Pulsed electromagnetic fields potentiate bone marrow mesenchymal stem cell chondrogenesis by regulating the Wnt/ß-catenin signaling pathway.

BACKGROUND: Pulsed electromagnetic fields (PEMFs) show promise as a treatment for knee osteoarthritis (KOA) by reducing inflammation and promoting chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). PURPOSE: To identify the efficacy window of PEMFs to induce BMSCs chondrogenic differentiation and explore the cellular mechanism under chondrogenesis of BMSCs in regular and inflammatory microenvironments. METHODS: BMSCs were exposed to PEMFs (75 Hz, 1.6/2/3/3.8 mT) for 7 and 14 days. The histology, proliferation, migration and chondrogenesis of BMSCs were assessed to identify the optimal parameters. Using these optimal parameters, transcriptome analysis was performed to identify target genes and signaling pathways, validated through immunohistochemical assays, western blotting, and qRT-PCR, with or without the presence of IL-1ß. The therapeutic effects of PEMFs and the effective cellular signaling pathways were evaluated in vivo. RESULTS: BMSCs treated with 3 mT PEMFs showed the optimal chondrogenesis on day 7, indicated by increased expression of ACAN, COL2A, and SOX9, and decreased levels of MMP3 and MMP13 at both transcriptional and protein levels. The advantages of 3 mT PEMFs diminished in the 14-day culture groups. Transcriptome analysis identified sFRP3 as a key molecule targeted by PEMF treatment, which competitively inhibited Wnt/ß-catenin signaling, regardless of IL-1ß presence or duration of exposure. This inhibition of the Wnt/ß-catenin pathway was also confirmed in a KOA mouse model following PEMF exposure. CONCLUSIONS: PEMFs at 75 Hz and 3 mT are optimal in inducing early-stage chondrogenic differentiation of BMSCs. The induction and chondroprotective effects of PEMFs are mediated by sFRP3 and Wnt/ß-catenin signaling, irrespective of inflammatory conditions.

IL-17B alleviates the pathogenesis of systemic lupus erythematosus by inhibiting FASN-mediated differentiation of B cells.

The interleukin-17 (IL-17) family of cytokines has emerged as a critical player in autoimmune disease, including systemic lupus erythematosus (SLE). However, the role of IL-17B, a poorly understood cytokine, in the pathogenesis of SLE is still not clear. In this study, we investigated the role of IL-17B in the activation and differentiation of B cells, and the pathogenesis of SLE. Intriguingly, IL-17B deficiency aggravated disease in lupus-prone mice and promoted the activation of B cells and the differentiation of germinal center (GC) B cells and plasma cells, while recombinant mouse IL-17B (rmIL-17B) significantly alleviated disease in lupus-prone mice. Mechanistically, rmIL-17B inhibited the activation of the Toll-like receptor (TLR) and interferon (IFN) pathways in B cells by downregulating the FASN-mediated lipid metabolism. Loss of FASN significantly alleviated the disease in lupus-prone mice and inhibited the activation and differentiation of B cells. In addition, B cells had greater FASN expression and lower IL-17RB levels in patients with SLE than in healthy controls. Our study described the role of IL-17B in regulating B-cell activation and differentiation, and alleviating the onset of SLE. These findings will lay a theoretical foundation for further understanding of the pathogenesis of SLE.

Development and validation of a novel screening tool for deep vein thrombosis in patients with spinal cord injury: A five-year cross-sectional study.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: Deep vein thrombosis (DVT) presents a significant risk of complication in patients with spinal cord injury (SCI), necessitating accurate screening methods. While the Caprini Risk Assessment Model (Caprini RAM) has seen extensive use for DVT screening, its efficacy remains under scrutiny. SETTING: First Affiliated Hospital of China University of Science and Technology. METHODS: We created and evaluated three nomograms for their effectiveness in DVT screening. Model 1 incorporated variables such as age, D-dimer level, red blood cell (RBC) counts, platelet counts, presence of type 2 diabetes mellitus, high blood pressure, mode and level of injury, degree of impairments, and Caprini scores. Model 2 was derived from Caprini scores alone, and Model 3 focused on independent risk factors. We assessed these models using the area under the curve (AUC) of the receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA), employing bootstrap resampling tests (500 iterations) to determine their accuracy, discriminative ability, and clinical utility. Internal validation was performed on a separate cohort. Nomogram was established with well-fitted calibration curves for model 1, 2 and 3(AUC = 0.808, 0.751 and 0.797; 95%CI = 0.76-0.86, 0.70-0.80 and 0.75-0.84; respectively), indicating model 1 outperformed the others in prediction DVT risk, followed by model 3 and 2. These findings were consistent in the validation cohort, with DCA further corroborating our conclusions. CONCLUSION: A nomogram integrating clinical data with Caprini RAM provides a superior option for DVT screening in SCI patients within rehabilitation settings, outperforming Caprini RAM.

Design, synthesis, and biological evaluation of novel highly selective non-carboxylic acid FABP1 inhibitors.

Histologic spectrum studies in patients revealed fatty acid binding proteins 1 (FABP1) as a potential new target for the treatment of metabolic associated fatty liver disease. However, there is no FABP1 inhibitor has been reported except the first-in-class FABP1 inhibitor bearing acid moiety reported by our laboratory. Herein, we firstly report the structure-activity relationship of novel non-carboxylic acid FABP1 inhibitors, which resulted in the identification of the potent and selective FABP1 inhibitor 30. The IC50 value of compound 30 for subtype FABP4 in the same family was greater than 80 µM. Moreover, compound 30 significantly alleviated the hepatic steatosis in DIO mice, which is equivalent to that of clinical drug obeticholic acid. This study might be provided a promising probe for the development of FABP1 inhibitors and thus can help to further elucidate the pharmacology of FABP1.

Comparison of different sources of mesenchymal stem cells: focus on inflammatory bowel disease.

Inflammatory bowel disease (IBD) poses a significant challenge in modern medicine, with conventional treatments limited by efficacy and associated side effects, necessitating innovative therapeutic approaches. Mesenchymal stem cells (MSC) have emerged as promising candidates for IBD treatment due to their immunomodulatory properties and regenerative potential. This thesis aims to explore and compare various sources of MSC and evaluate their efficacy in treating IBD. This study comprehensively analyses MSC derived from multiple sources, including bone marrow, adipose tissue, umbilical cord, and other potential reservoirs. Core elements of this investigation include assessing differences in cell acquisition, immunomodulatory effects, and differentiation capabilities among these MSC sources, as well as comparing their clinical trial outcomes in IBD patients to their therapeutic efficacy in animal models. Through meticulous evaluation and comparative analysis, this thesis aims to elucidate disparities in the efficacy of different MSC sources for IBD treatment, thereby identifying the most promising therapeutic applications. The findings of this study are intended to advance our understanding of MSC biology and offer valuable insights for selecting the most effective MSC sources for personalized IBD therapy. Ultimately, this research endeavor will optimise therapeutic strategies for managing inflammatory bowel disease through the utilization of MSC.

Invasive pneumococcal diseases in Chinese children: a multicentre hospital-based active surveillance from 2019 to 2021.

This study aimed to provide data for the clinical features of invasive pneumococcal disease (IPD) and the molecular characteristics of Streptococcus pneumoniae isolates from paediatric patients in China. We conducted a multi-centre prospective study for IPD in 19 hospitals across China from January 2019 to December 2021. Data of demographic characteristics, risk factors for IPD, death, and disability was collected and analysed. Serotypes, antibiotic susceptibility, and multi-locus sequence typing (MLST) of pneumococcal isolates were also detected. A total of 478 IPD cases and 355 pneumococcal isolates were enrolled. Among the patients, 260 were male, and the median age was 35 months (interquartile range, 12-46 months). Septicaemia (37.7%), meningitis (32.4%), and pneumonia (27.8%) were common disease types, and 46 (9.6%) patients died from IPD. Thirty-four serotypes were detected, 19F (24.2%), 14 (17.7%), 23F (14.9%), 6B (10.4%) and 19A (9.6%) were common serotypes. Pneumococcal isolates were highly resistant to macrolides (98.3%), tetracycline (94.1%), and trimethoprim/sulfamethoxazole (70.7%). Non-sensitive rates of penicillin were 6.2% and 83.3% in non-meningitis and meningitis isolates. 19F-ST271, 19A-ST320 and 14-ST876 showed high resistance to antibiotics. This multi-centre study reports the clinical features of IPD and demonstrates serotype distribution and antibiotic resistance of pneumococcal isolates in Chinese children. There exists the potential to reduce IPD by improved uptake of pneumococcal vaccination, and continued surveillance is warranted.

MDSC-derived S100A8/9 contributes to lupus pathogenesis by promoting TLR7-mediated activation of macrophages and dendritic cells.

Toll-like receptors (TLRs), especially TLR7, play an important role in systemic lupus erythematosus (SLE) pathogenesis. However, the regulatory mechanism underlying the abnormal activation of TLR pathways in patients with SLE has not been elucidated. Notably, accumulating evidence indicates that myeloid-derived suppressor cells (MDSCs) are important regulators of inflammation and autoimmune diseases. Compared with healthy control subjects, patients with SLE have a greater proportion of MDSCs among peripheral blood mononuclear cells (PBMCs); however, the effect of MDSCs on TLR7 pathway activation has not been determined. In the present study, lupus MDSCs significantly promoted TLR7 pathway activation in macrophages and dendritic cells (DCs), exacerbating the imiquimod-induced lupus model. RNA-sequencing analysis revealed significant overexpression of S100 calcium-binding protein A8 (S100A8) and S100A9 in MDSCs from diseased MRL/lpr mice. In vitro and in vivo studies demonstrated that S100A8/9 effectively promoted TLR7 pathway activation and that S100A8/9 deficiency reversed the promoting effect of MDSCs on TLR7 pathway activation in lupus. Mechanistically, MDSC-derived S100A8/9 upregulated interferon gamma (IFN-γ) secretion by macrophages and IFN-γ subsequently promoted TLR7 pathway activation in an autocrine manner. Taken together, these findings suggest that lupus MDSCs promote TLR7 pathway activation and lupus pathogenesis through the S100A8/9-IFN-γ axis. Our study identified an important target for SLE therapy.

Effect of eye-tracking-based attention training for patients with poststroke cognitive impairment: a study protocol for a prospective, single-blinded, single-centre, randomised controlled trial in China.

INTRODUCTION: Poststroke cognitive impairment (PSCI) is a common dysfunction that places a great burden on patients who had stroke and their families. Approximately 46%-92% of stroke survivors experience some degree of attention problems after a stroke. Improving attention is considered the core of successfully improving cognitive function and reintegrating patients into daily life. Eye tracking technology provides real-time feedback and accurate monitoring of cognitive processing, and using this technology to introduce attention training may improve patient treatment outcomes. The main purpose of this study was to investigate whether eye-tracking-based attention training has a positive effect on patients with PSCI. METHODS AND ANALYSIS: This study is a prospective randomised controlled trial. We will recruit 48 patients with PSCI referred to the Department of Rehabilitation Medicine at West China Hospital, Sichuan University, in Southwest China. The participants will be randomly distributed into two groups. Both groups will undergo conventional rehabilitation for 3 weeks, and the intervention group will receive 3 weeks of eye-tracking-based attention training (20-30 min/day). The primary outcome will be the patients' cognitive function, measured by the Montreal Cognitive Assessment. The secondary outcomes will be the patients' attention, independence of daily activities and event-related potential. These outcomes will be assessed at baseline, at the end of treatment (3 weeks) and at follow-up (1 month and 3 months after treatment). We will report the statistics and estimations using 95% CI. ETHICS AND DISSEMINATION: This trial received ethics approval from the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University (2023 review No. 258). The results from this study will be disseminated via academic publication. TRIAL REGISTRATION NUMBER: ChiCTR2300068727.

Patterns of antibiotic administration in Chinese neonates: results from a multi-center, point prevalence survey.

OBJECTIVES: In this study, we describe the patterns of antibiotic prescription for neonates based on World Health Organization's (WHO) Essential Medicines List Access, Watch, and Reserve (AWaRe), and the Management of Antibiotic Classification (MAC) Guidelines in China. METHODS: One-day point-prevalence surveys (PPS) on antimicrobial prescriptions were conducted on behalf of hospitalized neonates in China from September 1 and November 30, annually from 2017 to 2019. RESULTS: Data was collected for a total of 2674 neonatal patients from 15 hospitals in 9 provinces across China of which 1520 were newborns who received at least one antibiotic agent. A total of 1943 antibiotic prescriptions were included in the analysis. The most commonly prescribed antibiotic was meropenem (11.8%). The most common reason for prescribing antibiotic to neonates was pneumonia (44.2%). There were 419 (21.6%), 1343 (69.1%) and 6 (0.3%) antibiotic prescriptions in the Access, Watch and Reserve groups, respectively. According to MAC Guidelines in China, there were 1090 (56.1%) antibiotic agents in the Restricted and 414 (21.3%) in the Special group. CONCLUSION: Broad-spectrum antibiotics included in the Watch and Special groups were likely to be overused in Chinese neonates.

A clade of Streptococcus pneumoniae clonal complex 320 with increased tolerance to ß-lactam antibiotics in a Chinese metropolitan city.

OBJECTIVES: We characterized the population structure and features of clinical Streptococcus pneumoniae isolates associated with invasive pneumococcal disease (IPD) from 2009 to 2017 in a Chinese metropolitan city using a whole-genome sequencing approach. METHODS: Seventy-nine pneumococcal strains, including 60 serogroup-19 strains from children enduring IPD from a paediatric hospital in Shenzhen, were subjected to whole-genome sequencing. Population structure was characterized through phylogenetic analysis, sequence typing, serotyping, virulence factor, and antimicrobial drug resistance (AMR) gene profiling, combining the publicly available related WGS data. Clinical demography and antibiotic susceptibility profiles were compared among different populations to emphasize the higher-risk populations. Genetic regions associated with AMR gene mobilization were identified through comparative genomics. RESULTS: These IPD strains mainly belonged to clonal complex 320 (CC320) and were composed of serotypes 19A and 19F. In addition to sporadic possible importation-related isolates (ST320), we identified an independent clade, CC320_SZpop (ST271), that predominantly circulated in Shenzhen and possibly expanded its range. Clinical features and antibiotic susceptibility analysis revealed that CC320_SZpop might manifest much higher pathogenicity and tolerance to ß-lactams. Specific virulence factors in Shenzhen isolates of CC320_SZpop were identified. Furthermore, an ca. 40 kb hotspot genomic region enduring frequent recombination was identified, possibly associated with the divergence of S. pneumoniae strains. CONCLUSION: A novel pneumococcal clade, CC320_SZpop, circulating in Shenzhen and other regions in China, possibly under expansion, was found and deserves more study and surveillance. Our study also emphasizes the importance of continuous genomic surveillance of clinical S. pneumoniae isolates, especially IPD isolates.

Research on traffic accident prediction of expressway tunnel based on B-NB model.

OBJECTIVE: The study investigates the relationship between traffic accidents in expressway tunnels and their influencing factors, with the aim of predicting traffic accidents within tunnels and presenting reasonable recommendations to improve tunnel safety. METHODS: The study utilizes a dataset of 586 traffic accidents occurring exclusively within 8 tunnels along a Guangdong Province expressway from 2017 to 2021. It applies the geometric alignment consistency principle to segment road sections, defines tunnel boundaries based on driving behavior, and employs a Bayesian-modified negative binomial regression model (B-NB model) to identify 6 significant variables from a pool of 17 factors. RESULTS: The predictive performance of the B-NB model demonstrated similarities to that of the fixed parametric model. This outcome might be attributed to the chosen prior distribution settings and the limited amount of data. Nonetheless, the model effectively captures relationships among variables, leading to improved accuracy in accident prediction and the predictive model achieves a 76.1% accuracy rate. CONCLUSIONS: Drawing from the estimation results, practical measures are suggested across three dimensions: road geometric alignment design, tunnel traffic safety facilities, and traffic emergency management. These proposals aim to ameliorate the severe consequences of tunnel accidents. Future research will explore an in-depth comparison of estimation results, considering the impact of time and variable correlation on the prediction model by expanding the existing data. This will guide the direction of subsequent research endeavors.

Molecular characteristics and antimicrobial resistance of invasive pneumococcal isolates from children in the post-13-valent pneumococcal conjugate vaccine era in Shenzhen, China.

OBJECTIVES: This study aimed to evaluate the molecular epidemiology and antimicrobial resistance of invasive pneumococcal isolates from children in Shenzhen, China, in the early stage of the pneumococcal 13-valent conjugated vaccine (PCV-13) era from 2018 to 2020. METHODS: Invasive pneumococcal strains were isolated from hospitalized children with invasive pneumococcal diseases (IPDs) from January 2018 to December 2020. The serotype identification, multilocus sequence typing (MLST), and antibiotic susceptibility tests were performed on all culture-confirmed strains. RESULTS: Sixty-four invasive strains were isolated mainly from blood (70.3%). Prevalent serotypes were 23F (28.1%), 14 (18.8%), 19F (15.6%), 6A/B (14.1%), and 19A (12.5%), with a serotype coverage rate of 96.9% for PCV13. The most common sequence types (STs) were ST876 (17.1%), ST271 (10.9%), and ST320 (7.8%). Half of the strains were grouped in clonal complexes (CCs): CC271 (21.9%), CC876 (20.3%), and CC90 (14.1%). Meningitis isolates showed a higher resistance rate (90.9% and 45.5%) to penicillin and ceftriaxone than the rate (3.8% and 9.4%) of non-meningitis isolates. The resistance rates for penicillin (oral), cefuroxime, and erythromycin were 53.13%, 73.4%, and 96.9%, respectively. The dual ermB and mefA genotype was found in 81.3% of erythromycin-resistant strains. The elevated minimum inhibitory concentration (MIC) of ß-lactam antibiotics and dual-genotype macrolide resistance were related mainly to three major serotype-CC combinations: 19F-CC271, 19A-CC271, and 14-CC876. CONCLUSION: Invasive pneumococcus with elevated MICs of ß-lactams and increased dual ermB and mefA genotype macrolide resistance were alarming. Expanded PCV13 vaccination is expected to reduce the burden of paediatric IPD and to combat antibiotic-resistant pneumococcus in Shenzhen.

The implications of FASN in immune cell biology and related diseases.

Fatty acid metabolism, particularly fatty acid synthesis, is a very important cellular physiological process in which nutrients are used for energy storage and biofilm synthesis. As a key enzyme in the fatty acid metabolism, fatty acid synthase (FASN) is receiving increasing attention. Although previous studies on FASN have mainly focused on various malignancies, many studies have recently reported that FASN regulates the survival, differentiation, and function of various immune cells, and subsequently participates in the occurrence and development of immune-related diseases. However, few studies to date systematically summarized the function and molecular mechanisms of FASN in immune cell biology and related diseases. In this review, we discuss the regulatory effect of FASN on immune cells, and the progress in research on the implications of FASN in immune-related diseases. Understanding the function of FASN in immune cell biology and related diseases can offer insights into novel treatment strategies for clinical diseases.

Degradation of AZGP1 suppresses the progression of breast cancer cells via TRIM25.

Alpha-2-glycoprotein 1, zinc-binding (AZGP1) is a secreted protein, which has been shown to be a potential biomarker of cancer progression; however, its roles in breast cancer are still unclear. Currently, we analyzed the online datasets and found that AZGP1 was highly expressed in breast cancer tissues and its expression was negatively correlated with the survival of breast cancer patients. Functional experiments through AZGP1 knockdown revealed that AZGP1 could promote the proliferation, migration, and invasion ability of breast cancer cells. In vivo experiments obtained a consistent result. Mechanistically, it was found that AZGP1 interacted with tripartite motif-containing protein 25 (TRIM25), which subsequently promoted AZGP1 degradation through facilitating the ubiquitination. Furthermore, overexpression of TRIM25 partially reversed the promoting effects of AZGP1 overexpression on breast cancer progression. Therefore, this study indicates that AZGP1 might be a potential therapeutic target for breast cancer treatment.

Tanshinone IIA ameliorates cisplatin-induced toxicology and cisplatin resistance via regulating SLC7A11 expression.

Cisplatin, a potent chemotherapy agent, is highly effective against various cancers but is hindered by resistance and toxicities. This study aims to investigate the roles of SLC7A11, a cystine/glutamate transporter, in cisplatin resistance, and explored Tanshinone IIA as a therapeutic option. Cisplatin reduced SLC7A11 in renal cells, worsening toxicity. Cisplatin-resistant gastric cancer cells show increased SLC7A11, driving resistance, while SLC7A11 knockdown curbed resistance. Tanshinone IIA showed promise in alleviating cisplatin toxicity by enhancing SLC7A11 expression and reducing associated adverse effects, while it effectively reversed cisplatin resistance in gastric cancer cells by suppressing SLC7A11. Additionally, Tanshinone IIA counteracted cisplatin resistance by inhibiting PIAS4-mediated SUMOylation of SLC7A11. Simultaneously, overexpressing miR-375, which has been shown to target SLC7A11, exacerbated cisplatin toxicity via SLC7A11 downregulation, which Tanshinone IIA attenuates. In summary, our study unveils complex SLC7A11 regulation in cisplatin resistance and toxicity. Tanshinone IIA emerges as a promising modulator of SLC7A11 through individual pathways, offering novel insights into overcoming cisplatin resistance and reducing toxicities in cancer therapy.

Inducible nitric oxide synthase accelerates nonalcoholic fatty liver disease progression by regulating macrophage autophagy.

BACKGROUND: Cells and tissues, such as macrophages, express inducible nitric oxide synthase (INOS) after stimulation by certain factors. INOS helps mediate the macrophage inflammatory reaction, but few studies have explored how INOS affects macrophage function in nonalcoholic fatty liver disease (NAFLD). OBJECTIVE: This study investigated the role of INOS-mediated macrophage activity in NAFLD. METHODS: A high-fat diet was used to establish an NAFLD mouse model. After 12 weeks, blood was collected for immune cell and lipid analyses, and liver tissues were collected for pathological analyses with hematoxylin and eosin and Oil Red O staining. Peritoneal macrophages were extracted in situ, cultured in Dulbecco's modified Eagle's medium, and stimulated with palmitic acid to mimic in vivo conditions for further assays. Real-time polymerase chain reaction, western blot analysis, and immunofluorescence were used to verify the expression of target genes or proteins. RESULTS: In the NAFLD model, INOS expression in macrophages increased, and INOS knockdown significantly decreased the number of macrophages. Pathological examinations confirmed that INOS knockdown slowed NAFLD progression and macrophage infiltration during inflammation. INOS knockdown also enhanced phagocytosis and lipid transport by macrophages, and increased the expression of autophagy-related molecules in macrophages, which improved the autophagy level, promoted apoptotic cell degradation, and maintained intracellular environment homeostasis. CONCLUSIONS: These results indicate a correlation between INOS expression and macrophage function in NAFLD.

Application of the 'online assessment + FOBT at home' to improve participation and the efficacy of opportunistic screening for colorectal cancer: a retrospective cohort study.

BACKGROUND: Colorectal cancer (CRC) screening faces two major challenges: insufficient screening coverage and poor adherence. A smartphone applet named "Early Screening Assistant (ESA)" was developed to create an online risk-assessment and fecal occult blood test (FOBT) at home. This retrospective study was designed to evaluate whether the new CRC screening strategy can improve the colonoscopy participation rate (PR) and lesion detection rate (DR). METHODS: In total, 6194 individuals who accepted normal health examinations and CRC screening based on the ESA from June 2020 to May 2022 were assigned to the ESA group. Accordingly, 7923 inhabitants who only accepted normal health examinations were assigned to the control group. The colonoscopy PR and neoplastic lesion DR were then compared between the two groups. RESULTS: Overall, a higher proportion of subjects in the ESA group (285 of 6194 [4.6%]) completed colonoscopy than in the control group (126 of 7923, [1.6%]), p < 0.01). The neoplastic lesion DR also significantly increased in the ESA group (76 of 6194 [1.22%]) compared with the control group (15 of 7923 [0.19%]) (p < 0.01). The adjusted diagnostic sensitivity and specificity of the "Online assessment + FOBT at home" were 41.5% and 62.6% for neoplastic lesions, respectively. CONCLUSIONS: This retrospective cohort study confirmed that the new CRC screening strategy based on the "Online assessment + FOBT at home" can improve colonoscopy participation and the neoplastic lesion detection rate and may represent a promising screening strategy for CRC. TRIAL REGISTRATION: This study was registered in China Clinical Trial Registry ( https://www.chictr.org.cn ) on 29/09/2022. REGISTRATION NUMBER: ChiCTR2200064186.