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Background: Observational research has highlighted a potential relationship between rheumatoid arthritis (RA) and neurodegenerative diseases (NDs). However, the confirmation of a causal connection is impeded by the inherent limitations of such studies, including vulnerability to confounding factors and the possibility of reverse causality. This study employs a two-sample Mendelian randomization (MR) approach to assess the causal impact of RA on three NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Methods: We aggregated data from genome-wide association studies (GWASs) targeting RA or NDs within populations of European descent. Single nucleotide polymorphisms (SNPs) with robust associations to RA were identified as instrumental variables (IVs). To estimate the association between RA and AD, PD, and ALS, we utilized the inverse variance weighted (IVW) method in our univariable MR (UVMR) analysis. Validation of the IVW results ensued through supplementary analyses using MR-Egger and weighted median methods. The multivariable MR (MVMR) analysis was conducted, adjusting for body mass index (BMI), alcohol drinking, and type 2 diabetes mellitus (T2DM). Results: The UVMR analysis, based on the IVW method, revealed a significantly positive causal association between RA and late-onset (LO) AD (OR [95% CI] = 1.084 [1.020-1.153]; p = 9.980 × 10-3), while suggesting a possible inverse relationship with PD (OR [95% CI] = 0.727 [0.563-0.938]; p = 0.014). Our study did not detect any causal connections between RA and early-onset (EO) AD, atypical or mixed (AM) AD, and ALS (all p > 0.05). The MVMR analysis results indicated that after adjusting for alcohol drinking, RA remains a risk factor for LOAD (OR [95% CI] = 1.094 [1.024-1.169]; p = 0.008). However, MVMR analysis revealed no causal connections between RA and PD after adjustments for BMI, alcohol drinking, or T2DM (all p > 0.05). Sensitivity analyses showed no evidence of heterogeneity and horizontal pleiotropy. Conclusions: This research provides genetic evidence indicating that RA potentially causes an increased risk of developing LOAD and PD. Such a revelation underscores the importance for individuals suffering from RA to be vigilant about the potential emergence of LOAD and PD. Ongoing monitoring and prompt detection are essential for successfully managing and intervening in this possible risk.
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OBJECTIVES: To investigate the correlation between three-dimensional ultrasonography parameters and pelvic floor dysfunction (PFD) and its application value in diagnosis and treatment. METHODS: 92 patients with PFD and 22 without who underwent three-dimensional ultrasonography were selected. Transperineal three-dimensional ultrasonography was performed by Voluson E8 color Doppler ultrasonography to analyze the anteroposterior diameter (LHAD), transverse diameter (LHLD), pelvic diaphragmatic hiatus area (LHA), and bladder neck mobility (BND) of the patients. Diagnostic sensitivity and specificity of ultrasound parameters in PFD were analyzed using ROC curves. Paired sample t test was used to analyze the improvement of PFMT in patients with PFD. RESULTS: Patients with PFD had significantly higher levels of â³LHAD, â³LHLD, â³LHA and BND than controls (all P < 0.01). Binary logistic regression analysis showed that â³LHA or BND levels were independent risk factors for the development of PFD. The ROC results showed that the area under the ROC curve with BND level was the highest (0.917). The diagnostic sensitivity of BND in PFD was 100.0% and the specificity was 70.7%. In Urinary incontinence (UI) patients, there was a significant positive correlation between the occurrence of UI and BND levels (all r > 0, P < 0.05). After PFMT treatment, the levels of â³LHAD, â³LHLD, â³LHA and BND in patients with PFD were significantly decreased (all P < 0.001). CONCLUSION: The abnormal changes in the level of three-dimensional ultrasound parameters can be used as a sensitive indicator to evaluate PFD and a guiding parameter for PFMT treatment. ADVANCES IN KNOWLEDGE: The feasibility of operation and repetition by three-dimensional pelvic floor ultrasonography could provide a reliable imaging basis for clinical diagnosis and treatment of patients with PFD.
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The frequent occurrence of viral infections poses a serious threat to human life. Identifying effective antiviral components is urgent. In China, pearls have been important traditional medicinal ingredients since ancient times, exhibiting various therapeutic properties, including detoxification properties. In this study, a peptide, KKCH, which acts against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was derived from Pinctada fucata pearls. Molecular docking showed that it bound to the same pocket of the SARS-CoV-2 S protein and cell surface target angiotensin-converting enzyme II (ACE2). The function of KKCH was analyzed through surface plasmon resonance (SPR), Enzyme-Linked Immunosorbent Assays, immunofluorescence, and simulation methods using the SARS-CoV-2 pseudovirus and live virus. The results showed that KKCH had a good affinity for ACE2 (KD = 6.24 × 10-7 M) and could inhibit the binding of the S1 protein to ACE2 via competitive binding. As a natural peptide, KKCH inhibited the binding of the SARS-CoV-2 S1 protein to the surface of human BEAS-2B and HEK293T cells. Moreover, viral experiments confirmed the antiviral activity of KKCH against both the SARS-CoV-2 spike pseudovirus and SARS-CoV-2 live virus, with half-maximal inhibitory concentration (IC50) values of 398.1 µM and 462.4 µM, respectively. This study provides new insights and potential avenues for the prevention and treatment of SARS-CoV-2 infections.
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Enzima de Conversão de Angiotensina 2 , Antivirais , Tratamento Farmacológico da COVID-19 , Peptídeos , Pinctada , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , Humanos , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Antivirais/farmacologia , Antivirais/química , COVID-19/virologia , Células HEK293 , Simulação de Acoplamento Molecular , Peptídeos/farmacologia , Peptídeos/química , Ligação Proteica , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/químicaRESUMO
A subarachnoid hemorrhage (SAH) is life-threatening bleeding into the subarachnoid space that causes brain damage. Growing evidence has suggested that melatonin provides neuroprotection following SAH. Exploring the mechanisms underlying melatonin-mediated neuroprotection contributes to its clinical application in SAH. The plasma and cerebrospinal fluid (CSF) were collected from SAH patients, and SAH mice were established via pre-chiasmatic injection. Circodz3 expression, levels of IL-1ß and TNF-α, brain water content, neurological and beam-waling scores were determined. Ferroptosis was evaluated by analyzing levels of iron, lipid ROS, MDA, and GSH. The colocalization of circodz3 and Iba-1 was analyzed by immunofluorescence staining. Interaction of circodz3 and HuR was determined with RNA pull-down and RNA immunoprecipitation assays. Herein, we found that circodz3 was highly abundant in SAH patients and mice. Colocalization of circodz3 and Iba-1 in the left hemisphere of SAH mice suggested the implication of circodz3 in regulating microglia activation following SAH. Melatonin alleviated brain edema, neurological impairment, and microglia activation and inhibited circodz3 expression in SAH mice. Moreover, melatonin inhibited M1 polarization, oxidative stress and ferroptosis and restrained circodz3 expression in primary microglia following SAH. These effects were abrogated by circodz3 overexpression. Circodz3 knockdown inhibited ferroptosis and M1 polarization of BV2 microglia after SAH. Circodz3 interacted with HuR to facilitate ß-Trcp1-mediated ubiquitination and degradation, thus restraining the expression of SLC7A11 and GPX4. Collectively, melatonin exerted neuroprotection following SAH via inhibiting ferroptosis and M1 polarization through the circodz3/HuR axis. Our study suggests potential application of melatonin in the treatment of SAH.
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Proteína Semelhante a ELAV 1 , Ferroptose , Melatonina , Camundongos Endogâmicos C57BL , Microglia , Hemorragia Subaracnóidea , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Animais , Melatonina/farmacologia , Melatonina/uso terapêutico , Melatonina/metabolismo , Microglia/metabolismo , Microglia/efeitos dos fármacos , Camundongos , Humanos , Masculino , Proteína Semelhante a ELAV 1/metabolismo , RNA Circular/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Antibiotics residues can accelerate the growth of drug-resistant bacteria and harm the ecological environment. Under the effect of enrichment and biomagnification, the emergence of drug-resistant pathogenic bacteria may eventually lead to humans being ineffective to drugs in the face of bacterial or fungal disease infections in the future. It is urgent to develop an efficient separation medium and analytical method for simultaneous extraction and determination of antibiotics in the water environment. RESULTS: This work doped 2,6-Di-O-methyl-ß-cyclodextrin, randomly methyl-ß-cyclodextrin, 2-hydroxypropyl-ß-cyclodextrin with thymol:fatty acid respectively to construct non-covalent interaction-dominated pH-responsive ternary supramolecular deep eutectic solvents (SUPRADESs), which can undergo a hydrophilic/hydrophobic transition with aqueous phase to achieve an efficient microextraction. Semi-empirical method illustrated that SUPRADESs have a wide range of hydrogen bond receptor sites. We developed a SUPRADES-based analytical method combined with liquid chromatography-triple quadrupole mass spectrometry for the extraction and determination of trace quinolones and sulfonamides in wastewater. The overall limits of detection of the method were 0.0021-0.0334 ng mL-1 and the limits of quantification were 0.0073-0.1114 ng mL-1. The linearity maintained good in the spiked level of 0.01-100 ng mL-1 (R2 > 0.99). The overall enrichment factors of the method were 157-201 with lower standard deviations (≤8.7). SIGNIFICANCE: The method gave an extraction recovery of 70.1-115.3 % for 28 antibiotics in livestock farming wastewater samples from Zhejiang, China, at trace levels (minimum 0.5 ng mL-1). The results demonstrated that inducing the phase transition between SUPRADES and aqueous phase by adjusting pH for extraction is a novel and efficient pretreatment strategy. To our knowledge, this is the first application of cyclodextrin-based ternary SUPRADESs with pH-responsive reversible hydrophobicity-hydrophilicity transition behavior in wastewater analysis.
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Ciclodextrinas , Solventes Eutéticos Profundos , Quinolonas , Sulfonamidas , Águas Residuárias , Poluentes Químicos da Água , Águas Residuárias/química , Águas Residuárias/análise , Concentração de Íons de Hidrogênio , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/química , Poluentes Químicos da Água/isolamento & purificação , Sulfonamidas/química , Sulfonamidas/análise , Sulfonamidas/isolamento & purificação , Quinolonas/química , Quinolonas/isolamento & purificação , Quinolonas/análise , Ciclodextrinas/química , Solventes Eutéticos Profundos/químicaRESUMO
In this research, we unveil the medical potential of pearls by identifying a novel bioactive peptide within them for the first time. The peptide, termed KKCHFWPFPW, emerges as a pioneering angiotensin I-converting enzyme (ACE) inhibitor, originating from the pearl matrix of Pinctada fucata. Employing quadrupole time-of-flight mass spectrometry, this peptide was meticulously selected and pinpointed. With a molecular weight of 1417.5 Da and a theoretical isoelectric point of 9.31, its inhibitory potency was demonstrated through a half-maximal inhibitory concentration (IC50) of 4.17 µM, established via high-performance liquid chromatography. The inhibition of ACE by this peptide was found to be competitive, as revealed by Lineweaver-Burk plot analysis, where an increase in peptide concentration correlated with an enhanced rate of ACE inhibition. To delve into the interaction between KKCHFWPFPW and ACE, molecular docking simulations were conducted using the Maestro 2022-1 Glide software, shedding light on the inhibitory mechanism. This investigation suggests that peptides derived from the P. martensii pearl matrix hold promise as a novel source for antihypertensive agents.
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Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular event associated with high mortality and significant morbidity. Recent studies have highlighted the emerging role of ferroptosis, a novel form of regulated cell death, in the pathogenesis of SAH. Circular RNAs (circRNAs), have been found to play essential roles in various cellular processes, including gene regulation and disease pathogenesis. The expression profile of circRNAs in neural tissues, particularly in the brain, suggests their critical role in synaptic function and neurogenesis. Moreover, the interplay between circRNAs and ferroptosis-related pathways, such as iron metabolism and lipid peroxidation, is explored in the context of SAH. Understanding the functional roles of specific circRNAs in the context of SAH may provide potential therapeutic targets to attenuate ferroptosis-associated brain injury. Furthermore, the potential of circRNAs as diagnostic biomarkers for SAH severity, prognosis, and treatment response is discussed. Overall, this review highlights the significance of studying the intricate interplay between circRNAs and ferroptosis in the context of SAH. Unraveling the mechanisms by which circRNAs modulate ferroptotic cell death may pave the way for the development of novel therapeutic strategies and diagnostic approaches for SAH management, ultimately improving patient outcomes and quality of life.
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This study elucidates the mechanism of obesity-related adverse pregnancy outcomes and further investigates the effect of resveratrol on reproductive performance in a short- or long-term HFD-induced obese mouse model. Results show that maternal weight had a significant positive correlation with litter mortality in mice. A long-term HFD increased body weight and litter mortality with decreased expression of uterine cytochrome oxidase 4 (COX4), which was recovered by resveratrol in mice. Moreover, HFD decreased the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factors-1 (Nrf-1), and phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase (p-AMPK) and increased the expression of phosphorylated extracellular regulated protein kinases (p-ERK) in the uterus. Resveratrol, a polyphenol that can directly bind to the ERK protein, suppressed the phosphorylation of ERK, increased the expression of p-AMPK, PGC-1α and Nrf-1, and decreased litter mortality in mice.
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Dieta Hiperlipídica , Mitocôndrias , Resultado da Gravidez , Resveratrol , Útero , Animais , Resveratrol/farmacologia , Feminino , Gravidez , Camundongos , Dieta Hiperlipídica/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Útero/metabolismo , Útero/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismoRESUMO
Obesity is becoming a major global health problem in children that can cause diseases such as type 2 diabetes and metabolic disorders, which are closely related to the gut microbiota. However, the underlying mechanism remains unclear. In this study, a significant positive correlation was observed between Prevotella copri (P. copri) and obesity in children (p = 0.003). Next, the effect of P. copri on obesity was explored by using fecal microbiota transplantation (FMT) experiment. Transplantation of P. copri. increased serum levels of fasting blood glucose (p < 0.01), insulin (p < 0.01) and interleukin-1ß (IL-1ß) (p < 0.05) in high-fat diet (HFD)-induced obese mice, but not in normal mice. Characterization of the gut microbiota indicated that P. copri reduced the relative abundance of the Akkermansia genus in mice (p < 0.01). Further analysis on bile acids (BAs) revealed that P. copri increased the primary BAs and ursodeoxycholic acid (UDCA) in HFD-induced mice (p < 0.05). This study demonstrated for the first time that P. copri has a significant positive correlation with obesity in children, and can increase fasting blood glucose and insulin levels in HFD-fed obese mice, which are related to the abundance of Akkermansia genus and bile acids.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Obesidade Infantil , Prevotella , Humanos , Criança , Animais , Camundongos , Insulina , Ácidos e Sais Biliares/farmacologia , Glicemia , Camundongos Obesos , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BLRESUMO
Lushan Yunwu tea (LSYWT) is a famous green tea in China. However, the effects of intercropping tea with flowering cherry on the overall aroma of tea have not been well understood. In this study, headspace solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS) was used for analysis. A total of 54 volatile compounds from eight chemical classes were identified in tea samples from both the intercropping and pure-tea-plantation groups. Principal component analysis (PCA), orthogonal partial least-squares discriminant analysis (OPLS-DA), and odor activity value (OAV) methods combined with sensory evaluation identified cis-jasmone, nonanal, and linalool as the key aroma compounds in the intercropping group. Benzaldehyde, α-farnesene, and methyl benzene were identified as the main volatile compounds in the flowering cherry using headspace solid-phase microextraction/gas chromatography-mass spectrometry (HS-SPME/GC-MS). These findings will enrich the research on tea aroma chemistry and offer new insights into the product development and quality improvement of LSYWT.
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Background: Baseline serological biomarkers have the potential to predict the benefits of adjuvant chemotherapy in patients with gastric cancer. However, the fluctuating nature of postoperative recurrence risk makes precise treatment challenging. We aimed to develop a risk score in real-time predicting outcomes for postoperative GC patients using blood chemistry tests. Materials and methods: This was a retrospective, multicentre, longitudinal cohort study from three cancer centres in China, with a total of 2737 GC patients in the pTNM stage Ib to III. Among them, 1651 patients with at least two serological records were assigned to the training cohort. Model validation was carried out using separate testing data with area under curve (AUC). The least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) algorithm were used to select the parameters. Results: The Cox regression model derived six risk factors to construct a composite score (low-risk: 0-2 score; high risk: 3-6 score), including CEA, CA125, CA199, haemoglobin, albumin, and neutrophil to lymphocyte ratio. The risk score accurately predicted mortality in 1000-time bootstrap (AUROCs:0.658; 95% CI: 0.645, 0.670), with the highest AUROC (0.767; 95% CI: 0.743, 0.791) after 1 year since the gastrectomy. In validation dataset, the risk score had an AUROC of 0.586 (95% CI 0.544, 0.628). Furthermore, patients with high risk at 1 month derived significant clinical benefits from adjuvant chemotherapy (P for interaction <0.0001). Compared with the low-low-low risk group, the low-low-high risk group of the long-term state chain (risk state at baseline, 6 months, 1 year) had the worse OS (HR, 6.91; 95%CI: 4.27, 11.19) and DFS (HR, 7.27; 95%CI: 4.55, 11.63). Conclusion: The dynamic risk score is an accurate and user-friendly serological risk assessment tool for predicting outcomes and assisting clinical decisions after gastrectomy.
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OBJECTIVE: To analyze the therapeutic effect of acupuncture combined with mifepristone on uterine fibroids and its influence on sex hormones and inflammatory factors. METHODS: Data of 102 patients with uterine fibroids admitted to Shanxi Provincial Hospital of Chinese Medicine from January 2019 to January 2022 were retrospectively analyzed. Among them, there were 50 patients treated with mifepristone alone (control group) and 52 patients undergoing combined treatment of acupuncture and mifepristone (observation group). After 2 months of continuous treatment, the therapeutic efficacy, volume of uterine fibroids and uterus, levels of inflammatory factors (C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α)), as well as levels of estradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), along with hemodynamic levels and incidence of adverse reactions were recorded and compared between the two groups. Logistic analysis was employed to identify the independent risk factors for the recurrence of uterine fibroids in patients. RESULTS: Compared with the control group, the observation group was identified with significantly higher overall response rate (P < 0.05). The uterine fibroid volume and uterine volume significantly improved in both groups after treatment, and the improvements were more prominent in the observation group than in the control group (P < 0.05). After treatment, the serum CRP and TNF-α were both evidently decreased in the two groups, while levels of E2, FSH, LH and peak blood flow velocity were significantly ameliorated, and the improvements in the observation group were more significant than those in the control group (P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). Alcohol intake and treatment regime were independent risk factors for the recurrence of uterine fibroids in patients. CONCLUSION: Combining acupuncture with mifepristone can significantly improve uterine fibroids, estrogen and progesterone levels, as well as reduce inflammation, with a high level of safety, making it a promising treatment for clinical use.
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Dissipation, residue levels, and ingestion risks of carbendazim in peach (Amygdalus persica L.) were investigated with individual and joint applications in the present study. The dissipation kinetics of carbendazim, chlorpyrifos, prochloraz, and imidacloprid were evaluated by the first-order kinetics. When carbendazim was individually applied, the final residual concentration was 2.97 mg kg-1 and the half-life was 17.4 d. In the joint application of carbendazim with chlorpyrifos, prochloraz, and imidacloprid, the residual concentrations at 35 d after spraying were 7.16, 7.50, and 4.26 mg kg-1 and the half-lives were 30.8, 23.7, and 23.2 d, respectively, which showed an increase of 1.3-1.8 times compared with the single application of carbendazim. In addition, the effects of household processing of rinsing and peeling were investigated, and a high removal rate of 54.6% and 76.5% were found. Furthermore, the carbendazim ingestion risk assessment was conducted, which indicated that the acute health risk (aHI) and hazard quotient (HQ) of carbendazim were all within acceptable levels ranging from 21.7% to 40.9%. However, a higher ingestion risk of carbendazim was found under the joint application. This study provides some preliminary guidance for the joint application and risk assessment of carbendazim in peach, which is worth further investigation.
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Clorpirifos , Resíduos de Praguicidas , Prunus persica , Medição de Risco , Resíduos de Praguicidas/análiseRESUMO
Preeclampsia is a pregnancy disorder characterized by systemic organ damage and high blood pressure. It has been reported that microRNA-195 (miR-195) is associated with preeclampsia. In this study, we discovered the target of miR-195 in regulating human extravillous cytotrophoblast-derived transformed cell proliferation and migration. We analyzed the clinicopathological factors of preeclampsia and normal pregnancies. The messenger ribonucleic acid (mRNA) levels of miR-195 and tissue factor pathway inhibitor 2 (TFPI2) were measured in placental tissues derived from normal and preeclampsia patients by real-time polymerase chain reaction (PCR). Human umbilical cord mesenchymal stem cell (hUC-MSC)-derived extracellular vesicles were verified by western blot. HTR8-S/Vneo cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and cell migration rate was assessed by the transwell assay. Relative luciferase activities were measured in TFPI2 wild-type (WT) and mutant cells. miR-195 expression was negatively correlated with TFPI2 mRNA levels in preeclampsia patients. Extracellular vesicles derived from hUC-MSCs enhanced HTR8-S/Vneo cell proliferation and migration. In addition, miR-195 isolated from hUC-MSCs enhanced HTR8-S/Vneo cell proliferation and migration by targeting TFPI2. Our findings demonstrate that the upregulation of miR-195 in extracellular vesicles derived from hUC-MSCs promotes HTR8-S/Vneo cell proliferation and migration by targeting TFPI2.
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BACKGROUND: Glucocorticoids (GC)-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis, which leads to an increased risk of fracture in patients. The inhibition of the osteoblast effect is one of the main pathological characteristics of GIOP, but without effective drugs on treatment. PURPOSE: The aim of this study was to investigate the potential effects of orcinol glucoside (OG) on osteoblast cells and GIOP mice, as well as the mechanism of the underlying molecular target protein of OG both in vitro osteoblast cell and in vivo GIOP mice model. METHODS: GIOP mice were used to determine the effect of OG on bone density and bone formation. Then, a cellular thermal shift assay coupled with mass spectrometry (CETSA-MS) method was used to identify the target of OG. Surface plasmon resonance (SPR), enzyme activity assay, molecular docking, and molecular dynamics were used to detect the affinity, activity, and binding site between OG and its target, respectively. Finally, the anti-osteoporosis effect of OG through the target signal pathway was investigated in vitro osteoblast cell and in vivo GIOP mice model. RESULTS: OG treatment increased bone mineral density (BMD) in GIOP mice and effectively promoted osteoblast proliferation, osteogenic differentiation, and mineralization in vitro. The CETSA-MS result showed that the target of OG acting on the osteoblast is the p38 protein. SPR, molecular docking assay and enzyme activity assay showed that OG could direct bind to the p38 protein and is a p38 agonist. The cellular study found that OG could promote p38 phosphorylation and upregulate the proteins expression of its downstream osteogenic (Runx2, Osx, Collagen â , Dlx5). Meanwhile, it could also inhibit the nuclear transport of GR by increasing the phosphorylation site at GR226 in osteoblast cell. In vivo GIOP mice experiment further confirmed that OG could prevent bone loss in the GIOP mice model through promoting p38 activity as well as its downstream proteins expression and activity. CONCLUSIONS: This study has established that OG could promote osteoblast activity and revise the bone loss in GIOP mice by direct binding to the p38 protein and is a p38 agonist to improve its downstream signaling, which has great potential in GIOP treatment for targeting p38. This is the first report to identify OG anti-osteoporosis targets using a label-free strategy (CETSA-MS).
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Glucocorticoides , Osteoporose , Animais , Camundongos , Glucocorticoides/efeitos adversos , Osteogênese , Glucosídeos/uso terapêutico , Simulação de Acoplamento Molecular , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Osteoporose/metabolismoRESUMO
OBJECTIVES: To investigate the difference in intestinal microbiota between preterm infants with neurodevelopmental impairment (NDI) and those without NDI. METHODS: In this prospective cohort study, the preterm infants who were admitted to the neonatal intensive care unit of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region from September 1, 2019 to September 30, 2021 were enrolled as subjects. According to the assessment results of Gesell Developmental Scale at the corrected gestational age of 1.5-2 years, they were divided into two groups: normal (n=115) and NDI (n=100). Fecal samples were collected one day before discharge, one day before introducing solid food, and at the corrected gestational age of 1 year. High-throughput sequencing was used to compare the composition of intestinal microbiota between groups. RESULTS: Compared with the normal group, the NDI group had a significantly higher Shannon diversity index at the corrected gestational age of 1 year (P<0.05). The principal coordinate analysis showed a significant difference in the composition of intestinal microbiota between the two groups one day before introducing solid food and at the corrected gestational age of 1 year (P<0.05). Compared with the normal group, the NDI group had a significantly higher abundance of Bifidobacterium in the intestine at all three time points, a significantly higher abundance of Enterococcus one day before introducing solid food and at the corrected gestational age of 1 year, and a significantly lower abundance of Akkermansia one day before introducing solid food (P<0.05). CONCLUSIONS: There are significant differences in the composition of intestinal microbiota between preterm infants with NDI and those without NDI. This study enriches the data on the characteristics of intestinal microbiota in preterm infants with NDI and provides reference for the microbiota therapy and intervention for NDI in preterm infants.
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Microbioma Gastrointestinal , Doenças do Prematuro , Lactente , Criança , Recém-Nascido , Humanos , Pré-Escolar , Recém-Nascido Prematuro , Estudos Prospectivos , China , Idade GestacionalRESUMO
Importance: Neonatal seizures pose a significant challenge in critical care, and continuous video electroencephalography (cEEG) monitoring holds promise for early detection of seizures. However, large-scale data on the incidence of neonatal seizures and monitoring systems in China are lacking. Objectives: To determine the incidence of neonatal seizures in infants with high risk in China. Design, Setting, and Participants: A large, cross-sectional multicenter study was conducted from January 2017 to December 2018 in the neonatal intensive care units (NICUs) of 7 tertiary medical centers in China. Neonates with high risk were included, and cEEG monitoring was conducted. Data were collected between January 1, 2017, and January 31, 2020. The data were analyzed between January 2021 and January 2022. Main Outcomes and Measures: The incidence of neonatal seizures, categorized by etiology, and seizure burden. Results: A total of 20â¯310 neonates with high risk were included (10â¯495 [51.7%] male; mean [SD] postmenstrual age, 37.7 [3.7] weeks), and seizures were observed in 3423 infants (16.9%). The highest proportion of seizures was attributed to acute neonatal encephalopathy (1448 [42.3%]). The incidence of seizures decreased with postmenstrual age and birth weight, with the highest occurrence observed in neonates with postmenstrual age of less than 28 weeks (237 of 879 [27.0%]) or birth weight of less than 1.0 kg (269 of 914 [29.4%]). Preterm infants had a higher proportion of moderate and severe seizure burdens compared with full-term infants (moderate severity: 248 of 1199 [20.7%] vs 454 of 2224 [20.4%]), but no significant differences were observed in etiology. Seizure burden was highest with genetic syndromes (49 of 188 [26.1%]), central nervous system malformations (33 of 127 [26.0%]), and inborn errors of metabolism (27 of 113 [23.9%]). During hospitalization, 7.8% of neonates with seizures died (267 neonates), with 81.3% of these cases having a moderate or severe seizure burden (217 neonates). Mortality was generally higher in preterm vs full-term infants (98 of 1199 [8.2%] vs 169 of 2224 [7.6%]) and increased with the severity of seizure burden (217 of 267 neonates with moderate or severe burden [81.3%]). Conclusions and Relevance: This cross-sectional study of neonatal seizures underscores the substantial burden seizures pose to high-risk infants with brain injury in China, particularly those who are born prematurely or who have congenital conditions.
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Lesões Encefálicas , Epilepsia , Doenças do Recém-Nascido , Lactente , Recém-Nascido , Masculino , Humanos , Adulto , Feminino , Estudos Transversais , Recém-Nascido Prematuro , Peso ao Nascer , Incidência , Convulsões/diagnóstico , Convulsões/epidemiologia , Convulsões/etiologia , Lesões Encefálicas/complicações , EletroencefalografiaRESUMO
Spermatogenesis defects are important for male infertility; however, the etiology and pathogenesis are still unknown. Herein, we identified two loss-of-function mutations of STK33 in seven individuals with non-obstructive azoospermia. Further functional studies of these frameshift and nonsense mutations revealed that Stk33-/KI male mice were sterile, and Stk33-/KI sperm were abnormal with defects in the mitochondrial sheath, fibrous sheath, outer dense fiber, and axoneme. Stk33KI/KI male mice were subfertile and had oligoasthenozoospermia. Differential phosphoproteomic analysis and in vitro kinase assay identified novel phosphorylation substrates of STK33, fibrous sheath components A-kinase anchoring protein 3 and A-kinase anchoring protein 4, whose expression levels decreased in testis after deletion of Stk33. STK33 regulated the phosphorylation of A-kinase anchoring protein 3/4, affected the assembly of fibrous sheath in the sperm, and played an essential role in spermiogenesis and male infertility.