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Candidatus Accumulibacter, a prominent polyphosphate-accumulating organism (PAO) in wastewater treatment, plays a crucial role in enhanced biological phosphorus removal (EBPR). The genetic underpinnings of its polyphosphate accumulation capabilities, however, remain largely unknown. Here, we conducted a comprehensive genomic analysis of Ca. Accumulibacter-PAOs and their relatives within the Rhodocyclaceae family, identifying 124 core genes acquired via horizontal gene transfer (HGT) at its least common ancestor. Metatranscriptomic analysis of an enrichment culture of Ca. Accumulibacter revealed active transcription of 44 of these genes during an EBPR cycle, notably including the polyphosphate kinase 2 (PPK2) gene instead of the commonly recognized polyphosphate kinase 1 (PPK1) gene. Intriguingly, the phosphate regulon (Pho) genes showed minimal transcriptions, pointing to a distinctive fact of Pho dysregulation, where PhoU, the phosphate signaling complex protein, was not regulating the high-affinity phosphate transport (Pst) system, resulting in continuous phosphate uptake. To prevent phosphate toxicity, Ca. Accumulibacter utilized the laterally acquired PPK2 to condense phosphate into polyphosphate, resulting in the polyphosphate-accumulating feature. This study provides novel insights into the evolutionary emergence of the polyphosphate-accumulating trait in Ca. Accumulibacter, offering potential advancements in understanding the PAO phenotype in the EBPR process.
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Currently, as the largest family of E3 ubiquitin ligases, Skp1-Cullin 1-F-box (SCF) E3 ligase complexes have attracted extensive attention. Among SCF complexes, Skp2, ß-TrCP, and FBXW7 have undergone extensive research on their structures and functions. Previous studies suggest Skp2, ß-TrCP, and FBXW7 are overexpressed in numerous cancers. Thus, the SCF E3 ligase complex has become a significant target for the development of anti-cancer drugs. Over the past few decades, a variety of anti-tumor inhibitors targeting the SCF E3 ligase complex have been attempted. However, since almost none of the SCF E3 ligase inhibitors passed clinical trials, the design and synthesis of the new inhibitors are needed. Here, we will introduce the structure and function of Skp2, ß-TrCP, and FBXW7, their connections with cancer development, the relevant in vitro and in vivo activities, selectivity, structure-activity relationships, and the therapeutic or preventive application of small molecule inhibitors targeting these three F-box proteins reported in the patent (2010-present). This information will help develop drugs targeting the SCF E3 ubiquitin ligase, providing new strategies for future cancer treatments.
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Background: Studies have shown that work readiness is closely related to nurses' role adaptation, career development, and patient safety. However, we know little about the nursing students' work readiness and its influencing factors before participating in a nurse residency program, and whether factors have changed from before. Aim: (1) To investigate the work readiness of nursing students ready to engage in a nurse residency program; (2) to identify the factors affecting the nursing students' work readiness and the associations between emotional intelligence and work readiness; and (3) to discuss the changes of factors affecting nursing students' work readiness. Design: An online, multicenter cross-sectional study. Methods: 878 nursing students from eight tertiary hospitals in Chongqing, China were recruited. The online investigation used the General Information Questionnaire, the Nursing Students' Work Readiness Scale, and the Emotional Intelligence scale. The data were analyzed using IBM SPSS V23.0. Results: 768 valid questionnaires were included in this study. The nurses obtained a work readiness score of 277.08 ± 44.39 and an emotional intelligence score of 89.57 ± 13.89. Univariate analysis revealed that the following factors affected work readiness: age, sex, family support for becoming a nurse, voluntary choice of nursing major, previous experience as a student cadre, scholarship recipient status, willingness to engage in nursing work during the COVID-19 pandemic and confidence in clinical nursing practice. Frequent incidents of violence, poor salary for nurses for the nurse residency program, and low social acceptance were the top three reasons for decreased confidence in clinical nursing among nursing students. Furthermore, multiple linear regression analysis indicated that age, voluntary choice of nursing major, student leadership experience, confidence in clinical nursing work, self-emotion, and emotional application significantly influenced nurses' work readiness. Conclusion: Clinical instructors and administrators should dynamically assess nurses' work readiness, prioritize individuals aged ≤23, who have chosen the nursing profession involuntarily, lack prior experience as student cadres, and exhibit low confidence in clinical nursing work. This focus will enhance their emotional self-management skills and ability to apply emotions effectively, improving their work readiness and training efficacy.
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Background: Both intracranial atherosclerosis and white matter hyperintensity (WMH) are prevalent among the stroke population. However, the relationship between intracranial atherosclerosis and WMH has not been fully elucidated. Therefore, the aim of this study was to investigate the relationship between the characteristics of intracranial atherosclerotic plaques and the severity of WMH in patients with ischemic stroke using high-resolution magnetic resonance vessel wall imaging. Methods: Patients hospitalized with ischemic stroke and concurrent intracranial atherosclerosis at Beijing Tsinghua Changgung Hospital, a tertiary comprehensive stroke center, who underwent high-resolution magnetic resonance vessel wall imaging and conventional brain magnetic resonance imaging were continuously recruited from January 2018 to December 2018. Both intracranial plaque characteristics (plaque number, maximum wall thickness, luminal stenosis, T1 hyperintensity, and plaque length) and WMH severity (Fazekas score and volume) were evaluated. Spearman correlation or point-biserial correlation analysis was used to determine the association between clinical characteristics and WMH volume. The independent association between intracranial plaque characteristics and the severity as well as WMH score was analyzed using logistic regression. The associations of intracranial plaque characteristics with total white matter hyperintensity (TWMH) volume, periventricular white matter hyperintensity (PWMH) volume and deep white matter hyperintensity (DWMH) volume were determined using multilevel mixed-effects linear regression. Results: A total of 159 subjects (mean age: 64.0±12.5 years; 103 males) were included into analysis. Spearman correlation analysis indicated that age was associated with TWMH volume (r=0.529, P<0.001), PWMH volume (r=0.523, P<0.001) and DWMH volume (r=0.515, P<0.001). Point-biserial correlation analysis indicated that smoking (r=-0.183, P=0.021) and hypertension (r=0.159, P=0.045) were associated with DWMH volume. After adjusting for confounding factors, logistic regression analysis showed plaque number was significantly associated with the presence of severe WMH [odds ratio (OR), 1.590; 95% CI, 1.241-2.035, P<0.001], PWMH score of 3 (OR, 1.726; 95% CI, 1.074-2.775, P=0.024), and DWMH score of 2 (OR, 1.561; 95% CI, 1.150-2.118, P=0.004). Intracranial artery luminal stenosis was associated with presence of severe WMH (OR, 1.032; 95% CI, 1.002-1.064, P=0.039) and PWMH score of 2 (OR, 1.057; 95% CI, 1.008-1.109, P=0.023). Multilevel mixed-effects linear regression analysis showed that plaque number was associated with DWMH volume (ß=0.128; 95% CI, 0.016-0.240; P=0.026) after adjusted for age and sex. Conclusions: In ischemic stroke patients, intracranial atherosclerotic plaque characteristics as measured by plaque number and luminal stenosis were associated with WMH burden.
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Hexavalent chromium (Cr(VI)) exposure has been linked with gastrointestinal toxicity, whereas the molecular pathways and key targets remain elusive. Computational toxicology analysis predicted the correlation between protein phosphatase 2A (PP2A) and genes regarding Cr(VI)-induced intestinal injury. Here, we generated a mouse model with intestinal epithelium-specific knock-out of Ppp2r1a (encoding PP2A Aα subunit) to investigate the mechanisms underlying Cr(VI)-induced small intestinal toxicity. Heterozygous mice (HE) and matched wild-type (WT) littermates were administrated with Cr(VI) at 0, 5, 20, 80 mg/L for 28 successive days. Cr(VI) treatment led to crypt hyperplasia, epithelial cell apoptosis, and intestinal barrier dysfunction, accompanied by the decline of goblet cell counts and Occludin expression in WT mice. Notably, these effects were aggravated in HE mice, indicating that PP2A Aα deficiency conferred mice with susceptibility to Cr(VI)-induced intestinal injury. Integrated data analysis and biological experiments revealed Cr(VI) exposure could decrease YAP1 phosphorylation at Ser127 but increase protein expression and activity, together with elevated TAZ protein driving epithelial crypt cells proliferation following damage, suggesting the involvement of Hippo/YAP1 signaling pathway in Cr(VI)-induced intestinal toxicity. Nevertheless, the enhanced phosphorylation of YAP1 in HE mice resulted in proliferation/repair defects in intestinal epithelium, thereby exacerbating Cr(VI)-induced gut barrier dysfunction. Notably, by molecular docking and further studies, we identified Urolithin A, a microbial metabolite, attenuated Cr(VI)-induced disruption of intestinal barrier function, partly by modulating YAP1 expression and activity. Our findings reveal the novel molecular pathways participated in Cr(VI)-caused small intestinal injury and urolithin A could potentially protect against environmental hazards-induced intestinal diseases.
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Spliceosomal GTPase elongation factor Tu GTP binding domain containing 2 (EFTUD2) is a causative gene for mandibulofacial dysostosis with microcephaly (MFDM) syndrome comprising cerebellar hypoplasia and motor dysfunction. How EFTUD2 deficiency contributes to these symptoms remains elusive. Here, we demonstrate that specific ablation of Eftud2 in cerebellar Purkinje cells (PCs) in mice results in severe ferroptosis, PC degeneration, dyskinesia, and cerebellar atrophy, which recapitulates phenotypes observed in patients with MFDM. Mechanistically, Eftud2 promotes Scd1 and Gch1 expression, upregulates monounsaturated fatty acid phospholipids, and enhances antioxidant activity, thereby suppressing PC ferroptosis. Importantly, we identified transcription factor Atf4 as a downstream target to regulate anti-ferroptosis effects in PCs in a p53-independent manner. Inhibiting ferroptosis efficiently rescued cerebellar deficits in Eftud2 cKO mice. Our data reveal an important role of Eftud2 in maintaining PC survival, showing that pharmacologically or genetically inhibiting ferroptosis may be a promising therapeutic strategy for EFTUD2 deficiency-induced disorders.
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BACKGROUND: Neuropathic pain (NP) is the primary symptom of various neurological conditions. Patients with NP often experience mood disorders, particularly depression and anxiety, that can severely affect their normal lives. Microglial cells are associated with NP. Excessive inflammatory responses, especially the secretion of large amounts of pro-inflammatory cytokines, ultimately lead to neuroinflammation. Microglial pyroptosis is a newly discovered form of inflammatory cell death associated with immune responses and inflammation-related diseases of the central nervous system. AIM: To investigate the effects of botulinum toxin type A (BTX-A) on microglial pyroptosis in terms of NP and associated mechanisms. METHODS: Two models, an in vitro lipopolysaccharide (LPS)-stimulated microglial cell model and a selective nerve injury model using BTX-A and SPP1 knockdown treatments, were used. Key proteins in the pyroptosis signaling pathway, NLRP3-GSDMD, were assessed using western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence. Inflammatory factors [interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α] were assessed using enzyme-linked immunosorbent assay. We also evaluated microglial cell proliferation and apoptosis. Furthermore, we measured pain sensation by assessing the delayed hind paw withdrawal latency using thermal stimulation. RESULTS: The expression levels of ACS and GSDMD-N and the mRNA expression of TNF-α, IL-6, and IL-1ß were enhanced in LPS-treated microglia. Furthermore, SPP1 expression was also induced in LPS-treated microglia. Notably, BTX-A inhibited SPP1 mRNA and protein expression in the LPS-treated microglia. Additionally, depletion of SPP1 or BTX-A inhibited cell viability and induced apoptosis in LPS-treated microglia, whereas co-treatment with BTX-A enhanced the effect of SPP1 short hairpin (sh)RNA in LPS-treated microglia. Finally, SPP1 depletion or BTX-A treatment reduced the levels of GSDMD-N, NLPRP3, and ASC and suppressed the production of inflammatory factors. CONCLUSION: Notably, BTX-A therapy and SPP1 shRNA enhance microglial proliferation and apoptosis and inhibit microglial death. It improves pain perception and inhibits microglial activation in rats with selective nerve pain.
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Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), two prominent per- and polyfluoroalkyl substances (PFASs), are potentially harmful to many human organs. However, there only exist limited methods to mitigate their health hazards. The aim of this study is to combine a bioinformatics analysis with in vitro experiments to discover small molecules that can alleviate liver damage caused by PFOA/PFOS. We identified 192 and 82 key genes related to hepatocytes exposed to PFOA and PFOS, respectively. The functional enrichment analysis of key genes suggested cellular senescence may be important in PFOA/PFOS-induced hepatotoxicity. The in vitro models revealed that PFOA/PFOS led to hepatocyte senescence by increasing the activity of SA-ß-gal, inducing mitochondrial dysfunction, impacting cell cycle arrest, and elevating the expressions of p21, p53, IL-1ß, and SASP-related cytokines. The drug-target gene set enrichment analysis method was employed to compare the transcriptome data from the Gene Expression Omnibus database (GEO), Comparative Toxicogenomics Database (CTD), and the high-throughput experiment- and reference-guided database (HERB), and 21 traditional Chinese medicines (TCMs) were identified that may alleviate PFOA/PFOS-induced liver aging. The experimental results of co-exposure to PFOA/PFOS and TCMs showed that sanguinarine has particular promise in alleviating cellular senescence caused by PFOA/PFOS. Further investigations revealed that the mTOR-p53 signaling pathway was involved in PFOA/PFOS-mediated hepatic senescence and can be blocked using sanguinarine.
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The prognostic significance of the signet-ring cell component in gallbladder carcinoma (GBC) has not been systematically evaluated. The aim of this study was to assess the similarities and differences between gallbladder signet-ring cell carcinoma (GBSRCA) and gallbladder adenocarcinoma (GBAC) in terms of clinicopathological features and long-term survival. Using the Surveillance, Epidemiology, and End Results (SEER) database, we analyzed 6,612 patients diagnosed with gallbladder cancer between 2000 and 2021. The cohort included 147 patients with GBSRCA and 6,465 with GBAC. Patients with GBSRCA were significantly younger, with 33.3% being age 60 or younger compared to 23.9% of patients with GBAC (p = 0.009). There was a higher proportion of females in the GBSRCA group (77.6%) compared to the GBAC group (70.1%, p = 0.049). GBSRCA was associated with a more advanced tumor stage (T3-T4: 56.5% vs. 44.4%, P = 0.004), higher rates of lymph node metastasis (43.5% vs. 28.0%, P < 0.001), and poorer differentiation status (poorly to undifferentiated: 80.3% vs. 29.7%, P < 0.001). Survival analysis revealed that patients with GBSRCA had significantly worse overall survival (OS) and cancer-specific survival (CSS) compared to patients with GBAC (p < 0.001). GBSRCA was an independent prognostic factor for OS (P = 0.001) in the entire cohort, while the T stage and N stage were independent prognostic factors for OS and CSS in patients with GBSRCA. Even after propensity score matching, patients with GBSRCA still had a poorer prognosis.
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Lithium-sulfur batteries have emerged as a promising energy storage device due to ultra-high theoretical capacity, but the slow kinetics of sulfur and polysulfide shuttle hinder the batteries' further development. Here, the 10% cobalt-doped pyrite iron disulfide electrocatalyst deposited on acetylene black as a separator coating in lithium-sulfur batteries is reported. The adsorption rate to the intermediate Li2S6 is significantly improved while surface oxidation of FeS2 is inhibited: iron oxide and sulfate, thus avoiding FeS2 electrocatalyst deactivation. The electrocatalytic activity has been evaluated in terms of electronic resistivity, lithium-ion diffusion, liquid-liquid, and liquid-solid conversion kinetics. The coin batteries exhibit ultra-long cycle life at 1 C with an initial capacity of 854.7 mAh g-1 and maintained at 440.8 mAh g-1 after 920 cycles. Furthermore, the separator is applied to a laminated pouch battery with a sulfur mass of 326 mg (3.7 mg cm-2) and retained the capacity of 590 mAh g-1 at 0.1 C after 50 cycles. This work demonstrates that FeS2 electrocatalytic activity can be improved when Co-doped FeS2 suppresses surface oxidation and provides a reference for low-cost separator coating design in pouch batteries.
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Oxidase enzyme-based electrochemical bioassays have garnered considerable interest due to their specificity and high efficiency. However, in traditional solid-liquid diphase enzyme electrode systems, the low solubility of oxygen and its slow mass transfer rate limit the oxidase catalytic reaction kinetics, thereby affecting the bioassay performance, including the detection accuracy, sensitivity, and linear dynamic range. ZIF-8 nanoparticles (NPs) possess hydrophobic and high-porosity characteristics, enabling them to serve as oxygen nanocarriers. In this work, we constructed a solid-liquid-air triphase enzyme electrode by encapsulating ZIF-8 NPs within an oxidase network. Hydrophobic ZIF-8 NPs can provide a rapid and sufficient supply of oxygen for the oxidase-catalyzed reactions, which enhances and stabilizes the kinetics of oxidase-catalyzed reactions. This approach eliminates the issue of "oxygen deficiency" at the traditional solid-liquid diphase interface. Consequently, the triphase enzyme electrode exhibits a 12-fold higher linear detection range than the diphase system and possesses good detection accuracy in electrolytes even with fluctuating oxygen levels. This work proposes a novel approach to construct triphase reaction systems for addressing the gas deficiency problem in heterogeneous catalysis.
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Eletrodos , Cinética , Catálise , Oxigênio/química , Oxirredutases/química , Oxirredutases/metabolismo , Estruturas Metalorgânicas/química , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Nanopartículas/química , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Bioensaio , ImidazóisRESUMO
Pesticides are usually found as mixtures in surface water bodies, even though their regulation in aquatic ecosystems is usually approached individually. In this context, this work aimed to investigate the enzymatic- and transcriptional-level responses after the mixture exposure of phoxim (PHX) and prochloraz (PRC) in the livers of hook snout carp Opsariichthys bidens. These data exhibited that co-exposure to PHX and PRC induced an acute synergistic impact on O. bidens. The activities of catalase (CAT), superoxide dismutase (SOD), carboxylesterase (CarE), and caspase3 varied significantly in most of the individual and combined challenges relative to basal values, indicating the activation of oxidative stress, detoxification dysfunction, as well as cell apoptosis. Besides, the transcriptional levels of five genes (gst, erα, mn-sod, cxcl-c1c, and il-8) exhibited more pronounced changes when subjected to combined pesticide exposure in contrast to the corresponding individual compounds. The findings revealed the manifestation of endocrine dysfunction and immune disruption. These results underscored the potential biochemical and molecular toxicity posed by the combination of PHX and PRC to O. bidens, thereby contributing to a deeper comprehension of the ecological toxicity of pesticide mixtures on aquatic organisms. Importantly, the concurrent presence of PHX and PRC might exacerbate hepatocellular damage in hook snout carps, potentially attributable to their synergistic toxic interactions. This study underscored the toxicological potency inherent in the co-occurrence of PHX and PRC in influencing fish development, thereby offering valuable insights for the risk assessment of pesticide mixtures and the safeguarding of aquatic organisms.
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Astragali radix (AR, namded Huangqi in Chinese) is the dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. As a widely used ethnomedicine, the biological activities of AR include immunomodulatory, anti-hyperglycemic, anti-oxidant, anti-aging, anti-inflammatory, anti-viral, anti-tumor, cardioprotective, and anti-diabetic effects, with minimum side effects. Currently, it is known that polysaccharides, saponins, and flavonoids are the indispensable components of AR. In this review, we will elaborate the research advancements of AR on ethnobotany, ethnopharmacological practices, phytochemicals, pharmacological activities, clinical uses, quality control, production developments, and toxicology. The information is expected to assist clinicians and scientists in developing useful therapeutic medicines with minimal systemic side effects.
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In recent years, various transition metal compounds have been extensively studied to deal with the problems of slow reaction kinetics and the shuttle effect of lithium-sulfur (Li-S) batteries. Nevertheless, their catalytic performance still needs to be further improved by enhancing intrinsic catalytic activity and enriching active sites. Doping is an effective means to boost the catalytic performance through adjusting the electron structure of the catalysts. Herein, the electron structure of CoSe2 is adjusted by doping P, S with different p electron numbers and electronegativity. After S doping (S-CoSe2), the content of Co2+ increases, and charge is redistributed. Furthermore, more electrons are transferred between Li2S4/Li2S and S-CoSe2, and optimal Co-S bonds are formed between them with optimized d-p orbital hybridization, making the bonds of Li2S4/Li2S the longest and easy to break and decompose. Consequently, the Li-S batteries with the S-CoSe2-modified separator achieve improved rate performance and cycling performance, benefiting from the better bidirectional catalytic activity. This work will provide reference for the selection of the anion doping element to enhance the catalytic effect of transition metal compounds.
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Investigating the optimal laser processing parameters for industrial purposes can be time-consuming. Moreover, an exact analytic model for this purpose has not yet been developed due to the complex mechanisms of laser processing. The main goal of this study was the development of a backpropagation neural network (BPNN) with a grey wolf optimization (GWO) algorithm for the quick and accurate prediction of multi-input laser etching parameters (energy, scanning velocity, and number of exposures) and multioutput surface characteristics (depth and width), as well as to assist engineers by reducing the time and energy require for the optimization process. The Keras application programming interface (API) Python library was used to develop a GWO-BPNN model for predictions of laser etching parameters. The experimental data were obtained by adopting a 30 W laser source. The GWO-BPNN model was trained and validated on experimental data including the laser processing parameters and the etching characterization results. The R2 score, mean absolute error (MAE), and mean squared error (MSE) were examined to evaluate the prediction precision of the model. The results showed that the GWO-BPNN model exhibited excellent accuracy in predicting all properties, with an R2 value higher than 0.90.
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Although lithium-sulfur batteries possess the advantage of high theoretical specific capacity, the inevitable shuttle effect of lithium polysulfides is still a difficult problem restricting its application. The design of highly active catalysts to promote the redox reaction during charge-discharge and thus reduce the existence time of lithium polysulfides in the electrolyte is the mainstream solution at present. In particular, bimetallic compounds can provide more active sites and exhibit better catalytic properties than single-component metal compounds by regulating the electronic structure of the catalysts. In this work, bimetallic compounds-nitrogen-doped carbon nanotubes (NiCo)Se2-NCNT and (CuCo)Se2-NCNT are designed by introducing Ni and Cu into CoSe2, respectively. The (CuCo)Se2-NCNT delivers an optimized adsorption-catalytic conversion for lithium polysulfide, benefitting from adjusted electron structure with downshifted d-band center and increased electron fill number of Co in (CuCo)Se2 compared with that of (NiCo)Se2. This endows (CuCo)Se2 moderate adsorption strength for lithium polysulfides and better catalytic properties for their conversion. As a result, the lithium-sulfur batteries with (CuCo)Se2-NCNT achieve a high specific capacity of 1051.06 mAh g-1 at 1C and an enhanced rate property with a specific capacity of 838.27 mAh g-1 at 4C. The work provides meaningful insights into the design of bimetallic compounds as catalysts for lithium-sulfur batteries.
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This study aimed to investigate the association between dietary magnesium intake and all-cause mortality among diabetic retinopathy (DR) patients. In this retrospective cohort study, data of 1,034 DR patients were extracted from the National Health and Nutrition Examination Survey (NHANES) (1999-2018). Dietary magnesium data were obtained from two 24-hour dietary recall interviews, and categorized into quartiles. Potential confounders were selected using weighted univariate Cox regression models. Weighted univariate and multivariate Cox regression models were used to explore the association between dietary magnesium intake and all-cause mortality in DR patients. The results were presented with hazard ratios (HRs) and 95% confidence intervals (CIs). Associations were further explored for subgroups related to age, gender, cardiovascular disease, and chronic kidney disease. Our study included 1,034 DR patients, of whom 438 (42.36%) died. The mean age of all patients was 63.26 (0.51) years old, with a median follow-up time of 75.00 months. Higher magnesium intake was associated with lower all-cause mortality risk (HR=0.58, 95% CI: 0.38-0.88) in DR patients. The association remained for those aged <65 years (HR=0.35, 95% CI: 0.15-0.81), male patients (HR=0.48, 95% CI: 0.27-0.84), patients without chronic kidney disease (HR=0.43, 95% CI: 0.23-0.82), and patients with a history of cardiovascular disease (HR=0.63, 95% CI: 0.39-1.02). DR patients with adequate magnesium intake exhibited a lower incidence of all-cause mortality. Further studies are needed to validate our findings and explore the optimal strategy for magnesium supplementation in DR patients.
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Retinopatia Diabética , Magnésio , Inquéritos Nutricionais , Humanos , Masculino , Feminino , Magnésio/administração & dosagem , Estudos Retrospectivos , Pessoa de Meia-Idade , Retinopatia Diabética/mortalidade , Retinopatia Diabética/epidemiologia , Dieta , Idoso , Estudos de CoortesRESUMO
To reveal the toxicological mechanisms of pesticide mixtures on soil organisms, this study concentrated on evaluating enzymatic activity and gene expression changes in the earthworm Eisenia fetida (Savigny 1826). Despite being frequently exposed to multiple pesticides, including the common combination of abamectin (ABA) and carbendazim (CAR), environmental organisms have primarily been studied for the effects of individual pesticides. Acute toxicity results exhibited that the combination of ABA and CAR caused a synergistic impact on E. fetida. The levels of MDA, ROS, T-SOD, and caspase3 demonstrated a significant increase across most individual and combined groups, indicating the induction of oxidative stress and cell death. Additionally, the expression of three genes (hsp70, gst, and crt) exhibited a significant decrease following exposure to individual pesticides and their combinations, pointing toward cellular damage and impaired detoxification function. In contrast, a noteworthy increase in ann expression was observed after exposure to both individual pesticides and their mixtures, suggesting the stimulation of reproductive capacity in E. fetida. The present findings contributed to a more comprehensive understanding of the potential toxicity mechanisms of the ABA and CAR mixture, specifically on oxidative stress, cell death, detoxification dysfunction, and reproductive capacity in earthworms. Collectively, these data offered valuable toxicological insights into the combined effects of pesticides on soil organisms, enhancing our understanding of the underlying risks associated with the coexistence of different pesticides in natural soil environments.
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Benzimidazóis , Carbamatos , Ivermectina , Oligoquetos , Poluentes do Solo , Solo , Animais , Oligoquetos/efeitos dos fármacos , Ivermectina/análogos & derivados , Ivermectina/toxicidade , Carbamatos/toxicidade , Benzimidazóis/toxicidade , Solo/química , Poluentes do Solo/toxicidade , Estresse Oxidativo , Praguicidas/toxicidadeRESUMO
Background: The causal relationship between daily habits, diseases, drugs, and knee osteoarthritis (KOA) remains unclear. This study utilized a two-sample Mendelian randomization (MR) method to investigate the causal links between these factors and KOA, providing new insights for KOA prevention. Methods: SNPs strongly associated with exposure factors (daily habits, diseases, drugs) were extracted from publicly available genome-wide association study (GWAS) as instrumental variables (IVs). We then selected GWAS of KOA as the outcome, conducting a two-sample MR analysis. Results: Our findings revealed significant causal relationships between several factors and KOA. There was a notable association with time spent watching TV (OR = 4.038; 95% CI: 1.859-8.770; P = 4.192E-04), frequency of friend/family visits (OR = 0.415; 95% CI: 0.219-0.788; P = 7.174E-03), smoking history (OR = 0.781; 95% CI: 0.663-0.921; P = 3.235E-03), gastroesophageal reflux disease (GERD) (OR = 1.519; 95% CI: 1.244-1.856; P = 4.183E-05), hypercholesterolemia (OR = 0.498; 95% CI: 0.290-0.855; P = 0.011), hypothyroidism (OR = 1.048; 95% CI: 1.013-1.084; P = 6.645E-03), use of antithrombotic agents (OR = 0.892; 95% CI: 0.816-0.976; P = 0.013), statin medication (OR = 0.956; 95% CI: 0.916-0.998; P = 0.041), and thyroid preparations (OR = 1.042; 95% CI: 1.014-1.071; P = 2.974E-03) with KOA. Specifically, KOA was positively associated with longer time spent watching TV, GERD, hypothyroidism and thyroid preparations, however showed a negative correlation with more frequent visits from friends or family, smoking history, hypercholesterolemia, antithrombotic agents and statin medication. Sensitivity analysis indicated no significant pleiotropy in these studies (P > 0.05). Conclusion: This comprehensive study underscores the significance of modifying certain habits to mitigate the risk of KOA. Additionally, the elevated risk of KOA among individuals with GERD, hypothyroidism, and those using thyroid preparations warrants attention. These results would be beneficial for clinical research and nursing education.
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Background: Myeloid differentiation factor 88 (MyD88) is the core adaptor for Toll-like receptors defending against microbial invasion and initiating a downstream immune response during microbiota-host interaction. However, the role of MyD88 in the pathogenesis of inflammatory bowel disease is controversial. This study aims to investigate the impact of MyD88 on intestinal inflammation and the underlying mechanism. Methods: MyD88 knockout (MyD88-/-) mice and the MyD88 inhibitor (TJ-M2010-5) were used to investigate the impact of MyD88 on acute dextran sodium sulfate (DSS)-induced colitis. Disease activity index, colon length, histological score, and inflammatory cytokines were examined to evaluate the severity of colitis. RNA transcriptome analysis and 16S rDNA sequencing were used to detect the potential mechanism. Results: In an acute DSS-colitis model, the severity of colitis was not alleviated in MyD88-/- mice and TJ-M2010-5-treated mice, despite significantly lower levels of NF-κB activation being exhibited compared to control mice. Meanwhile, 16S rDNA sequencing and RNA transcriptome analysis revealed a higher abundance of intestinal Proteobacteria and an up-regulation of the nucleotide oligomerization domain-like receptors (NLRs) signaling pathway in colitis mice following MyD88 suppression. Further blockade of the NLRs signaling pathway or elimination of gut microbiota with broad-spectrum antibiotics in DSS-induced colitis mice treated with TJ-M2010-5 ameliorated the disease severity, which was not improved solely by MyD88 inhibition. After treatment with broad-spectrum antibiotics, downregulation of the NLR signaling pathway was observed. Conclusion: Our study suggests that the suppression of MyD88 might be associated with unfavorable changes in the composition of gut microbiota, leading to NLR-mediated immune activation and intestinal inflammation.