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ETHNOPHARMACOLOGICAL RELEVANCE: Zhubi Decoction (ZBD) is a modified formulation derived from the classic traditional Chinese medicine prescription "Er-Xian Decoction" documented in the esteemed "Clinical Manual of Chinese Medical Prescription". While the utilization of ZBD has exhibited promising clinical outcomes in treating rheumatoid arthritis (RA), the precise bioactive chemical constituents and the underlying mechanisms involved in its therapeutic efficacy remain to be comprehensively determined. AIM OF THE STUDY: This study aims to systematically examine ZBD's pharmacological effects and molecular mechanisms for RA alleviation. MATERIALS AND METHODS: Utilizing the collagen-induced arthritis (CIA) rat model, we comprehensively evaluated the anti-rheumatoid arthritis effects of ZBD in vivo through various indices, such as paw edema, arthritis index, ankle diameter, inflammatory cytokine levels, pathological conditions, and micro-CT analysis. The UPLC-MS/MS technique was utilized to analyze the compounds of ZBD. The potential therapeutic targets and signaling pathways of ZBD in the management of RA were predicted using network pharmacology. To analyze comprehensive metabolic profiles and identify underlying metabolic pathways, we conducted a serum-based widely targeted metabolomics analysis utilizing LC-MS technology. Key targets and predicted pathways were further validated using immunofluorescent staining, which integrated findings from serum metabolomics and network pharmacology analysis. Additionally, we analyzed the gut microbiota composition in rats employing 16 S rDNA sequencing and investigated the effects of ZBD on the microbiota of CIA rats through bioinformatics and statistical methods. RESULTS: ZBD exhibited remarkable efficacy in alleviating RA symptoms in CIA rats without notable side effects. This included reduced paw redness and swelling, minimized joint damage, improved the histopathology of cartilage and synovium, mitigated the inflammatory state, and lowered serum concentrations of cytokines TNF-α, IL-1ß and IL-6. Notably, the effectiveness of ZBD was comparable to MTX. Network pharmacology analysis revealed inflammation and immunity-related signaling pathways, such as PI3K/AKT, MAPK, IL-17, and TNF signaling pathways, as vital mediators in the effectual mechanisms of ZBD. Immunofluorescence analysis validated ZBD's ability to inhibit PI3K/AKT pathway proteins. Serum metabolomics studies revealed that ZBD modulates 170 differential metabolites, partially restored disrupted metabolic profiles in CIA rats. With a notable impact on amino acids and their metabolites, and lipids and lipid-like molecules. Integrated analysis of metabolomics and network pharmacology identified 6 pivotal metabolite pathways and 3 crucial targets: PTGS2, GSTP1, and ALDH2. Additionally, 16 S rDNA sequencing illuminated that ZBD mitigated gut microbiota dysbiosis in the CIA group, highlighting key genera such as Ligilactobacillus, Prevotella_9, unclassified_Bacilli, and unclassified_rumen_bacterium_JW32. Correlation analysis disclosed a significant link between 47 distinct metabolites and specific bacterial species. CONCLUSION: ZBD is a safe and efficacious TCM formulation, demonstrates efficacy in treating RA through its multi-component, multi-target, and multi-pathway mechanisms. The regulation of inflammation and immunity-related signaling pathways constitutes a crucial mechanism of ZBD's efficacy. Furthermore, ZBD modulates host metabolism and intestinal flora. The integrated analysis presents experimental evidence of ZBD for the management of RA.

Assuntos

Artrite Experimental , Artrite Reumatoide , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Metabolômica , Farmacologia em Rede , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Masculino , Ratos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Citocinas/sangue , Citocinas/metabolismo , Transdução de Sinais/efeitos dos fármacos

RESUMO

Arsenic (As) methylation in soils affects the environmental behavior of As, excessive accumulation of dimethylarsenate (DMA) in rice plants leads to straighthead disease and a serious drop in crop yield. Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security. Here, soils including un-arsenic contaminated (N-As), low-arsenic (L-As), medium-arsenic (M-As), and high-arsenic (H-As) soils were incubated under continuous anoxic, continuous oxic, and consecutive anoxic/oxic treatments respectively, to profile arsenic methylating process and microbial species involved in the As cycle. Under anoxic-oxic (A-O) treatment, methylated arsenic was significantly increased once oxygen was introduced into the incubation system. The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic (A), oxic (O), and oxic-anoxic (O-A) treatments, under which arsenic was methylated slightly and then decreased in all four As concentration soils. In fact, the most plentiful arsenite S-adenosylmethionine methyltransferase genes (arsM) contributed to the increase in As methylation. Proteobacteria (40.8%-62.4%), Firmicutes (3.5%-15.7%), and Desulfobacterota (5.3%-13.3%) were the major microorganisms related to this process. These microbial increased markedly and played more important roles after oxygen was introduced, indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic (flooding) and oxic (drainage) environment. The novel findings provided new insights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.

Assuntos

Arsênio , Oryza , Microbiologia do Solo , Poluentes do Solo , Solo , Arsênio/análise , Poluentes do Solo/análise , Metilação , Solo/química , Microbiota , Oxirredução , Bactérias/metabolismo

RESUMO

Currently, there is no cure or effective treatment for Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying ALS remain unclear, with immunological factors potentially playing a significant role. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), a systematic review of preclinical studies was conducted, searching seven databases including PubMed, covering literature from the inception of the databases to April 10, 2024. Methodological quality of the included literature was assessed using CAMARADES, while the risk of bias in the included studies was evaluated using SYRCLE's ROB tool. Review Manager 5.4.1 statistical software was used for meta-analysis of the outcomes. The scoping review followed the Joanna Briggs Institute Methodological Guidelines and reporting of this review followed the PRISMA-extension for Scoping Reviews (PRISMA -ScR) checklist to explore the immunological mechanisms of Herbal Medicine (HM) in treating ALS. This systematic review and meta-analysis involved 18 studies with a total of 443 animals. The studies scored between 4 to 8 for methodological quality and 3 to 7 for risk of bias, both summing up to 10.A remarkable effects of HM in ALS mice, including onset time(Standardized Mean Difference(SMD): 1.75, 95% Confidence Interval(CI) (1.14 ~ 2.36), Z = 5.60, P < 0.01), survival time(SMD = 1.42, 95% CI (0.79 ~ 2.04), Z = 4.44, P < 0.01), stride length(SMD=1.90, 95% CI (1.21 to 2.59), Z = 5.39, P < 0.01) and duration time (Mean Difference(MD)=6.79, 95% CI [-0.28, 13.87], Z=1.88, P =0.06), showing HM's certain efficiency in treating ALS mice. The scoping review ultimately included 35 articles for review. HMs may treat ALS through mechanisms such as combating oxidative stress, excitatory amino acid toxicity, and calcium cytotoxicity, understanding and exploring the mechanisms will bring hope to patients. Individual herbs and their formulations within HM address ALS through a variety of immune pathways, including safeguarding the blood-brain barrier, countering neuroinflammation, impeding complement system activation, mitigating natural killer cell toxicity, and regulating T cell-mediated immune pathways. The preclinical evidence supports the utilization of HM as a conventional treatment for ALS mice. Growing evidence indicates that HM may potentially delay neurological degeneration in ALS by activating diverse signaling pathways, especially immune pathways.

Assuntos

Esclerose Lateral Amiotrófica , Modelos Animais de Doenças , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/genética , Animais , Camundongos , Camundongos Transgênicos , Humanos , Superóxido Dismutase-1/genética , Medicina Herbária

RESUMO

Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II+ (CaMKII+) target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRNDA → dBNSTCaMKII+ neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression.

Assuntos

Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Depressão , Neurônios Dopaminérgicos , Núcleo Dorsal da Rafe , Núcleos Septais , Animais , Neurônios Dopaminérgicos/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Camundongos , Núcleos Septais/metabolismo , Núcleos Septais/fisiopatologia , Masculino , Feminino , Depressão/metabolismo , Depressão/fisiopatologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Camundongos Endogâmicos C57BL , Comportamento Animal , Modelos Animais de Doenças , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Dopamina D2/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Transmissão Sináptica/fisiologia

RESUMO

The emerging presence of environmental obesogens, chemicals that disrupt energy balance and contribute to adipogenesis and obesity, has become a major public health challenge. Molecular initiating events (MIEs) describe biological outcomes resulting from chemical interactions with biomolecules. Machine learning models based on MIEs can predict complex toxic end points due to chemical exposure and improve the interpretability of models. In this study, a system was constructed that integrated six MIEs associated with adipogenesis and obesity. This system showed high accuracy in external validation, with an area under the receiver operating characteristic curve of 0.78. Molecular hydrophobicity (SlogP_VSA) and direct electrostatic interactions (PEOE_VSA) were identified as the two most critical molecular descriptors representing the obesogenic potential of chemicals. This system was further used to predict the obesogenic effects of chemicals on the candidate list of substances of very high concern (SVHCs). Results from 3T3-L1 adipogenesis assays verified that the system correctly predicted obesogenic or nonobesogenic effects of 10 of the 12 SVHCs tested, and identified four novel potential obesogens, including 2-benzotriazol-2-yl-4,6-ditert-butylphenol (UV-320), 4-(1,1,5-trimethylhexyl)phenol (p262-NP), 2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethanol (OP1EO) and endosulfan. These validation data suggest that the screening system has good performance in adipogenic prediction.

RESUMO

Objective: To investigate the characteristics and drug resistance patterns of Klebsiella pneumoniae (K. pneumoniae) infection in pediatric intensive care unit (PICU). Methods: K. pneumoniae strains from 17 domestic PICUs were analyzed for overall condition and drug resistance using WHO-NET software. Results: From 2016 to 2022, there was a linear increase in the detection rate of K. pneumoniae (P<0.05), with a total of 2591 (9.7%) strains detected. The primary sites of K. pneumoniae detection were the respiratory tract (71.1%), blood (8.6%), and urinary tract (7.1%). K. pneumoniae's resistance to penicillin drugs exceeded 90%, and are over 50% to cephalosporins. Resistance to cefoperazone-sulbactam decreased from 51.7% to 25.7%, and ranged from 9.1% to 20.8% for ceftolozane-tazobactam. Carbapenem-resistant K. pneumoniae strains constituted 32.3%. Resistance to imipenem and meropenem have decreased to 33.8% and 40.2%, while increased to 35.2% for ertapenem. Levofloxacin and amikacin resistance rates have decreased to 25.7% and 9.1%, but remain high at 63.8% for moxifloxacin and 44.6% for ciprofloxacin. K. pneumoniae demonstrated the lowest resistance rates to polymyxin B (0.9%), tigecycline (2.2%), and polymyxin E (3.1%). No strain of K. pneumoniae was resistant to both polymyxin B and meropenem. However, some strains showed co-resistance to meropenem with other antibiotics, including tigecycline (2%), imipenem (16%), amikacin (27%), colistin (37%), and levofloxacin (41%). Conclusion: The rates of isolation and drug resistance of K. pneumoniae in PICU have significantly increased over 7 years. Careful antibiotic use, infection control strategies, and appropriate antibiotic combinations are crucial in addressing this problem.

RESUMO

This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.

Assuntos

Transtorno Depressivo Maior , Giro do Cíngulo , Imageamento por Ressonância Magnética , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/fisiopatologia , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Antidepressivos/uso terapêutico , Escitalopram/uso terapêutico , Escitalopram/farmacologia , Resultado do Tratamento , Conectoma , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Rede Nervosa/efeitos dos fármacos

RESUMO

Purpose: To study the MRI features (based on LI-RADS) and clinical characteristics of P53-mutated hepatocellular carcinoma (HCC) patients. Patients and Methods: This study enrolled 344 patients with histopathologically confirmed HCC (P53-mutated group [n = 196], non-P53-mutated group [n = 148]). We retrospectively evaluated the preoperative MRI features, clinical and pathologic features of the lesions and assigned each lesion according to the LI-RADS. MRI findings, clinical features, and pathologic findings were compared using the Student's t test, χ2 test, and multivariable regression analysis. Results: Most HCC patients were categorized as LR-5. On multivariate analysis, the Edmondson-Steiner grade (odds ratio, 2.280; 95% CI: 1.268, 4.101; p = 0.006) and rim enhancement (odds ratio, 2.517; 95% CI: 1.095, 5.784; p = 0.030) were found to be independent variables associated with P53-mutated HCC. In the group of HCC lesions with the largest tumor diameter (LTD) greater than or equal to 10mm and less than or equal to 20mm, enhancing capsule was an independent predictor of P53-mutated HCC (odds ratio, 6.200; 95% CI: 1.116, 34.449; p = 0.037). Among the HCC lesions (20 mm ˂ LTD ≤ 50 mm), corona enhancement (odds ratio, 2.102; 95% CI: 1.022, 4.322; p = 0.043) and nodule-in-nodule architecture (odds ratio, 2.157; 95% CI: 1.033, 4.504; p = 0.041) were found to be independent risk factors for P53 mutation. Among the HCC lesions (50 mm ˂ LTD ≤ 100 mm), diameter (odds ratio, 1.035; 95% CI: 1.001, 1.069; p = 0.044) and AFP ≥ 400 (ng/mL) (odds ratio, 3.336; 95% CI: 1.052, 10.577; p = 0.041) were found to be independent variables associated with P53-mutated HCC. Conclusion: Poor differentiation and rim enhancement are potential predictive biomarkers for P53-mutated HCC, while HCCs of different diameters have different risk factors for predicting P53 mutations.

RESUMO

The development of electrocatalysts with low cost, high efficiency, and long-term durability is crucial for advancing green hydrogen production. Transition metal phosphides (TMPs) have been proved to be efficient electrocatalyst, while the improvement in the performance and durability of the TMPs remains a big challenge. Employing atmospheric pressure chemical vapor deposition (APCVD) and phosphorization, FeP/Ti electrodes are fabricated featuring controllable oxygen ingredients (O-FeP/Ti). This manipulation of oxygen content fine-tunes the electronic structure of the catalyst, resulting in improved surface reaction kinetics and catalytic activity. The optimized O-FeP-400/Ti exhibits outstanding HER activity with overpotentials of 142 and 159 mV at -10 mA cm-2 in 0.5 M H2SO4 and 1 M KOH, respectively. Notably, the obtained O-FeP/Ti cathode also displays remarkable durability of up to 200 h in acidic electrolyte with surface topography remaining intact. For the first time, the low-valence titanium oxide (Ti3O) interlayer is identified in the composite electrode and ascribed for the superior connection between Ti substrate and the surface O-FeP catalyst, as supported by experimental results and density functional theory (DFT) analysis. This work has expanded the potential applications of transition metal phosphides (TMPs) as a cost-effective, highly efficient and durable catalyst for water splitting.

RESUMO

Fabrication of ion-conducting membranes with continuous sub-nanometer channels holds fundamental importance for flow batteries in achieving safe integration of renewable energy into grids. Self-standing covalent organic polymer (COP) membranes provide feasibility due to their rapid and selective ion transport. However, the development of a scale-up possible, mechanically robust and chemically stable membranes remains a significant challenge. Herein, using irreversible strong secondary amine linkage, we propose a self-standing COP membrane with sub-nanometer pores ranging from 4.5 to 6.4 Å, by a simple and efficient in-situ polymerization approach. This membrane exhibits enhanced selectivity for proton and vanadium ions, especially excellent electrochemical stability, delivering an energy efficiency of over 80% at the current density of 200 mA cm-2 over 1000 cycles for an all-vanadium redox flow battery (VFB). This study provides novel insights for COP-based ion-sieving membranes in sustainable energy fields.

RESUMO

Background: Recurrent acute myocardial infarction requiring unplanned percutaneous coronary intervention (PCI) is one of the major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS) after PCI. There is a continuing controversy about the association between serum cystatin C, a biomarker for the evaluation of renal function, and the prognosis of ACS patients following PCI. The retrospective study evaluated the association between serum cystatin C level and MACE in ACS patients after PCI. Methods: Data were retrieved for 330 patients with ACS for primary PCI in a single center. Serum cystatin C levels were measured before PCI. All patients underwent regular follow-ups after PCI, and the studied endpoint was MACE, defined as the need for a repeat revascularization in the heart. The predictive value of serum cystatin C for MACE was analyzed using univariate and multivariate analysis. Restricted cubic spline (RCS) analysis was applied to evaluate the dose-response relationship between serum cystatin C level and MACE in ACS patients following PCI. Results: After a median follow-up of 63 months (range, 1-148 months), 121 of the 330 patients experienced MACE. Compared to patients who did not have MACE, patients who had MACE showed a significant decrease in serum cystatin C levels (0.99±0.32 vs. 1.15±0.78 mg/L, P=0.03). In multivariate regression analysis, serum cystatin C level was an independent risk factor for MACE. According to the serum cystatin C level, patients were divided into 4 categories, Cox regression analysis illustrated that the second quartile of serum cystatin C level indicated an increased risk of MACE in patients with PCI for primary ACS compared to the highest quartile [Q2: adjusted hazard ratio (HR) =2.109; 95% confidence interval (CI): 1.193-3.727; P=0.01]. RCS analysis showed a significant U-shaped dose-response relationship between cystatin C level and MACE in patients with PCI for ACS (P for non-linearity =0.004). Conclusions: These results indicated an association between serum cystatin C level and post-PCI MACE in ACS patients.

RESUMO

Purpose: Ischemic stroke is a refractory disease wherein the reperfusion injury caused by sudden restoration of blood supply is the main cause of increased mortality and disability. However, current therapeutic strategies for the inflammatory response induced by cerebral ischemia-reperfusion (I/R) injury are unsatisfactory. This study aimed to develop a functional nanoparticle (MM/ANPs) comprising apelin-13 (APNs) encapsulated in macrophage membranes (MM) modified with distearoyl phosphatidylethanolamine-polyethylene glycol-RVG29 (DSPE-PEG-RVG29) to achieve targeted therapy against ischemic stroke. Methods: MM were extracted from RAW264.7. PLGA was dissolved in dichloromethane, while Apelin-13 was dissolved in water, and CY5.5 was dissolved in dichloromethane. The precipitate was washed twice with ultrapure water and then resuspended in 10 mL to obtain an aqueous solution of PLGA nanoparticles. Subsequently, the cell membrane was evenly dispersed homogeneously and mixed with PLGA-COOH at a mass ratio of 1:1 for the hybrid ultrasound. DSPE-PEG-RVG29 was added and incubated for 1 h to obtain MM/ANPs. Results: In this study, we developed a functional nanoparticle delivery system (MM/ANPs) that utilizes macrophage membranes coated with DSPE-PEG-RVG29 peptide to efficiently deliver Apelin-13 to inflammatory areas using ischemic stroke therapy. MM/ANPs effectively cross the blood-brain barrier and selectively accumulate in ischemic and inflamed areas. In a mouse I/R injury model, these nanoparticles significantly improved neurological scores and reduced infarct volume. Apelin-13 is gradually released from the MM/ANPs, inhibiting NLRP3 inflammasome assembly by enhancing sirtuin 3 (SIRT3) activity, which suppresses the inflammatory response and pyroptosis. The positive regulation of SIRT3 further inhibits the NLRP3-mediated inflammation, showing the clinical potential of these nanoparticles for ischemic stroke treatment. The biocompatibility and safety of MM/ANPs were confirmed through in vitro cytotoxicity tests, blood-brain barrier permeability tests, biosafety evaluations, and blood compatibility studies. Conclusion: MM/ANPs offer a highly promising approach to achieve ischemic stroke-targeted therapy inhibiting NLRP3 inflammasome-mediated pyroptosis.

Assuntos

Inflamassomos , AVC Isquêmico , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nanopartículas , Piroptose , Animais , Camundongos , AVC Isquêmico/tratamento farmacológico , Células RAW 264.7 , Piroptose/efeitos dos fármacos , Nanopartículas/química , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Masculino , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/química , Polietilenoglicóis/química , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/tratamento farmacológico , Fosfatidiletanolaminas/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo

RESUMO

BACKGROUND: We describe our experience with single-incision retroperitoneal laparoscopic (SIRL) for resection of adrenal tumors in pediatric patients and discuss the technique's clinical value. METHODS: We retrospectively analyzed clinical data of 27 pediatric patients who underwent SIRL between January 2020 and September 2023. Patients with tumors >5 cm in size and those requiring vascular skeletonization surgery or extensive lymph node dissection were excluded. Demographic, perioperative, and prognostic data were collected, and computed tomography (CT) and magnetic resonance imaging were used for preoperative tumor assessment. RESULTS: Of 27 patients, 16 were male and 11 were female; mean age 54 ± 45 months and mean body mass index 17.2 ± 3.6 kg/m2. Mean tumor length, width, and height were 4.1 ± 1.8 cm, 3.3 ± 2.1 cm, and 2.9 ± 1.7 cm, respectively. One patient experienced a diaphragmatic tear, three patients incurred peritoneal damage, and one patient developed postoperative renal artery injury, leading to thrombosis and renal atrophy. No surgery was converted to open surgery, and no intraoperative or postoperative blood transfusions were required. Operative time, blood loss, and postoperative dietary recovery time were satisfactory. No local recurrence or distant metastases were detected during the 6-48 months of follow-up involving outpatient and telephone assessments. CONCLUSIONS: Application of SIRL in pediatric patients with adrenal tumors achieved favorable clinical outcomes with an effective, minimally invasive surgical option for treating children with adrenal tumors. This technique demands a high level of surgical expertise, specialized instruments and experienced surgeons. Our findings indicate that SIRL is safe and provides significant postoperative benefits in pediatric patients. LEVEL OF EVIDENCE: Level IV.

RESUMO

BACKGROUND: The association between the length of sleep and atherosclerosis has been reported in many observational studies. However, little is known about its significance as a risk factor for atherosclerosis or as a negative consequence of atherosclerosis. OBJECTIVE: This study aimed to assess the causal association between sleep duration and the risk of atherosclerosis using publicly available genome-wide association studies (GWAS) summary statistics. METHODS: We employed a two-sample Mendelian randomization (MR) method with 2 cohorts from MRC-IEU (n=460,099) and UK Biobank (n=361,194) to investigate the causal association between sleep duration and the risk of atherosclerosis. Three methods including the inverse-variance weighted (IVW) technique, Robust adjusted profile score (RAPS), and simple-and weighted-median approach were used to obtain reliable results, and an odds ratio with a 95% confidence interval (CI) was calculated. P<0.05 was considered as a statistical difference. In addition, MR-Egger regression, Radial MR, MR-PRESSO, and leave-one-out analyses were used to assess the possible pleiotropy effects. RESULTS: No causal association of sleep duration with atherosclerosis was found [OR (95%CI): 0.90 (0.98-1.00), p = 0.186]. Leave-one-out, MR-Egger, and MR-PRESSO analyses failed to detect horizontal pleiotropy. CONCLUSIONS: This MR analysis indicated no causal association between genetically predicted sleep duration and atherosclerosis across European populations.

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FUNDAMENTO: A associação entre a duração do sono e a aterosclerose foi relatada em muitos estudos observacionais. No entanto, pouco se sabe sobre a sua importância como fator de risco para aterosclerose ou como consequência negativa da aterosclerose. OBJETIVO: Este estudo teve como objetivo avaliar a associação causal entre a duração do sono e o risco de aterosclerose usando estatísticas resumidas de estudos de associação genômica ampla (GWAS) disponíveis publicamente. MÉTODOS: Empregamos um método de randomização mendeliana (RM) de duas amostras com 2 coortes do MRC-IEU (n = 460.099) e do UK Biobank (n = 361.194) para investigar a associação causal entre a duração do sono e o risco de aterosclerose. Três métodos, incluindo a técnica de variância inversa ponderada (IVW), escore de perfil ajustado robusto (RAPS) e abordagem de mediana simples e ponderada, foram usados para obter resultados confiáveis, e uma razão de chances com intervalo de confiança (IC) de 95% foi calculada. P<0,05 foi considerado diferença estatística. Além disso, foram utilizadas análises de regressão: MR-Egger regression, Radial MR, MR-PRESSO e leave-one-out para avaliar os possíveis efeitos de pleiotropia. RESULTADOS: Não foi encontrada associação causal entre duração do sono e aterosclerose [OR (IC95%): 0,90 (0,98-1,00), p = 0,186]. As análises Leave-one-out, MR-Egger, e MR-PRESSO não conseguiram detectar pleiotropia horizontal. CONCLUSÕES: Esta análise de RM não indicou nenhuma associação causal entre a duração do sono geneticamente prevista e a aterosclerose nas populações europeias.

Assuntos

Aterosclerose , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Sono , Humanos , Aterosclerose/genética , Sono/genética , Sono/fisiologia , Fatores de Risco , Fatores de Tempo , Feminino , Masculino , Pessoa de Meia-Idade , Duração do Sono

RESUMO

Objective: This study aimed to evaluate the effects of microRNA-650 (miR-650) on melanoma metastasis and reveal the regulatory relationship between miR-650 and the inhibitor of growth family member 4 (ING4). Methods: miR-650 expression was determined in human melanoma WM115 and A-375 cells. WM115 cells were transfected with miR-650 mimic or mimic control. The invasion and migration abilities of transfected WM115 cells were analyzed using Transwell and wound healing assays, respectively. Then, miR-650-overexpression lentivirus vector was constructed and transfected into WM115 cells. After injection into the mice, the number of micro-metastatic foci in the lung tissues was counted. A regulatory relationship between miR-650 and ING4 was identified in WM115 and A-375 cells. Results: The miR-650 expression was upregulated in WM115 and A-375 cells. WM115 cells transfected with the miR-650 mimic exhibited higher invasive and migratory abilities than mock cells or cells transfected with negative control (NC). The number of micro-metastatic foci was significantly higher in mice injected with Lenti-miR-650 than that in those injected with mock or NC controls. Transfection with miR-650 mimic observably inhibited the expression of ING4 in WM115 and A-375 cells, whereas transfection with miR-650 inhibitor had the opposite effect. Dual-luciferase reporter gene assay showed that the miR-650 mimic inhibited the luciferase activity of ING4. Conclusion: miR-650 promotes melanoma metastasis by downregulating ING4 expression.

RESUMO

The sludge contains many high-value biological materials. However, current extraction methods focus only on individual materials, neglecting the further extraction potential of the residual after extraction. This study used continuous extraction to extract extracellular polymeric substances (EPS) and proteins (PN) from sludge, verified the flame retardancy of EPS and the foaming properties of PN and finally analyzed the economic feasibility of continuous extraction. The results showed that continuous extraction increased the protein extraction from 857.11 mg/L to 1089.41 mg/L. EPS reduced the heat release rate of linen fabric from 379.2 (J/g·K) to 38.3 (J/g·K), and PN achieved foaming capacity and stability reaching 770% and 71%, meeting the standards of foam extinguishing agents. The binding form of EPS with linen fabric and the peptide content in PN are crucial factors affecting their application effectiveness. Economic analysis showed that continuous extraction reduced processing costs by 37.64% compared to traditional sludge disposal methods.

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Engineering the glycerol-3-phosphate pathway could enhance erythritol production by accelerating glycerol uptake. However, little work has been conducted on the alternative dihydroxyacetone (DHA) pathway in Yarrowia lipolytica. Herein, this route was identified and characterized in Y. lipolytica by metabolomic and transcriptomic analysis. Moreover, the reaction catalyzed by dihydroxyacetone kinase encoded by dak2 was identified as the rate-limiting step. By combining NHEJ-mediated insertion mutagenesis with a push-and-pull strategy, Y. lipolytica strains with high-yield erythritol synthesis from glycerol were obtained. Screening of a library of insertion mutants allows the identification of a mutant with fourfold increased erythritol production. Overexpression of DAK2 and glycerol dehydrogenase GCY3 together with gene encoding transketolase and transaldolase from the nonoxidative part of the pentose phosphate pathway led to a strain with further increased productivity with a titer of 53.1 g/L and a yield 0.56 g/g glycerol, which were 8.1- and 4.2-fold of starting strain.

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BACKGROUND: Intestinal ischemia-reperfusion (II/R) injury is a common clinical emergency with high morbidity and mortality. Given the absence of efficacious prophylactic and therapeutic interventions and specific drugs, sustained efforts are essential to develop new targeted drugs. Corilagin, a naturally polyphenolic tannic acid widespread in longan, rambutan and many other edible economic crops with medicinal properties in China, is of interest due to its multiple bioactivities, including the potential to mitigate II/R injuries. Nevertheless, a clear understanding of its molecular targets and the intricate mechanisms against II/R injury remains obscure and requires further elucidation. OBJECTIVE: This study aimed to investigate corilagin's pharmacological impact and molecular mechanism for II/R injury. METHODS: An animal II/R model was established by clamping superior mesenteric artery (SMA), and the therapeutic efficacy of corilagin against II/R was evaluated by biochemical and pathological analysis. Next, integrated transcriptomic and proteomic analyses was performed to identify key targets. Moreover, endoplasmic reticulum stress (ERS) damage was respectively observed by transmission electron microscope (TEM), immunohistochemistry, TUNEL, flow cytometry and western blotting (WB). Finally, molecular docking, molecular dynamics (MD) simulation, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays were utilized to assess the interaction between corilagin and binding immunoglobulin protein (Bip, Grp78 or Hspa5), and co-IP assay was conducted to investigate the interaction between Bip and its substrate proteins. RESULTS: Corilagin exhibited robust protection against II/R injuries, effectively alleviating intestinal tissue damage and oxidative stress induced by II/R. The modulation of ERS as a potential regulatory mechanism was investigated through an integrated transcriptomic and proteomic analysis, identifying Bip as a key target contributing to corilagin's protective effects. Further experimental evidence using molecular docking, MD simulation, CETSA, and DARTS assays confirmed the potentially direct interaction of corilagin with Bip. This interaction promoted the ubiquitin-dependent degradation of the Bip-substrate complex, thereby suppressing ERS-related signalling pathways, including the IRE1 branch, PERK branch, and ATF6 branch, to alleviate tissue damage. CONCLUSION: This study confirmed that corilagin could selectively bind to Bip, facilitating its ubiquitin-dependent recognition and degradation, thereby inhibiting severe endoplasmic reticulum stress signalling and alleviating II/R injury. A detailed mechanistic insight into the action mode of corilagin had been proposed, supporting its potential usage as an ERS inhibitor.

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Rigid solenoid coils have long been indispensable in modern intelligent devices. However, their sparse structure and challenging preparation of flexible coils for soft robots impose limitations. Here, a transformable 3D curved high-density liquid metal coil (HD-LMC) is introduced that surpasses the structural density level of enameled wire. The fabrication technique employed for high-density channels in elastomers is universally applicable. Such HD-LMCs demonstrated excellent performance in pressure, temperature, non-contact distance sensors, and near-field communication. Soft electromagnetic actuators thus achieved significantly improved the electromagnetic force and power density. Moreover, precise control of swinging tail motion enables a bionic pufferfish to swim. Finally, HD-LMC is further utilized to successfully implement a soft rotary robot with integrated sensing and actuation capabilities. This groundbreaking research provides a theoretical and experimental basis for expanding the applications of liquid metal-based multi-dimensional complex flexible electronics and is expected to be widely used in liquid metal-integrated robotic systems.

RESUMO

Objective: Hypertension (HTN) is a prevalent global health concern. From the standpoint of preventive and personalized medicine (PPPM/3PM), early detection of HTN offers a crucial opportunity for targeted prevention and personalized treatment. This study aimed to evaluate the association between the weight-adjusted waist index (WWI) and HTN risk. Methods: A case-control study using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018 was conducted. Logistic regression models assessed the association between WWI and HTN. Subgroup analyses explored differences in age, sex, ethnicity, and diabetes status. Restricted cubic spline (RCS) analyses examined potential nonlinear relationships. Results: A total of 32,116 participants, with an average age of 49.28 ± 17.56 years, were included in the study. A significant positive association between WWI and the risk of HTN was identified (odds ratio [OR], 2.49; 95% CI, 2.39-2.59; P < 0.001). When WWI was categorized into quartiles (Q1-Q4), the highest quartile (Q4) exhibited a stronger association compared to Q1 (OR, 2.94; 95% CI, 2.65-3.27; P < 0.001). Subgroup analyses indicated that WWI was a risk factor for HTN across different populations, although variations in the magnitude of effect were observed. Furthermore, the findings from the RCS elucidated a nonlinear positive correlation between WWI and HTN. Conclusion: WWI is independently associated with HTN risk, highlighting its potential as a risk assessment tool in clinical practice. Incorporating WWI into early detection strategies enhances targeted prevention and personalized management of HTN. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00375-3.