Shenling Baizhu San ameliorates non-alcoholic fatty liver disease in mice by modulating gut microbiota and metabolites.

Purpose: The prevalence of non-alcoholic fatty liver disease (NAFLD) and its related mortality is increasing at an unprecedented rate. Traditional Chinese medicine (TCM) has been shown to offer potential for early prevention and treatment of NAFLD. The new mechanism of "Shenling Baizhu San" (SLBZS) is examined in this study for the prevention and treatment of NAFLD at the preclinical level. Methods: Male C57BL/6J mice were randomly divided into three groups: normal diet (ND), western diet + CCl4 injection (WDC), and SLBZS intervention (WDC + SLBZS). Body weights, energy intake, liver enzymes, pro-inflammatory factors, and steatosis were recorded in detail. Meanwhile, TPH1, 5-HT, HTR2A, and HTR2B were tested using qRT-PCR or ELISA. Dynamic changes in the gut microbiota and metabolites were further detected through the 16S rRNA gene and untargeted metabolomics. Results: SLBZS intervention for 6 weeks could reduce the serum and liver lipid profiles, glucose, and pro-inflammatory factors while improving insulin resistance and liver function indexes in the mice, thus alleviating NAFLD in mice. More importantly, significant changes were found in the intestinal TPH-1, 5-HT, liver 5-HT, and related receptors HTR2A and HTR2B. The 16S rRNA gene analysis suggested that SLBZS was able to modulate the disturbance of gut microbiota, remarkably increasing the relative abundance of probiotics (Bifidobacterium and Parvibacter) and inhibiting the growth of pro-inflammatory bacteria (Erysipelatoclostridium and Lachnoclostridium) in mice with NAFLD. Combined with metabolomics in positive- and negative-ion-mode analyses, approximately 50 common differential metabolites were selected via non-targeted metabolomics detection, which indicated that the targeting effect of SLBZS included lipid metabolites, bile acids (BAs), amino acids (AAs), and tryptophan metabolites. In particular, the lipid metabolites 15-OxEDE, vitamin D3, desoxycortone, and oleoyl ethanol amide were restored by SLBZS. Conclusion: Integrating the above results of multiple omics suggests that SLBZS ameliorates NAFLD via specific gut microbiota, gut-derived 5-HT, and related metabolites to decrease fat accumulation in the liver and inflammatory responses.

[Comparison of the effects of sciatic nerve block combined with continuted femoral nerve block or continuted adductor canal block on pain and motor function after total knee arthroplasty].

Objective: To compare the effect of sciatic nerve block (SNB) combined with continuted femoral nerve block (FNB) or continuted adductor canal block (ACB) on pain and motor function after total knee arthroplasty (TKA). Methods: A total of 60 patients with TKA-treated osteoarthritis of the knee who met the selection criteria were enrolled between November 2020 and February 2021 and randomised allocated into the study group (SNB combined with continuted ACB) and the control group (SNB combined with continuted FNB), with 30 cases in each group. There was no significant difference in gender, age, body mass, height, body mass index, preoperative Hospital for Special Surgery (HSS) score, femoral tibial angle, and medial proximal tibial angle between the two groups ( P>0.05). The operation time, the initial time to the ground, the initial walking distance, and the postoperative hospital stay were recorded. At 2, 4, 6, 12, 24, and 48 hours after operation, the numerical rating scale (NRS) score was used to evaluate the rest pain around the knee joint, the quadriceps femoris muscle strength was evaluated by the freehand muscle strength method, and the knee flexion and extension angles were measured. Results: There was no significant difference in the operation time and initial walking distance between the two groups ( P>0.05); the initial time to the ground and postoperative hospital stay of the study group were significantly shorter than those of the control group ( P<0.05). Except for the 48-hour postoperative NRS score of the study group, which was significantly lower than that of the control group ( P<0.05), there was no significant difference in the NRS scores between the two groups at the remaining time points ( P>0.05). The quadriceps femoris muscle strength from 4 to 24 hours postoperatively and the knee extension angle from 2 to 6 hours postoperatively of the study group were significantly better than those of the control group ( P<0.05); the differences in the quadriceps femoris muscle strength and knee extension and flexion angles between the two groups at the remaining time points were not significant ( P>0.05). Conclusion: SNB combined with either continuted ACB or continuted FNB can effectively relieve pain in patients after TKA, and compared with combined continuted FNB, combined continuted ACB has less effect on quadriceps femoris muscle strength, and patients have better recovery of knee flexion and extension mobility.

Global, regional, and national burden of atrial fibrillation/flutter related to metabolic risks over three decades: estimates from the global burden of disease study 2019.

AIMS: Atrial fibrillation/atrial flutter (AF/AFL) remains a significant public health concern on a global scale, with metabolic risks playing an increasingly prominent role. This study aimed to investigate comprehensive epidemiological data and trends concerning the metabolic risks related-AF/AFL burden based on the data from the Global Burden of Disease (GBD) study 2019. METHODS & RESULTS: The analysis of disease burden focused on numbers, age-standardized rates (ASR) of deaths, disability-adjusted life years (DALYs), and estimated annual percentage change (EAPC), while considering factors of age, sex, sociodemographic index (SDI), and locations. In 2019, there was a culmination of 137 179 deaths and 4 099 146 DALYs caused by metabolic risks related-AF/AFL worldwide, with an increase of 162.95% and 120.30% respectively from 1990. High and high-middle SDI regions predominantly carried the burden of AF/AFL associated with metabolic risks, while a shift towards lower SDI regions had been occurring. Montenegro had the highest recorded death rate (7.6 per 100 000) and DALYs rate (146.3 per 100 000). An asymmetrically inverted V-shaped correlation was found between SDI and deaths/DALYs rates. Moreover, females and the elderly exhibited higher AF/AFL burdens, and young adults (over 40 years old) also experienced an annual increase. CONCLUSIONS: The global AF/AFL burden related to metabolic risks has significantly increased over past three decades, with considerable spatiotemporal, gender-based, and age-related heterogeneity. These findings shed valuable light on the trends in the burden of metabolic risks related-AF/AFL, and offered insights into corresponding strategies.

Two-layer cascaded catalytic hairpin assemblies based on locked nucleic acids for one-step and highly sensitive ctDNA detection.

Enzyme-free signal amplification of catalytic hairpin assembly (CHA) has enabled sensitive detection of circulating tumor DNA (ctDNA) in early clinical diagnosis. Conventional CHA strategies are restrained by the limited amplification efficiency of the single-stage system, and signal leakage from "breathing" influence and nuclease degradation. Here, we introduced two-layer cascaded locked nucleic acid (LNA)-assisted CHA circuits with the intelligent incorporation of LNA in the hairpins and reporter for the highly sensitive one-step detection of scarce ctDNA. The target-triggered upstream CHA reaction continuously generates hybrid products to catalyze the downstream CHA reaction for transducing the primary sensing event, and the released target and the produced hybrid product trigger the next catalytic reaction round at the same time and finally cascade to amplify the target ctDNA fluorescence output signal. Meanwhile, the stronger binding affinity of the LNA-DNA duplex endows the two-layer LNA-assisted CHA system with thermodynamic stability and nuclease resistance, and thus our designed system exhibits an excellent detection performance for target ctDNA in the range from 2 pM to 5 nM with a low detection limit of 0.6 pM. Significantly, the two-layer LNA-assisted CHA circuits have been successfully implemented for the feasible analysis of clinical samples. This two-layer cascaded LNA-assisted CHA strategy provides a promising high sensitivity tool for one-step detection of scarce ctDNA from complex clinical samples and would facilitate the reconfiguration of DNA circuit-based DNA nanotechnology for the precise analysis of other biomarkers in clinical research fields.

Relationship of mTORC1 and ferroptosis in tumors.

Ferroptosis is a novel form of programmed death, dependent on iron ions and oxidative stress, with a predominant intracellular form of lipid peroxidation. In recent years, ferroptosis has gained more and more interest of people in the treatment mechanism of targeted tumors. mTOR, always overexpressed in the tumor, and controlling cell growth and metabolic activities, has an important role in both autophagy and ferroptosis. Interestingly, the selective types of autophay plays an important role in promoting ferroptosis, which is related to mTOR and some metabolic pathways (especially in iron and amino acids). In this paper, we list the main mechanisms linking ferroptosis with mTOR signaling pathway and further summarize the current compounds targeting ferroptosis in these ways. There are growing experimental evidences that targeting mTOR and ferroptosis may have effective impact in many tumors, and understanding the mechanisms linking mTOR to ferroptosis could provide a potential therapeutic approach for tumor treatment.

Identification and Functional Assessment of Eight CYP3A4 Allelic Variants *39-*46 Detected in the Chinese Han Population.

Cytochrome P450 3A4 (CYP3A4), a key enzyme, is pivotal in metabolizing approximately half of the drugs used clinically. The genetic polymorphism of the CYP3A4 gene significantly influences individual variations in drug metabolism, potentially leading to severe adverse drug reactions (ADRs). In this study, we conducted a genetic analysis on CYP3A4 gene in 1163 Chinese Han individuals to identify the genetic variations that might affect their drug metabolism capabilities. For this purpose, a multiplex polymerase chain reaction (PCR) amplicon sequencing technique was developed, enabling us to perform the genotyping of CYP3A4 gene efficiently and economically on a large scale. As a result, a total of 14 CYP3A4 allelic variants were identified, comprising six previously reported alleles and eight new nonsynonymous variants that were nominated as new allelic variants *39-*46 by the PharmVar Association. Further, functional assessments of these novel CYP3A4 variants were undertaken by coexpressing them with cytochromes P450 oxidoreductase (CYPOR) in Saccharomyces cerevisiae microsomes. Immunoblot analysis indicated that with the exception of CYP3A4.40 and CYP3A4.45, the protein expression levels of most new variants were similar to that of the wild-type CYP3A4.1 in yeast cells. To evaluate their catalytic activities, midazolam was used as a probe drug. The results showed that variant CYP3A4.45 had almost no catalytic activity, whereas the other variants exhibited significantly reduced drug metabolism abilities. This suggests that the majority of the CYP3A4 variants identified in the Chinese population possess markedly altered capacities for drug metabolism. SIGNIFICANCE STATEMENT: In this study, we established a multiplex polymerase chain reaction (PCR) amplicon sequencing method and detected the maximum number of new CYP3A4 variants in a single ethnic population. Additionally, we performed the functional characterizations of these eight novel CYP3A4 allele variants in vitro. This study not only contributes to the understanding of CYP3A4 genetic polymorphism in the Chinese Han population but also holds substantial reference value for their potential clinical applications in personalized medicine.

Impact of high-power short-duration atrial fibrillation ablation technique on the incidence of silent cerebral embolism: a prospective randomized controlled study.

BACKGROUND: High-power short-duration (HPSD) ablation strategy has emerged as a popular approach for treating atrial fibrillation (AF), with shorter ablation time. The utilized Smart Touch Surround Flow (STSF) catheter, with 56 holes around the electrode, lowers electrode-tissue temperature and thrombus risk. Thus, we conducted this prospective, randomized study to investigate if the HPSD strategy with STSF catheter in AF ablation procedures reduces the silent cerebral embolism (SCE) risk compared to the conventional approach with the Smart Touch (ST) catheter. METHODS: From June 2020 to September 2021, 100 AF patients were randomized 1:1 to the HPSD group using the STSF catheter (power set at 50 W) or the conventional group using the ST catheter (power set at 30 to 35 W). Pulmonary vein isolation was performed in all patients, with additional lesions at operator's discretion. High-resolution cerebral diffusion-weighted magnetic resonance imaging (hDWI) with slice thickness of 1 mm was performed before and 24-72 h after ablation. The incidence of new periprocedural SCE was defined as the primary outcome. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA) test. RESULTS: All enrolled AF patients (median age 63, 60% male, 59% paroxysmal AF) underwent successful ablation. Post-procedural hDWI identified 106 lesions in 42 enrolled patients (42%), with 55 lesions in 22 patients (44%) in the HPSD group and 51 lesions in 20 patients (40%) in the conventional group (p = 0.685). No significant differences were observed between two groups regarding the average number of lesions (p = 0.751), maximum lesion diameter (p = 0.405), and total lesion volume per patient (p = 0.669). Persistent AF and CHA2DS2-VASc score were identified as SCE determinants during AF ablation procedure by multivariable regression analysis. No significant differences in MoCA scores were observed between patients with SCE and those without, both immediately post-procedure (p = 0.572) and at the 3-month follow-up (p = 0.743). CONCLUSIONS: Involving a small sample size of 100 AF patients, this study reveals a similar incidence of SCE in AF ablation procedures, comparing the HPSD strategy using the STSF catheter to the conventional approach with the ST catheter. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04408716. AF = Atrial fibrillation, DWI = Diffusion-weighted magnetic resonance imaging, HPSD = High-power short-duration, ST = Smart Touch, STSF = Smart Touch Surround Flow.

A rapid and highly sensitive ctDNA detection platform based on locked nucleic acid-assisted catalytic hairpin assembly circuits.

As a promising biomarker of liquid biopsy, circulating tumor DNA (ctDNA) plays a paramount role in the early diagnosis of noninvasive cancer. The isothermal catalytic hairpin assembly (CHA) strategy has great potential for in vitro detection of ctDNA in low abundance. However, a traditional CHA strategy for ctDNA detection at the earlier stages of cancer remains extremely challenging, as annoying signal leakage from the 'breathing' phenomenon and nuclease degradation occur. Herein, we report a locked nucleic acid (LNA)-incorporated CHA circuit for the rapid and sensitive detection of target ctDNA. The target ctDNA intelligently catalyzed LNA-modified hairpins H1 and H2via a range of toehold-mediated strand displacement processes, leading to the continuous generation of an H1-H2 hybrid for the amplified fluorescence signal. In comparison to conventional CHA circuits, the stronger binding affinity of LNA-DNA bases greatly inhibited the breathing effect, which endowed it with greater thermodynamic stability and resistance to nuclease degradation in the LNA-assisted CHA system, thus achieving a high signal gain. The developed CHA circuit demonstrated excellent performance during target ctDNA detection, with a linear range from 10 pM to 5 nM, and its target detection limit was reached at 3.3 pM. Moreover, this LNA-assisted CHA system was successfully applied to the analysis of target ctDNA in clinical serum samples of breast cancer patients. This updated CHA system provides a general and robust platform for the sensitive detection of biomarkers of interest, thus facilitating the accurate identification and diagnosis of cancers.

Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro.

Genetic polymorphism of the cytochrome P450 (CYP) gene can significantly influence the metabolism of endogenous and xenobiotic compounds. However, few studies have focused on the polymorphism of CYP2J2 and its impact on drug catalytic activity, especially in the Chinese Han population. In this study, we sequenced the promoter and exon regions of CYP2J2 in 1,163 unrelated healthy Chinese Han individuals using the multiplex PCR amplicon sequencing method. Then, the catalytic activities of the detected CYP2J2 variants were evaluated after recombinant expression in S. cerevisiae microsomes. As a result, CYP2J2*7, CYP2J2*8, 13 variations in the promoter region and 15 CYP2J2 nonsynonymous variants were detected, of which V15A, G24R, V68A, L166F and A391T were novel missense variations. Immunoblotting results showed that 11 of 15 CYP2J2 variants exhibited lower protein expression than wild-type CYP2J2.1. In vitro functional analysis results revealed that the amino acid changes of 14 variants could significantly influence the drug metabolic activity of CYP2J2 toward ebastine or terfenadine. Specifically, 4 variants with relatively higher allele frequencies, CYP2J2.8, 173_173del, K267fs and R446W, exhibited extremely low protein expression and defective catalytic activities for both substrates. Our results indicated that a high genetic polymorphism of CYP2J2 could be detected in the Chinese Han population, and most genetic variations in CYP2J2 could influence the expression and catalytic activity of CYP2J2. Our data significantly enrich the knowledge of genetic polymorphisms in CYP2J2 and provide new theoretical information for corresponding individualized medication in Chinese and other Asian populations.

Disruption of Bacterial Thiol-Dependent Redox Homeostasis by Magnolol and Honokiol as an Antibacterial Strategy.

Some traditional Chinese medicines (TCMs) possess various redox-regulation properties, but whether the redox regulation contributes to antibacterial mechanisms is not known. Here, ginger juice processed Magnoliae officinalis cortex (GMOC) was found to show strong antibacterial activities against some Gram-positive bacteria, but not Gram-negative bacteria including E. coli, while the redox-related transcription factor oxyR deficient E. coli mutant was sensitive to GMOC. In addition, GMOC and its main ingredients, magnolol and honokiol, exhibited inhibitory effects on the bacterial thioredoxin (Trx) system, a major thiol-dependent disulfide reductase system in bacteria. The effects of magnolol and honokiol on cellular redox homeostasis were further verified by elevation of the intracellular ROS levels. The therapeutic efficacies of GMOC, magnolol and honokiol were further verified in S. aureus-caused mild and acute peritonitis mouse models. Treatments with GMOC, magnolol and honokiol significantly reduced the bacterial load, and effectively protected the mice from S. aureus-caused peritonitis infections. Meanwhile, magnolol and honokiol produced synergistic effects when used in combination with several classic antibiotics. These results strongly suggest that some TCMs may exert their therapeutic effects via targeting the bacterial thiol-dependent redox system.

Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects.

Cytochrome P450 2C9 (CYP2C9) participates in about 15% of clinical drug metabolism, and its polymorphism is associated with individual drug metabolism differences, which may lead to the adverse drug reactions (ADRs). In this study, 1163 Chinese Han individuals were recruited to investigate their distribution pattern of CYP2C9 gene and find out the variants that may affect their drug metabolic activities. We successfully developed a multiplex PCR amplicon sequencing method and used it for the genetic screening of CYP2C9 in a large scale. Besides the wild type CYP2C9*1, totally 26 allelic variants of CYP2C9 were detected, which included 16 previously reported alleles and 10 new non-synonymous variants that had not been listed on the PharmVar website. The characteristics of these newly detected CYP2C9 variants were then evaluated after co-expressing them with CYPOR in S. cerevisiae microsomes. Immunoblot analysis revealed that except for Pro163Ser, Glu326Lys, Gly431Arg and Ile488Phe, most of newly detected variants showed comparable protein expression levels to wild type in yeast cells. Two typical CYP2C9 probe drugs, losartan and glimepiride, were then used for the evaluation of metabolic activities of variants. As a result, 3 variants Thr301Met, Glu326Lys, and Gly431Arg almost lost their catalytic activities and most of other variants exhibited significantly elevated activities for drug metabolism. Our data not only enriches the knowledge of naturally occurring CYP2C9 variants in the Chinese Han population, but also provides the fundamental evidence for its potential clinical usage for personalized medicine in the clinic.

High-cholesterol diet promotes depression- and anxiety-like behaviors in mice by impact gut microbe and neuroinflammation.

Neuropsychiatric disorders, including anxiety and depression, are one of the most common mental illnesses worldwide. A growing body of evidence shows that there is a complex relationship between dietary patterns and mental health. In our study, C57BL/6J mice were divided into three groups: control diet group (CON, 10 % kcal fat), high-cholesterol diet model group (HCD, 42.0 % kcal fat + 1.25 % kcal Cholesterol), and chronic restraint stress group (CRS, 10 % kcal fat) which as a positive control group for the depression model. Six weeks later, depressive- and anxiety-like behavior were evaluated for using the OFT, SPT and TST. Glucose intolerance and liver fat were detected by IGTT and liver lipid kit. The expression of peripheral and central inflammation was detected by LEGEND plex kits. 5-HT (also named 5-hydroxytryptamine, 5-HT) and related receptors expression were monitored by ELISA, RT-PCR and Western blot. Meantime, gut microbe of stool samples was performed by 16S rRNA gene sequencing. Similar to CRS model, short-term HCD intervention induced anxiety and depression-like behavior behavioral abnormalities in mice. HCD consumption resulted in significantly increased body weight, liver fat (LDL-C, TC, TG), peripheral inflammation (IL-1ß, MCP-1, IL-17A) and neuroinflammation (MCP-1). The concentration of 5-HT increased in the hippocampus, meanwhile, the expression of 5-HT receptor HTR2A was distinct in different regions of the brain tissue. More importantly, we found that compared with the CON diet, HCD induced the decrease of intestinal flora diversity, especially the decrease the relative abundance of Akkermansia_muciniphila, which was statistically significant. Further, Pearson correlation analysis showed that Akkermansia_muciniphila was significantly negatively correlated with the concentration of MCP-1, IL-17A in serum and 5-HT in hippocampus. Therefore, we speculated that the disorder of neuroinflammation induced by HCD consumption promotes depression- and anxiety-like behaviors in mice through the gut microbe.

Identification and Validation a Necroptosis-Related Prognostic Signature in Cervical Cancer.

Necroptosis is a promising novel target for cervical cancer therapy. Nevertheless, differentially expressed necroptosis-related genes (NRGs) in cervical cancer and their associations with prognosis are far from fully clarified. In this study, differentially expressed NRGs (DE-NRGs) were screened out and their bio-function was elucidated. Subsequently, a prognostic scoring model based on the regression coefficients of the screened out NRGs and their corresponding mRNA expressions were constructed and validated. Finally, the survival probability of cervical cancer patients based on the constructed prognostic scoring model in 3 and 5 years was predicted and assessed. We found 17 DE-NRGs in cervical cancer tissues which were closely related to cancer progression, and most of them were significantly highly expressed. Furthermore, 3 NRG were confirmed as the prognostic signature genes from 17 DE-NRGs by regression analysis. Overall survival predicted through our prognostic scoring model was lower in the high-risk group than in the low-risk group (p < 0.05) in both the TCGA cohort and the external GEO44001 validation cohort. What's more, the prediction performance of our prognostic scoring models well verified by the ROC curve, and the risk score calculated could act as an independent prognostic factor for cervical cancer patients. The calibration curve and C-index (0.776) of the nomogram analysis suggested that the predictive performance of the nomogram was satisfactory. Our study identified and validated a necroptosis-related prognostic signature in cervical cancer, which could well predict the prognosis for cervical cancer patients.

Clinicopathological and prognostic significance of COX-2 in glioma patients: a meta-analysis.

BACKGROUND: In recent years, cyclooxygenase-2 (COX-2) has been identified as a cancer stem cell (CSC) marker in gliomas. Nevertheless, the clinical and prognostic significance of COX-2 in glioma patients remains controversial. OBJECTIVE: To evaluate the correlation of COX-2 with the prognosis in glioma patients. METHODS: Eligible studies on this subject were included, and pooled odd ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95%CIs) were estimated. Publication bias was assessed through funnel plots, and heterogeneity and sensitivity were analyzed as well. RESULTS: In the present study, 11 articles with a total of 641 patients were included. The high expression of COX-2 in glioma patients was negatively associated with overall survival (OS) (n = 11; HR = 2.26; 95%CI = 1.79-2.86), and the subgroup analysis showed no differences in OS between Asian (n = 5; HR = 2.16; 95%CI = 1.57-2.97) and non-Asian (n = 6; HR = 2.39; 95%CI = 1.69-3.38) glioma patients. The Begg funnel plots test indicated that there was no evident risk of publication bias in the meta-analysis. CONCLUSION: The present study suggests that COX-2 could be recommended as a useful pathological and prognostic biomarker in the clinical practice.

INTRODUçãO: Nos últimos anos, a ciclooxigenase-2 (COX-2) foi identificada como um marcador de células-tronco cancerígenas (CSC) em gliomas. No entanto, o significado clínico e prognóstico da COX-2 em pacientes com glioma permanece controverso. OBJETIVO: Avaliar a correlação da COX-2 com o prognóstico em pacientes com glioma. MéTODOS: Estudos elegíveis sobre este assunto foram incluídos e foram estimados odds ratios (ORs) e hazard ratios (HRs) com intervalos de confiança de 95% (IC 95%). O viés de publicação foi avaliado por meio de gráficos de funil, e a heterogeneidade e a sensibilidade também foram analisadas. RESULTADOS: No presente estudo foram incluídos 11 artigos com um total de 641 pacientes. A alta expressão de COX-2 em pacientes com glioma foi negativamente associada à sobrevida global (OS) (n = 11; HR = 2,26; IC 95% = 1,79-2,86), e a análise de subgrupo não mostrou diferenças na OS entre asiáticos (n = 5; HR = 2,16; IC 95% = 1,57­2,97) e não asiáticos (n = 6; HR = 2,39; IC 95% = 1,69­3,38) pacientes com glioma. O teste de gráficos de funil de Begg indicou que não havia risco evidente de viés de publicação na metanálise. CONCLUSãO: O presente estudo sugere que a COX-2 pode ser recomendada como um biomarcador patológico e prognóstico útil na prática clínica.

Clinicopathological and prognostic significance of COX-2 in glioma patients: a meta-analysis / Significância clinicopatológica e prognóstica da COX-2 em pacientes com glioma: uma metanálise

Abstract Background In recent years, cyclooxygenase-2 (COX-2) has been identified as a cancer stem cell (CSC) marker in gliomas. Nevertheless, the clinical and prognostic significance of COX-2 in glioma patients remains controversial. Objective To evaluate the correlation of COX-2 with the prognosis in glioma patients. Methods Eligible studies on this subject were included, and pooled odd ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95%CIs) were estimated. Publication bias was assessed through funnel plots, and heterogeneity and sensitivity were analyzed as well. Results In the present study, 11 articles with a total of 641 patients were included. The high expression of COX-2 in glioma patients was negatively associated with overall survival (OS) (n = 11; HR = 2.26; 95%CI = 1.79-2.86), and the subgroup analysis showed no differences in OS between Asian (n = 5; HR = 2.16; 95%CI = 1.57-2.97) and non-Asian (n = 6; HR = 2.39; 95%CI = 1.69-3.38) glioma patients. The Begg funnel plots test indicated that there was no evident risk of publication bias in the meta-analysis. Conclusion The present study suggests that COX-2 could be recommended as a useful pathological and prognostic biomarker in the clinical practice.

Resumo Introdução Nos últimos anos, a ciclooxigenase-2 (COX-2) foi identificada como um marcador de células-tronco cancerígenas (CSC) em gliomas. No entanto, o significado clínico e prognóstico da COX-2 em pacientes com glioma permanece controverso. Objetivo Avaliar a correlação da COX-2 com o prognóstico em pacientes com glioma. Métodos Estudos elegíveis sobre este assunto foram incluídos e foram estimadosodds ratios (ORs) ehazard ratios (HRs) com intervalos de confiança de 95% (IC 95%). O viés de publicação foi avaliado por meio de gráficos de funil, e a heterogeneidade e a sensibilidade também foram analisadas. Resultados No presente estudo foram incluídos 11 artigos com um total de 641 pacientes. A alta expressão de COX-2 em pacientes com glioma foi negativamente associada à sobrevida global (OS) (n = 11; HR = 2,26; IC 95% = 1,79-2,86), e a análise de subgrupo não mostrou diferenças na OS entre asiáticos (n = 5; HR = 2,16; IC 95% = 1,57-2,97) e não asiáticos (n = 6; HR = 2,39; IC 95% = 1,69-3,38) pacientes com glioma. O teste de gráficos de funil de Begg indicou que não havia risco evidente de viés de publicação na metanálise. Conclusão O presente estudo sugere que a COX-2 pode ser recomendada como um biomarcador patológico e prognóstico útil na prática clínica.

The Role of the Thioredoxin System in Brain Diseases.

The thioredoxin system, consisting of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, plays a fundamental role in the control of antioxidant defenses, cell proliferation, redox states, and apoptosis. Aberrations in the Trx system may lead to increased oxidative stress toxicity and neurodegenerative processes. This study reviews the role of the Trx system in the pathophysiology and treatment of Alzheimer's, Parkinson's and Huntington's diseases, brain stroke, and multiple sclerosis. Trx system plays an important role in the pathophysiology of those disorders via multiple interactions through oxidative stress, apoptotic, neuro-immune, and pro-survival pathways. Multiple aberrations in Trx and TrxR systems related to other redox systems and their multiple reciprocal relationships with the neurodegenerative, neuro-inflammatory, and neuro-oxidative pathways are here analyzed. Genetic and environmental factors (nutrition, metals, and toxins) may impact the function of the Trx system, thereby contributing to neuropsychiatric disease. Aberrations in the Trx and TrxR systems could be a promising drug target to prevent and treat neurodegenerative, neuro-inflammatory, neuro-oxidative stress processes, and related brain disorders.

Breaking down the cell wall: Still an attractive antibacterial strategy.

Since the advent of penicillin, humans have known about and explored the phenomenon of bacterial inhibition via antibiotics. However, with changes in the global environment and the abuse of antibiotics, resistance mechanisms have been selected in bacteria, presenting huge threats and challenges to the global medical and health system. Thus, the study and development of new antimicrobials is of unprecedented urgency and difficulty. Bacteria surround themselves with a cell wall to maintain cell rigidity and protect against environmental insults. Humans have taken advantage of antibiotics to target the bacterial cell wall, yielding some of the most widely used antibiotics to date. The cell wall is essential for bacterial growth and virulence but is absent from humans, remaining a high-priority target for antibiotic screening throughout the antibiotic era. Here, we review the extensively studied targets, i.e., MurA, MurB, MurC, MurD, MurE, MurF, Alr, Ddl, MurI, MurG, lipid A, and BamA in the cell wall, starting from the very beginning to the latest developments to elucidate antimicrobial screening. Furthermore, recent advances, including MraY and MsbA in peptidoglycan and lipopolysaccharide, and tagO, LtaS, LspA, Lgt, Lnt, Tol-Pal, MntC, and OspA in teichoic acid and lipoprotein, have also been profoundly discussed. The review further highlights that the application of new methods such as macromolecular labeling, compound libraries construction, and structure-based drug design will inspire researchers to screen ideal antibiotics.

The Assessment on Synergistic Activity of Ebselen and Silver Ion Against Yersinia pseudotuberculosis.

Yersinia pseudotuberculosis is a foodborne zoonotic bacterium that is pathogenic to guinea pigs, rabbits, and mice. It also causes pseudotuberculosis in humans. However, it still lacked the scientific basis for control. Here, we found out that Ebselen (EbSe) exhibited synergistic antibacterial activity with silver nitrate (Ag+) against Y. pseudotuberculosis YpIII strain with high efficacy in vitro using UV-visible light absorption spectrum, 5,5'-dithiobis-(2-nitrobenzoic acid), laser scanning confocal microscope, flow cytometry, transmission electron microscopy and Western blotting assays. The depletion of total glutathione (GSH) amount and inhibition of thioredoxin reductase (TrxR) activity in thiol-dependent redox system revealed the destructiveness of EbSe-Ag+-caused intracellular oxidative stress. Furthermore, a YpIII-caused mice gastroenteritis model was constructed. EbSe-Ag+ significantly reduced bacterial loads with low toxicity. It also down-regulated the expression levels of interferon (IL)-1ß and tumor necrosis factor-α, up-regulated the expression level of IL-10 on-site. All the in vivo results demonstrated the antibacterial activity and immune-modulatory property of EbSe-Ag+. Collectively, these results provided academic fundament for further analysis and development of EbSe-Ag+ as the antibacterial agents for pseudotuberculosis control.

The MELD-XI score predicts 3-year mortality in patients with chronic heart failure.

Objectives: The relationship between the MELD-XI score, a modified version of the MELD score, and the long-term prognosis of hospitalized patients with chronic heart failure is unclear. The aim of this study was to determine the long-term prognostic relationship of MELD-XI score in patients with chronic heart failure. Methods: This is a retrospective cohort study of patients with chronic heart failure who were initially hospitalized in the Second Affiliated Hospital of Chongqing Medical University from February 2017 to December 2017. The primary clinical outcome was all-cause mortality within 3 years. Cox regression and lasso regression were used to screen variables and build a prognostic model. Combined with the MELD-XI score, the final model was adjusted, and the predictive ability of the model was evaluated. Survival curves were estimated using the Kaplan-Meier method and compared by the log rank test. Results: A total of 400 patients with chronic heart failure were included (median age 76 years, 51.5% female). During the 3-year follow-up period, there were 97 all-cause deaths, including 63 cardiac deaths. Six characteristic variables (NT-proBNP, BUN, RDW CV, Na+ and prealbumin) were selected by univariate Cox regression and lasso regression. Survival analysis results showed that elevated MELD-XI score at baseline predicted the risk of all-cause mortality at 3 years in patients (HR 3.19, 95% CI 2.11-4.82, P < 0.001; HRadjusted 1.79, 95% CI 1.09-2.92, P = 0.020). Subgroup analysis showed that MELD-XI score still had prognostic value in the subgroup without chronic kidney disease (HR 3.30 95%CI 2.01-5.42 P < 0.001; HRadjusted 1.88 95%CI 1.06-3.35 P = 0.032, P for interaction = 0.038). Conclusions: This study proved that the MELD-XI score at admission was related to the poor prognosis of hospitalized patients with chronic heart failure within 3 years.

Peony-like 3D-MoS2/graphene nanostructures with enhanced mimic peroxidase performance for colorimetric determination of dopamine.

Fast and quantitative detection of dopamine (DA) is highly desirable but still challenging in the clinical diagnosis due to the complexity of the biological samples. Herein, a novel peony-like 3D-MoS2/Graphene (peony-like 3D-MoS2/GR) nanomaterial is designed and characterized. The nanomaterial exhibits outstanding the peroxidase-like activity, which can be employed as a nanozyme for facile and fast colorimetric determination of dopamine. The peony-like 3D-MoS2/GR-based colorimetric assay presents a wide liner dependence on the DA concentration in the range of 1-400 µM and a low detection limit of 0.21 µM. Such excellent results originate from its unique structure, which offers abundant active sites, high specific surface area, interconnected network and the special microenvironment. Furthermore, this reported colorimetric assay is successfully employed for detection of DA in human serum and urine samples. The recovery percentage ranges from 98 to 105.6%. Hence, the peony-like 3D-MoS2/GR paves a new avenue for detection of DA in real biological systems.