations proliferation. This study uncovers the underlying molecular mechanisms enabling HFs de novo regeneration in an age-dependent model.
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Background: With the number of people with dementia dramatically increasing over time and dementia becoming a major health concern worldwide, scales have been developed to assess the stigma socially attached to this neurodegenerative disorder. There are, however, almost no available methods and assessment constructs for person-centered translation of dementia public stigma scales. Objective: To develop such a method and such an assessment construct by translating the Dementia Public Stigma Scale (DPSS) into standard written Chinese. Methods: We translated the DPSS following three major steps: (1) literal translation and mistranslation identification; (2) panel discussions of items with problematic translations; and (3) the final checking of the translated scale. Informed by the translation and adaptation process, we then developed a method for person-centered translation of dementia public stigma scales. Based on this method and our panel discussions, we finally proposed a tripartite assessment construct for quality evaluation of the translation of dementia public stigma scales. Results: Forward and backward translation did not work sufficiently in dementia public stigma scale translation. Mistranslations were induced by three major causes, including confusion caused by multiple Chinese meanings of the immediate Chinese direct translation, the lack of immediate Chinese direct translation because of varying positive/negative emotions attached to multiple translations, and the lack of culture-specific idioms in Chinese. Based on these factors, we proposed a tripartite dementia translation assessment construct. Following this assessment tool, we determined the best Chinese version that could further be tested for its psychometric properties among the public. Conclusion: A method and an assessment construct for person-centered translation of dementia public stigma scales were developed. Such a method and such an assessment construct could be followed in the translation of dementia public stigma scales and the translation evaluation of such scales.
Subject(s)
Dementia , Translations , Humans , Reproducibility of Results , Psychometrics , Social StigmaABSTRACT
Background: The oxidative balance score (OBS), an encompassing scoring mechanism for assessing oxidative stress, is formulated based on nutritional and lifestyle components. The emergence of metabolic syndrome (MetS) is intricately linked to oxidative stress. Nonetheless, the correlation between OBS and MetS displays variability within distinct cohorts. Objective: We worked on the relationships between OBS and the risk of MetS, MetS severity, and all-cause mortality of MetS patients. Methods: A total of 11,171 adult participants were collected from the U.S. National Health Examination Survey (NHANES) 2007-2018. Employing survey-weighted logistic models, we evaluated the relationship between OBS and MetS risk. Furthermore, survey-weighted linear models were utilized to investigate the connection between OBS and MetS severity. Among the participants, 3,621 individuals had their survival status recorded, allowing us to employ Cox proportional hazards regression models in order to ascertain the association between OBS and the all-cause mortality within the subset of individuals with MetS. The OBS (where a higher OBS signified an increased prevalence of anti- or pro-oxidant exposures) weighed the 20 factors, while the MetS severity score weighed the five factors. Results: After multivariable adjustment, individuals with elevated OBS were found to exhibit a decreased susceptibility to MetS [odds ratio (OR) 0.95; 95% CI 0.94-0.96]. The adjusted OR was 0.42 (95% CI 0.33-0.53) for MetS risk in the fourth OBS quartile compared with those in the first OBS quartile (P for trend < 0.001). A one-unit increase in OBS was linked to a 3% reduction in MetS severity score by 3% (mean difference, -0.03; 95% CI, -0.04 to -0.03). Moreover, increased OBS correlated with decreased hazard of all-cause mortality risk among MetS subjects (adjusted hazard ratio, 0.95; 95% CI, 0.93-0.98). These associations retained their strength even subsequent to the introduction of sensitivity analyses. There existed a statistically significant negative correlation between diet/lifestyle OBS and both MetS risk as well as MetS severity. Conclusions: An inverse correlation was observed between OBS and the susceptibility to MetS, MetS severity, and all-cause mortality of MetS patients. Health outcomes for MetS patients were positively related to antioxidant diets and lifestyles.
Subject(s)
Metabolic Syndrome , Adult , Humans , Metabolic Syndrome/epidemiology , Metabolic Syndrome/complications , Nutrition Surveys , Oxidation-Reduction , Diet , Oxidative StressABSTRACT
Polycystic ovary syndrome (PCOS) is a common and complex disorder impairing female fertility, yet its etiology remains elusive. It is reported that circadian rhythm disruption might play a crucial role in PCOS pathologic progression. Here, in this research, we investigated the effect of environmental long-term circadian rhythm dysfunction and clarified its pathogenic mechanism in the development of PCOS, which might provide the targeted clinical strategies to patients with PCOS. Female SD rats were used to construct a circadian rhythm misalignment model with constant darkness (12/12-h dark/dark cycle), and the control group was kept under normal circadian rhythm exposure (12/12-h light/dark cycle) for 8 weeks. We measured their reproductive, endocrinal, and metabolic profiles at different zeitgeber times (ZTs). Different rescue methods, including melatonin receptor agonist and normal circadian rhythm restoration, and in vitro experiments on the KGN cell line were performed. We found that long-term darkness caused PCOS-like reproductive abnormalities, including estrous cycle disorder, polycystic ovaries, LH elevation, hyperandrogenism, and glucose intolerance. In addition, the expression of melatonin receptor 1A (Mtnr1a) in ovarian granulosa cells significantly decreased in the darkness group. Normal light/dark cycle and melatonin receptor agonist application relieved hyperandrogenism of darkness-treated rats. In vitro experiments demonstrated that decreased MTNR1A inhibited androgen receptor (AR) and CYP19A1 expression, and AR acted as an essential downstream factor of MTNR1A in modulating aromatase abundance. Overall, our finding demonstrates the significant influence of circadian rhythms on PCOS occurrence, suggests that MTNR1A and AR play vital roles in pathological progression of hyperandrogenism, and broadens current treatment strategies for PCOS in clinical practice.
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DNA damage plays an essential role in the initiation and development of colon cancer. Histone crotonylation is a newly discovered post-translational modification that is thought to promote gene expression. Whether histone crotonylation plays a role in DNA damage of cancer remains unknown, as does the putative underlying molecular mechanism. This study aimed to investigate the relationship between histone crotonylation and DNA damage of colon cancer using multiple bioinformatics analysis and western blotting. We discovered that genes with promoter occupied by histone crotonylation were associated with the activity of DNA damage in colon cancer patients. Additionally, we uncovered that the level of crotonylation on Lys27 of histone H3 (H3K27cr) decreased during camptothecin and etoposide treatment. Interestingly, sirtuin 6 was found to regulate the cellular level of H3K27cr. Taking these data together, our study provided a new perspective about histone crotonylation and DNA damage in colon cancer.
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Background: The ability to assess adverse outcomes in patients with community-acquired pneumonia (CAP) could improve clinical decision-making to enhance clinical practice, but the studies remain insufficient, and similarly, few machine learning (ML) models have been developed. Objective: We aimed to explore the effectiveness of predicting adverse outcomes in CAP through ML models. Methods: A total of 2,302 adults with CAP who were prospectively recruited between January 2012 and March 2015 across three cities in South America were extracted from DryadData. After a 70:30 training set: test set split of the data, nine ML algorithms were executed and their diagnostic accuracy was measured mainly by the area under the curve (AUC). The nine ML algorithms included decision trees, random forests, extreme gradient boosting (XGBoost), support vector machines, Naïve Bayes, K-nearest neighbors, ridge regression, logistic regression without regularization, and neural networks. The adverse outcomes included hospital admission, mortality, ICU admission, and one-year post-enrollment status. Results: The XGBoost algorithm had the best performance in predicting hospital admission. Its AUC reached 0.921, and accuracy, precision, recall, and F1-score were better than those of other models. In the prediction of ICU admission, a model trained with the XGBoost algorithm showed the best performance with AUC 0.801. XGBoost algorithm also did a good job at predicting one-year post-enrollment status. The results of AUC, accuracy, precision, recall, and F1-score indicated the algorithm had high accuracy and precision. In addition, the best performance was seen by the neural network algorithm when predicting death (AUC 0.831). Conclusions: ML algorithms, particularly the XGBoost algorithm, were feasible and effective in predicting adverse outcomes of CAP patients. The ML models based on available common clinical features had great potential to guide individual treatment and subsequent clinical decisions.
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Macrophages can transform into M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes, which mediate the immune/inflammatory response in rheumatoid arthritis (RA). Activated M1 phenotype macrophages and overexpression of folate (FA) receptors are abundant in inflammatory synovium and joints and promote the progression of RA. Germacrone (GER) can regulate the T helper 1 cell (Th1)/the T helper 2 cell (Th2) balance to delay the progression of arthritis. To deliver GER to inflammatory tissue cells to reverse M1-type proinflammatory cells and reduce inflammation, FA receptor-targeting nanocarriers loaded with GER were developed. In activated macrophages, FA-NPs/DiD showed significantly higher uptake efficiency than NPs/DiD. In vitro experiments confirmed that FA-NPs/GER could promote the transformation of M1 macrophages into M2 macrophages. In adjuvant-induced arthritis (AIA) rats, the biodistribution profiles showed selective accumulation at the inflammatory site of FA-NPs/GER, and significantly reduced the swelling and inflammation infiltration of the rat's foot. The levels of pro-inflammatory cytokines (TNF-α, IL-1ß) in the rat's inflammatory tissue were significantly lower than other treatment groups, which indicated a significant therapeutic effect in AIA rats. Taken together, macrophage-targeting nanocarriers loaded with GER are a safe and effective method for the treatment of RA.