RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes.

The leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and their phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the LRRK2-regulated RAB GTPase in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brain through phosphoproteomics profiling and solve the structure of RAB12-LRRK2 protein complex through Cryo-EM analysis. Mechanistically, RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes through enhancing the phosphorylation of RAB10 and recruiting RILPL1, while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 activity. Furthermore, the ciliary and centrosome defects caused by the PD-linked LRRK2-G2019S mutation are prevented by Rab12 deletion in astrocytes. Thus, our study reveals a physiological function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis. The RAB12-LRRK2 structure offers a guidance in the therapeutic development of PD by targeting the RAB12-LRRK2 interaction.

Prevalence and risk factors of sexual dysfunction in female participants with rheumatoid arthritis: a systematic review and meta-analysis.

BACKGROUND: The prevalence and risk factors of female sexual dysfunction (FSD) in female participants with rheumatoid arthritis (RA) were reported with inconsistent results. However, no systematic review and meta-analysis of pooled data provide reliable estimates of FSD prevalence in female participants with RA. AIM: To investigate the global prevalence and risk factors of FSD in female participants with RA and to analyze the association between FSD risk and RA. METHODS: The study search of this systematic review and meta-analysis was conducted through PubMed, Cochrane Library, Web of Science, and Embase from the inception date to December 10, 2023. Random effects meta-analysis was performed to derive the pooled prevalence. Q and I2 tests were used to analyze heterogeneity among the studies. Subgroup analyses and meta-regression were used to detect the sources of heterogeneity. OUTCOMES: The pooled prevalence of FSD in female participants with RA was calculated, and odds ratios (ORs) and 95% CIs were used to assess the strength of the association between FSD-related risk factors and RA. RESULTS: A total of 13 studies were included in our analysis, involving 2327 participants. The pooled prevalence of FSD in female participants with RA was 49.1% (95% CI, 38.2%-60%). The participants with RA had a higher risk of FSD than healthy controls (OR, 3.10; 95% CI, 1.74-5.53). The significant risk factors of FSD in female participants with RA were depression status (OR, 1.42; 95% CI, 0.88-2.29) and menopause (OR, 5.46; 95% CI, 2.04-14.63). CLINICAL IMPLICATIONS: Female participants with RA had a significantly increased prevalence of FSD, indicating that sexual function in female participants with RA should be concerned by clinicians. STRENGTHS AND LIMITATIONS: The strength of this study is that it is the first meta-analysis to assess the global prevalence and risk factors of FSD in female participants with RA. A limitation is that the results, after the articles were pooled, showed significant heterogeneity and publication bias. CONCLUSIONS: The present systematic review and meta-analysis revealed that the overall prevalence of FSD in female participants with RA was 49.1%, indicating a significant association between FSD risk and RA among females. Moreover, menopause and depression status were significantly associated with FSD in female participants with RA.

Exploring the protective effect and mechanism of icariside II on the bladder in a rat model of radiation cystitis based on transcriptome sequencing.

PURPOSE: Radiation cystitis (RC) is a complex and common complication after radiotherapy for pelvic cancer. Icariside II (ICAII) is a flavonoid compound extracted from Epimedium, a traditional Chinese medicine, with various pharmacological activities. The aim of the present study was to investigate the cysto-protective effects of ICAII in RC rats and its possible mechanisms. MATERIALS AND METHODS: A rat model of induced radiation cystitis using pelvic X-ray irradiation was used, and bladder function was assessed by bladder volume and bladder leakage point pressure (LPP) after ICAII treatment. HE and Masson stains were used to assess the histopathological changes in the bladder. IL-6, TNF-α, IL-10, IL-4 and IL-1ß were measured by ELISA to assess the level of inflammation. The gene-level changes in ICAII-treated RC were observed by transcriptome sequencing, and then the potential targets of action and biological mechanisms were explored by PPI, GO and KEGG enrichment analysis of the differentially expressed genes. Finally, the predicted targets of action were experimentally validated using immunohistochemistry, RT-qPCR, molecular docking and CETSA. RESULTS: ICAII significantly increased bladder volume and the LPP, ameliorated pathological damage to bladder tissues, decreased the levels of IL-6, TNF-α, and IL-1ß, and increased the levels of IL-10 and IL-4 in radiation-injured rats. A total of 90 differentially expressed genes were obtained by transcriptome sequencing, and PPI analysis identified H3F3C, ISG15, SPP1, and LCN2 as possible potential targets of action. GO and KEGG analyses revealed that these differentially expressed genes were mainly enriched in the pathways metabolism of xenobiotics by cytochrome P450, arachidonic acid metabolism, Staphylococcus aureus infection and chemical carcinogenesis - reactive oxygen species. Experimental validation showed that ICAII could significantly increase the expression of H3F3C and ISG15 and inhibit the expression of SPP1 and LCN2. ICAII binds well to H3F3C, ISG15, SPP1 and LCN2, with the best binding ability to H3F3C. Furthermore, ICAII inhibited the protein degradation of H3F3C in bladder epithelial cells. CONCLUSIONS: ICAII may alleviate the bladder inflammatory response and inhibit the fibrosis process of bladder tissues through the regulation of H3F3C, ISG15, SPP1, and LCN2 targets and has a protective effect on the bladder of radioinjured rats. In particular, H3F3C may be one of the most promising therapeutic targets.

Synergistic combination of RAD51-SCR7 improves CRISPR-Cas9 genome editing efficiency by preventing R-loop accumulation.

CRISPR-Cas9 has emerged as a powerful tool for genome editing. However, Cas9 genome editing faces challenges, including low efficiency and off-target effects. Here, we report that combined treatment with RAD51, a key factor in homologous recombination, and SCR7, a DNA ligase IV small-molecule inhibitor, enhances CRISPR-Cas9-mediated genome-editing efficiency in human embryonic kidney 293T and human induced pluripotent stem cells, as confirmed by cyro- transmission electron microscopy and functional analyses. First, our findings reveal the crucial role of RAD51 in homologous recombination (HR)-mediated DNA repair process. Elevated levels of exogenous RAD51 promote a post-replication step via single-strand DNA gap repair process, ensuring the completion of DNA replication. Second, using the all-in-one CRISPR-Cas9-RAD51 system, highly expressed RAD51 improved the multiple endogenous gene knockin/knockout efficiency and insertion/deletion (InDel) mutation by activating the HR-based repair pathway in concert with SCR7. Sanger sequencing shows distinct outcomes for RAD51-SCR7 in the ratio of InDel mutations in multiple genome sites. Third, RAD51-SCR7 combination can induce efficient R-loop resolution and DNA repair by enhanced HR process, which leads to DNA replication stalling and thus is advantageous to CRISPR-Cas9-based stable genome editing. Our study suggests promising applications in genome editing by enhancing CRISPR-Cas9 efficiency through RAD51 and SCR7, offering potential advancements in biotechnology and therapeutics.

Taxonomic characterization and comparative genomic analysis of a novel Devosia species revealed that phenolic acid-degrading traits are ubiquitous in the Devosia genus.

Phenolic acids (PAs) are widely distributed allelochemicals in various environments. To better understand the fate of PAs in environments, a halotolerant PAs-degrading bacterium (named strain RR2S18T) isolated from rhizosphere soil was identified as a novel species of Devosia, named Devosia rhizosphaerae sp. nov. The strain initially degraded PAs into central ring-fission intermediates (protocatechuic acid) using the CoA-dependent non-ß-oxidation pathway. The produced ring-fission intermediates were then consecutively degraded by an ortho-cleavage reaction and the ß-ketoadipic acid pathway. A comparative genomics analysis of 62 Devosia strains revealed that PAs-degrading genes were ubiquitous in their genomes, indicating that PAs degradation is universal among members of this genus. The analysis also suggested that the genes involved in CoA-dependent non-ß-oxidation are inherent to Devosia strains, while those involved in ring-fission and ß-ketoadipic acid pathways were obtained by horizontal gene transfer.

Highly Sensitive Surface-Enhanced Raman Scattering Detection of Hydroxyl Radicals in Water Microdroplets Using Phthalhydrazide/Ag Nanoparticles Nanosensor.

The spontaneous generation of hydrogen peroxide (H2O2) within atmospheric microdroplets, such as raindrops and aerosols, plays a crucial role in various environmental processes including pollutant degradation and oxidative stress. However, quantifying hydroxyl radicals (•OH), essential for H2O2 formation, remains challenging due to their short lifespan and low concentration. This study addresses this gap by presenting a highly sensitive and selective surface-enhanced Raman scattering (SERS) nanosensor specifically designed for quantifying •OH within water microdroplets. Utilizing a phthalhydrazide (Phth) probe, the SERS technique enables rapid, interference-free detection of •OH at nanomolar concentrations. It achieves a linear detection range from 2 nM to 2 µM and a limit of detection as low as 0.34 nM. Importantly, the SERS sensor demonstrates robustness and accuracy within water microdroplets, paving the way for comprehensive mechanistic studies of H2O2 generation in the atmosphere. This innovative approach not only offers a powerful tool for environmental research but also holds potential for advancing our understanding of atmospheric H2O2 formation and its impact on air quality and pollutant degradation.

Role of S100ß in Unstable Angina Pectoris: Insights from Quantitative Flow Ratio.

BACKGROUND AND OBJECTIVE: Disturbed autonomic nervous system (ANS) may promote inflammatory, immune, and oxidative stress responses, which may increase the risk of acute coronary events. S100ß has been proposed as a biomarker of neuronal injury that would provide an insightful understanding of the crosstalk between the ANS, immune-inflammatory cells, and plaques that drive atherosclerosis. This study investigates the correlation between S100ß, and functional coronary stenosis as determined by quantitative flow ratio (QFR). METHODS: Patients with unstable angina pectoris (UAP) scheduled for coronary angiography and QFR were retrospectively enrolled. Serum S100ß levels were determined by enzyme-linked immunosorbent assay. The Gensini score was used to estimate the extent of atherosclerotic lesions and the cumulative sum of three-vessel QFR (3V-QFR) was calculated to estimate the total atherosclerotic burden. RESULTS: Two hundred thirty-three patients were included in this study. Receiver operator characteristic (ROC) curve indicated that S100ß>33.28 pg/mL predicted functional ischemia in patients with UAP. Multivariate logistic analyses showed that a higher level of S100ß was independently correlated with a functional ischemia-driven target vessel (QFR ≤0.8). This was also closely correlated with the severity of coronary lesions, as measured by the Gensini score (OR = 5.058, 95% CI: 2.912-8.793, p <0.001). According to 3V-QFR, S100ß is inversely associated with total atherosclerosis burden (B = -0.002, p <0.001). CONCLUSIONS: S100ß was elevated in the functional ischemia stages of UAP. It was independently associated with coronary lesion severity as assessed by Gensini score and total atherosclerosis burden as estimated by 3V-QFR in patients with UAP.

Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases, and they affect millions of people worldwide, particularly older individuals. Therefore, there is a clear need to develop novel drug targets for the treatment of age-related neurodegenerative diseases. Emerging evidence suggests that mitochondrial dysfunction and reactive oxygen species (ROS) generation play central roles in the onset and progression of neurodegenerative diseases. Mitochondria are key regulators of respiratory function, cellular energy adenosine triphosphate production, and the maintenance of cellular redox homeostasis, which are essential for cell survival. Mitochondrial morphology and function are tightly regulated by maintaining a balance among mitochondrial fission, fusion, biogenesis, and mitophagy. In this review, we provide an overview of the main functions of mitochondria, with a focus on recent progress highlighting the critical role of ROS-induced oxidative stress, dysregulated mitochondrial dynamics, mitochondrial apoptosis, mitochondria-associated inflammation, and impaired mitochondrial function in the pathogenesis of age-related neurodegenerative diseases, such as AD and PD. We also discuss the potential of mitochondrial fusion and biogenesis enhancers, mitochondrial fission inhibitors, and mitochondria-targeted antioxidants as novel drugs for the treatment of these diseases.

RAB12-LRRK2 Complex Suppresses Primary Ciliogenesis and Regulates Centrosome Homeostasis in Astrocytes.

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and the phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the specific RAB GTPase targeted by LRRK2 signaling in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brains through phosphoproteomics profiling and solve the structure of RAB12-LRRK2 protein complex through Cryo-EM analysis. Mechanistically, RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes through enhancing the phosphorylation of RAB10 and recruiting Rab interacting lysosomal protein like 1 (RILPL1), while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 kinase activity. Furthermore, the ciliary deficits and centrosome alteration caused by the PD-linked LRRK2-G2019S mutation are prevented by the deletion of Rab12 in astrocytes. Thus, our study reveals a physiological function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis. The RAB12-LRRK2 structure offers a guidance in the therapeutic development of PD by targeting the RAB12-LRRK2 interaction.

Prediction models for urinary incontinence after robotic-assisted laparoscopic radical prostatectomy: a systematic review.

Even though robotic-assisted laparoscopic radical prostatectomy (RARP) is superior to open surgery in reducing postoperative complications, 6-20% of patients still experience urinary incontinence (UI) after surgery. Therefore, many researchers have established predictive models for UI occurrence after RARP, but the predictive performance of these models is inconsistent. This study aims to systematically review and critically evaluate the published prediction models of UI risk for patients after RARP. We conducted a comprehensive literature search in the databases of PubMed, Cochrane Library, Web of Science, and Embase. Literature published from inception to March 20, 2024, which reported the development and/or validation of clinical prediction models for the occurrence of UI after RARP. We identified seven studies with eight models that met our inclusion criteria. Most of the studies used logistic regression models to predict the occurrence of UI after RARP. The most common predictors included age, body mass index, and nerve sparing procedure. The model performance ranged from poor to good, with the area under the receiver operating characteristic curves ranging from 0.64 to 0.98 in studies. All the studies have a high risk of bias. Despite their potential for predicting UI after RARP, clinical prediction models are restricted by their limited accuracy and high risk of bias. In the future, the study design should be improved, the potential predictors should be considered from larger and representative samples comprehensively, and high-quality risk prediction models should be established. And externally validating models performance to enhance their clinical accuracy and applicability.

Effects of Weak Electric Fields on the Denitrification Performance of Pseudomonas stutzeri: Insights into Enzymes and Metabolic Pathways.

Enhanced denitrification has been reported under weak electric fields. However, it is difficult to investigate the mechanism of enhanced denitrification due to the complex interspecific interactions of mixed-culture systems. In this study, Pseudomonas stutzeri, capable of denitrification under anaerobic conditions, was selected for treating low COD/N (2.0, ratio between concentration of chemical oxygen demand and NO3--N) artificial wastewater under constant external voltages of 0.2, 0.4, and 0.6 V. The results revealed that P. stutzeri exhibited the highest efficiency in nitrate reduction at 0.2 V. Moreover, the maximum nitrate removal rate was 15.96 mg/(L·h) among the closed-circuit groups, 19.39% higher than that under the open-circuit group. Additionally, a notable reduction in nitrite accumulation was observed under weak electric fields. Enzyme activity analysis showed that the nitrate reductase activities were significantly increased among the closed-circuit groups, while nitrite reductase activities were inhibited. Transcriptomic analysis indicated that amino acid metabolism, carbohydrate metabolism, and energy metabolism were increased, enhancing the resistance of P. stutzeri to environmental stress and the efficiency of carbon source utilization for denitrification. The current study examined the impacts of weak electric fields on enzyme activities and microbial metabolic pathways and offers valuable insights into the mechanism by which denitrification is enhanced by weak electric fields.

Causal relationship between prostatic diseases and prostate cancer: a mendelian randomization study.

BACKGROUND: Although it is thought that prostatitis or benign prostatic hyperplasia (BPH) is related to prostate cancer (PCa), the underlying causal effects of these diseases are unclear. METHODS: We assessed the causal relationship between prostatitis or BPH and PCa using a two-sample Mendelian randomization (MR) approach. The data utilized in this study were sourced from genome-wide association study. The association of genetic variants from cohorts of prostatitis or BPH and PCa patients was determined using inverse-variance weighted and MR Egger regression techniques. The direction of chance was determined using independent genetic variants with genome-wide significance (P < 5 × 10-6). The accuracy of the results was confirmed using sensitivity analyses. RESULTS: MR analysis showed that BPH had a significant causal effect on PCa (Odds Ratio = 1.209, 95% Confidence Interval: 0.098-0.281, P = 5.079 × 10- 5) while prostatitis had no significant causal effect on PCa (P > 0.05). Additionally, the pleiotropic test and leave-one-out analysis showed the two-sample MR analyses were valid and reliable. CONCLUSIONS: This MR study supports that BPH has a positive causal effect on PCa, while genetically predicted prostatitis has no causal effect on PCa. Nonetheless, further studies should explore the underlying biochemical mechanism and potential therapeutic targets for the prevention of these diseases.

Identification of YUC genes associated with leaf wrinkling trait in Tacai variety of Chinese cabbage.

Chinese cabbage (Brassica campestris L. ssp. chinensis (L.) Makino) stands as a widely cultivated leafy vegetable in China, with its leaf morphology significantly influencing both quality and yield. Despite its agricultural importance, the precise mechanisms governing leaf wrinkling development remain elusive. This investigation focuses on 'Wutacai', a representative cultivar of the Tacai variety (Brassica campestris L. ssp. chinensis var. rosularis Tsen et Lee), renowned for its distinct leaf wrinkling characteristics. Within the genome of 'Wutacai', we identified a total of 18 YUCs, designated as BraWTC_YUCs, revealing their conservation within the Brassica genus, and their close homology to YUCs in Arabidopsis. Expression profiling unveiled that BraWTC_YUCs in Chinese Cabbage exhibited organ-specific and leaf position-dependent variation. Additionally, transcriptome sequencing data from the flat leaf cultivar 'Suzhouqing' and the wrinkled leaf cultivar 'Wutacai' revealed differentially expressed genes (DEGs) related to auxin during the early phases of leaf development, particularly the YUC gene. In summary, this study successfully identified the YUC gene family in 'Wutacai' and elucidated its potential function in leaf wrinkling trait, to provide valuable insights into the prospective molecular mechanisms that regulate leaf wrinkling in Chinese cabbage.

A comprehensive comparative genomic analysis revealed that plant growth promoting traits are ubiquitous in strains of Stenotrophomonas.

Stenotrophomonas strains, which are often described as plant growth promoting (PGP) bacteria, are ubiquitous in many environments. A total of 213 genomes of strains of Stenotrophomonas were analyzed using comparative genomics to better understand the ecological roles of these bacteria in the environment. The pan-genome of the 213 strains of Stenotrophomonas consists of 27,186 gene families, including 710 core gene families, 11,039 unique genes and 15,437 accessory genes. Nearly all strains of Stenotrophomonas harbor the genes for GH3-family cellulose degradation and GH2- and GH31-family hemicellulose hydrolase, as well as intact glycolysis and tricarboxylic acid cycle pathways. These abilities suggest that the strains of this genus can easily obtain carbon and energy from the environment. The Stenotrophomonas strains can respond to oxidative stress by synthesizing catalase, superoxide dismutase, methionine sulfoxide reductase, and disulfide isomerase, as well as managing their osmotic balance by accumulating potassium and synthesizing compatible solutes, such as betaine, trehalose, glutamate, and proline. Each Stenotrophomonas strain also contains many genes for resistance to antibiotics and heavy metals. These genes that mediate stress tolerance increase the ability of Stenotrophomonas strains to survive in extreme environments. In addition, many functional genes related to attachment and plant colonization, growth promotion and biocontrol were identified. In detail, the genes associated with flagellar assembly, motility, chemotaxis and biofilm formation enable the strains of Stenotrophomonas to effectively colonize host plants. The presence of genes for phosphate-solubilization and siderophore production and the polyamine, indole-3-acetic acid, and cytokinin biosynthetic pathways confer the ability to promote plant growth. These strains can produce antimicrobial compounds, chitinases, lipases and proteases. Each Stenotrophomonas genome contained 1-9 prophages and 17-60 genomic islands, and the genes related to antibiotic and heavy metal resistance and the biosynthesis of polyamines, indole-3-acetic acid, and cytokinin may be acquired by horizontal gene transfer. This study demonstrates that strains of Stenotrophomonas are highly adaptable for different environments and have strong potential for use as plant growth-promoting bacteria.

Negative life events and college students' adjustment: the mediating role of self-esteem and the moderating role of grade.

The present research explored the relationship among negative life events, self-esteem, grade, and adjustment of college students. In total, 1,717 college students were investigated by the adolescent life events scale, Rosenberg self-esteem inventory, and Chinese college students' adjustment scale. The results showed that negative life events were negatively correlated with self-esteem and college students' adjustment. Moreover, self-esteem was positively correlated with college students' adjustment. Negative life events significantly negatively predicted college students' adjustment, and self-esteem mediated the relationship between negative life events and college students' adjustment. Grade moderated the effects of negative life events on college students' adjustment. These findings have broad implications for college students' mental health.

The protective effects of Chromofungin in oligomeric amyloid ß42 (Aß42)-induced toxicity in neurons in Alzheimer's disease.

Oligomeric Aß42 is considered to play a harmful role in the pathophysiology of Alzheimer's disease (AD). Prolonged exposure to oligomeric Aß42 could induce neuronal damage including cellular senescence. Amelioration of Aß42-induced cellular senescence has been considered as a promising strategy for the treatment of AD. Chromofungin, a chromogranin A-derived peptide, has displayed various biological functions in different types of cells and tissues. However, the effects of Chromofungin on oligomeric Aß42-induced cellular senescence have not been previously reported. In the current study, we report a novel function of Chromofungin by showing that treatment with Chromofungin could ameliorate Aß42-induced neurotoxicity in M17 neuronal cells. The Cell Counting Kit-8 (CCK-8) assay and the lactate dehydrogenase (LDH) release experiments revealed that 0.5 and 1 mM are the optimal concentrations of Chromofungin for cell culture in M17 cells. Challenging with oligomeric Aß42 (5 µM) for 7 and 14 days led to a significant decrease in telomerase activity, which was rescued by Chromofungin dose-dependently. Additionally, the senescence-associated ß-galactosidase (SA-ß-gal) staining assay demonstrated that Chromofungin mitigated oligomeric Aß42-induced cellular senescence. Correspondingly, treatment with Chromofungin reversed the gene expression of human telomerase reverse transcriptase (hTERT), telomeric repeat-binding factor 2 (TERF2), and p21 against oligomeric Aß42 in M17 neurons. Interestingly, Chromofungin attenuated oligomeric Aß42-induced oxidative stress (OS) in M17 cells by reducing the production of intracellular reactive oxygen species (ROS) but increasing the levels of intracellular superoxide dismutase (SOD). Importantly, the presence of Chromofungin reduced the expression of cyclooxygenase2 (COX-2) as well as the generation of prostaglandin E2 (PGE2). Transduction with Ad-COX-2 impaired the effects of Chromofungin on telomerase activity and the profile of cellular senescence. Our findings suggest that Chromofungin might act as a potential agent for the treatment of AD.

Structural basis of human NOX5 activation.

NADPH oxidase 5 (NOX5) catalyzes the production of superoxide free radicals and regulates physiological processes from sperm motility to cardiac rhythm. Overexpression of NOX5 leads to cancers, diabetes, and cardiovascular diseases. NOX5 is activated by intracellular calcium signaling, but the underlying molecular mechanism of which - in particular, how calcium triggers electron transfer from NADPH to FAD - is still unclear. Here we capture motions of full-length human NOX5 upon calcium binding using single-particle cryogenic electron microscopy (cryo-EM). By combining biochemistry, mutagenesis analyses, and molecular dynamics (MD) simulations, we decode the molecular basis of NOX5 activation and electron transfer. We find that calcium binding to the EF-hand domain increases NADPH dynamics, permitting electron transfer between NADPH and FAD and superoxide production. Our structural findings also uncover a zinc-binding motif that is important for NOX5 stability and enzymatic activity, revealing modulation mechanisms of reactive oxygen species (ROS) production.

Advances in the application of traditional Chinese medicine during the COVID-19 recovery period: A review.

Since the emergence of the Coronavirus Disease 2019 (COVID-19) outbreak, significant advancements has been made in research, from limited knowledge about the disease to the development of a vaccine. Although the severity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) appears to be decreasing and the threat of COVID-19 is waning, there have been widespread concerns about persistent symptoms or sequelae experienced by some patients even after recovering from COVID-19. Traditional Chinese medicine (TCM) has shown favorable treatment outcomes during the onset of COVID-19, and extensive studies have been carried out to explore the efficacy of TCM interventions during the COVID-19 recovery period. The purpose of this review is to comprehensively analyze these studies and provide new insights for the prevention and treatment of the post-COVID-19 condition.

CRL4DCAF4 E3 ligase-mediated degradation of MEN1 transcriptionally reactivates hTERT to sustain immortalization in colorectal cancer cells.

Telomerase reactivation is implicated in approximately 85% of human cancers, yet its underlying mechanism remains elusive. In this study, we elucidate that the cullin-RING ubiquitin ligase 4 (CRL4) complex drives the reactivation of human telomerase reverse transcriptase (hTERT) in colorectal cancer (CRC) by degrading the tumor suppressor, menin 1 (MEN1). Our data show that, in noncancerous intestinal epithelial cells, the transcription factor specificity protein 1 (Sp1) recruits both the histone acetyltransferase p300 and MEN1 to suppress hTERT expression, thus maintaining telomere shortness post-cell division. Inflammation-induced microenvironments trigger an activation of the CRL4DCAF4 E3 ligase, leading to MEN1 ubiquitination and degradation in CRC cells. This process nullifies MEN1's inhibitory action, reactivates hTERT expression at the transcriptional level, interrupts telomere shortening and spurs uncontrolled cellular proliferation. Notably, MEN1 overexpression in CRC cells partially counteracts these oncogenic phenotypes. NSC1517, an inhibitor of the CRL4DCAF4 complex identified through high-throughput screening from a plant-derived chemical pool, hinders MEN1 degradation, attenuates hTERT expression and suppresses tumor growth in mouse xenograft models. Collectively, our research elucidates the transcriptional mechanism driving hTERT reactivation in CRC. Targeting the CRL4DCAF4 E3 ligase emerges as a promising strategy to counteract cancer cell immortalization and curb tumor progression.

Effect of acupotomy combined with electroacupuncture on knee function of patients with knee osteoarthritis. / åˆƒé’ˆç»“åˆç”µé’ˆæ²»ç–—å¯¹è†å ³èŠ‚éª¨å ³èŠ‚ç‚Žæ‚£è€ è†å ³èŠ‚åŠŸèƒ½çš„å½±å“.

OBJECTIVES: To compare the clinical effect of combined therapy of acupotomy and electroacupuncture (EA) with the simple application of EA on knee osteoarthritis (KOA), and their influence on knee function. METHODS: Sixty-eight KOA patients were randomly divided into 2 groups, an acupotomy group and an EA group. In the acupotomy group, the combined therapy of acupotomy and EA was adopted. In the EA group, EA was simply used, delivered once every two days, 3 treatments a week；and the duration of treatment was 4 weeks. In the acupotomy group, besides the treatment as the EA group, acupotomy was combined once weekly, and the duration of treatment was 4 weeks. Separately, before and after treatment, and in 4 and 12 weeks after treatment completion (1-month and 3-month follow-up), the results of the timed up and go test (TUG), the 9-step stair climb test (9-SCT) and the knee function (Western Ontario and McMaster University osteoarthritis index visualization scale ［WOMAC］) were measured in the two groups. RESULTS: By the intention-to-treat analysis, the results of TUG, 9-SCT and WOMAC scores were reduced after treatment and in 1-month and 3-month follow-up when compared with those before treatment in the patients of the two groups (P<0.05). Compared with the EA group at the same time point, TUG results were decreased after treatment and in 1-month follow-up, and WOMAC score was reduced after treatment in the acupotomy group. WOMAC score in 1-month follow-up was reduced when compared with that before treatment within the acupotomy group (P<0.05). CONCLUSIONS: Either the simple application of EA or the combined therapy of acupotomy and EA can improve knee function, but the combined therapy obviously increases the walking speed and relieves the symptoms such as joint pain and morning stiffness. The treatment with acupotomy and EA is safe and effective on KOA and the long-term effect is satisfactory.