Objective: To explore the changes of mechanosensitive channels Piezos (Piezo 1 and Piezo 2) in neurogenic bladder (NB) of young rats and their effects，so as to provide reference for clinical search of new therapeutic targets. Methods: A total of 30 female young SD rats were divided into 5 groups based on random number table method：sham operation group (sham)，2-week nerve transection group (NB-2W)，6-week nerve transection group (NB-6W)，2-week nerve transection + Piezos inhibitor group (NB-P-2W) and 6-week nerve transection + Piezos inhibitor group (NB-P-6W)，with 6 rats in each group.The NB models were constructed by transecting the L6 and S1 spinal nerves of young rats.The NB-2W and NB-6W groups were not intervened after modeling，while the NB-P-2W and NB-P-6W groups were intraperitoneally injected with Piezos inhibitor GsMTx4 (10 mg/kg) every 2 days after modeling.Bladder cystometry and ultrasound were performed after 2 and 6 weeks of transection.The expressions of Piezos and fibrosis-related indexes (Collagen Ⅰ and α-smooth muscle actin) were detected in bladder tissues. Results: The results of bladder cystometry showed that the basal bladder pressure in NB-2W group was significantly increased，while it was slightly decreased but was still higher in NB-6W group than in the sham group (P<0.05).Basal bladder pressure was lower in NB-P-2W group than in NB-2W group，but was higher than that in the sham group; basal bladder pressure was lower in NB-P-6W group than in NB-6W group，but higher than that in the sham group (P<0.05).Compared with the sham group，the NB-2W and NB-6W groups had firstly increased and then decreased maximum cystometric capacity (MCC) (P<0.05).Compared with NB-2W group，NB-P-2W group had lower bladder leakage point pressure (BLPP)，but higher MCC and bladder compliance (BC) (P<0.05).Compared with NB-6W group，NB-P-6W group had significantly lower BLPP but higher MCC and BC (P<0.05).HE and MASSON staining and ultrasound results showed that，with the extension of nerve transection time，bladder fibrosis gradually worsened，the bladder wall became rough and thickened，calculi were visible inside，and hydronephrosis gradually appeared; the degree of fibrosis in NB-P-2W and NB-P-6W groups was less than that in NB-2W and NB-6W groups，and no hydronephrosis was observed in the upper urinary tract.In addition，Western blotting and immunohistochemical results showed that NB-2W and NB-6W groups had significantly higher relative expression levels of Piezos，Collagen Ⅰ and α-SMA than the sham group (P<0.01)，while NB-P-2W and NB-P-6W groups had lower relative expression levels of Piezos,Collagen Ⅰ and α-SMA than NB-2W and NB-6W groups (P<0.01). Conclusion: The increased expressions of mechanosensitive channels Piezos in NB young rats may be involved in the progression of bladder fibrosis，but its mechanism needs further study.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

Arginine methylation is a critical post-translational modification that plays multifaceted biological functions. However, the manipulation of protein arginine methylation largely depends on genetic or pharmaceutic inhibition of the regulatory enzymes, protein arginine methyltransferases (PRMTs), or non-methylation substitution of corresponding arginine residue to lysine or alanine of protein of interest (POI), which inevitably affects other substrates, or disrupts the structure of POI. Thus, it urges an approach to specifically modulate the arginine methylation of a POI under physiological conditions. To this end, we report the discovery of a methylation tagging system (MeTAG), that enables targeted modification of protein arginine methylation. Through bridging the methyltransferase PRMT5 proximity to a POI, MeTAG facilitates the arginine methylation of POIs, including known arginine methylated proteins, androgen receptor (AR) and protein kinase B (AKT), as well as a neo-substrate E1A binding protein (p300), in a reversible and PRMT5-dependent manner. Moreover, MeTAG can regulate downstream signaling in a methylation dependent manner, leading to downregulation of PSMA mRNA level and activation of AKT. Therefore, MeTAG represents a feasible approach to modulate protein methylation and thereby perturbs protein function in biological and therapeutic contexts.

High mobility group box 1 (HMGB1), when released extracellularly, plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system. In experimental autoimmune encephalomyelitis (EAE), a condition that models multiple sclerosis, the levels of extracellular HMGB1 and interleukin-33 (IL-33) have been found to be inversely correlated. However, the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive. Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes, upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice. Conversely, the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes. These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Astrocytes/metabolism* ; Interleukin-33/metabolism* ; HMGB1 Protein/metabolism* ; Acetylation ; Mice, Knockout ; Mice, Inbred C57BL ; p300-CBP Transcription Factors/metabolism* ; Mice ; Spinal Cord/metabolism* ; Cells, Cultured ; Female ; Signal Transduction

Objective To explore clinical application value of fetal heart quantification(HQ)technology in evaluating morphology and function of fetal heart in gestational hypertension pregnancy patients.Methods A total of 85 women with gestational hypertension(GH)during gestational age of 20-40 weeks from March 2020 to March 2024 had been selected as experimental group.According to blood pressure,urine protein,and symptoms of pregnant women,experimental group was divided into GH group(n=35),mild preeclampsia(MPE)group(n=28),and severe preeclampsia(SPE)group(n=22).Additionally,150 normal pregnant women with matched gestational age were randomly selected as control group.Fetal HQ technique was adopted to obtain cardiac morphological and functional indicators of groups,and statistical analysis was conducted.Results There was statistically significant difference in global spherical index(GSI)in each group(P＜0.05).Patients in SPE group had rounder fetal hearts.Bariance analysis was performed on fractional area change(FAC),Tei index,and global longitudinal strain(GLS)for each group of patients.There were statistically significant differences in right ventricular GLS and right ventricular Tei index(P＜0.05).The absolute value of right ventricular GLS in SPE group and MPE group was lower than that in control group,while right ventricular Tei index in SPE group was higher than that in control group.Conclusion Fetal HQ technique provides quick and easy quantitative assessment of fetal heart shape and function.Gestational hypertension not only changes the fetal heart morphology,but also affects the fetal heart function,and the fetal right heart system is more affected than the fetal left heart.

Objective:To evaluate the long-term clinical efficacy and the influence on anal function of surgery combined with ustekinumab (UST) in active Crohn's disease (CD) patients with perianal fistula.Methods:A retrospective cohort study was conducted. Clinical data of active CD patients with perianal fistula undergoing surgery combined with UST at Longhua Hospital of Shanghai University of Traditional Chinese Medicine from August 2020 to December 2022 were collected. The primary endpoints were clinical healing rate, Wexner score, and anorectal manometry values at week 52 of treatment. Secondary endpoints included the Crohn's disease activity index (CDAI), perianal Crohn's disease activity index (PDAI), laboratory indicators [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC) ], endoscopic remission rate, Van Assche score, and radiographic healing rate at week 52 of treatment.Results:A total of 28 patients were included, with 22 males (78.6%) and 6 females (21.4%) ; age (25.2 ± 7.7) (16.0-52.0) years. There was 1 patient (3.6%) of simple anal fistula. There were 27 patients (96.4%) of complex anal fistulas, including 12 of high intersphincteric type, 15 of high transsphincteric type, in which 15 with branched tracts (or ≥2 fistula tracts). The pre-treatment CDAI was 187.0 (156.0, 245.0), and the PDAI was 10.0 (9.0, 12.0). Among the 28 patients, 23 (82.1%) underwent fistulotomy, 1 (3.6%) underwent transanal opening of intersphincteric space (TROPIS), and 4 (14.3%) underwent video-assisted anal fistula treatment (VAAFT) combined with fistula-tract laser closure (FiLaC). All the patients received UST treatment postoperatively, without concurrent use of immunosuppressants or corticosteroid therapy. At week 52 of treatment, 28 (100%) patients achieved clinical healing. Compared to pre-treatment, Wexner score of patients at week 52 of treatment was significantly lower [0 (0, 0) vs. 1.0 (0, 3.0), P < 0.001], maximum anal sphincter pressure increased [ (137.6±40.9) mmHg vs. (105.1±29.2) mmHg, P < 0.001], maximum anal sphincter contraction time extended [9.0 (5.0, 15.0) s vs. 4.0 (2.0, 6.0) s, P < 0.001], and there was no significant decrease in anal resting pressure ( P > 0.05). Compared to pre-treatment, CDAI, PDAI, Van Assche scores, and simple endoscopic score for Crohn's disease (SES-CD) of patients at week 52 of treatment all significantly decreased (all P < 0.001), and CRP, ESR, and FC all decreased (all P < 0.05), with statistically significant differences. The radiographic healing rate at week 52 of treatment was 75.0% (21/28), and the radiographic remission rate was 92.9% (26/28). The endoscopic remission rate was 57.1% (16/28), and the endoscopic response rate was 82.1% (23/28) . Conclusion:The long-term clinical healing rate of active CD patients with perianal fistula receiving surgery combined with UST is high, and the anal function can be improved significantly.

Objective To explore the efficacy of ozone gas bath on necrotizing fasciitis after debride-ment.Methods Fifty patients with necrotizing fasciitis who underwent debridement in the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine from January 2020 to July 2024 were selected and divided into control group(25 cases)and observation group(25 cases)according to random number table method.The control group was given routine dressing change(normal saline,povidone iodine,hydrogen per-oxide,metronidazole sodium chloride injection),and the observation group was treated with ozone gas bath.The clinical efficacy,pain scores,laboratory indicators,postoperative complications,and total hospital days of the two groups were compared before and after treatment.Results Compared with the control group,the ob-servation group had a higher total effective rate(92.0%vs.68.0%),lower numerical rating scale for pain(NRS)scores at 1 week postoperatively,2 weeks postoperatively,and before discharge,as well as lower levels of WBC,C reactive protein(CRP),and procalcitonin(PCT),and a lower total incidence of complications(52.0%vs.80.0%).The hospital stay was shorter[(22.40±2.06)d vs.(29.28±2.28)d)],with statistical-ly significant differences(P<0.05).Conclusion Ozone gas bath can reduce postoperative pain and promote recovery in necrotizing fasciitis after debridement.

Radiation-induced lung injury (RILI) is one of the most common complications of thoracic radiotherapy, seriously affecting patients' quality of life and survival. The mechanisms underlying RILI and its therapeutic strategies have long been major focuses of research. Interleukin-17A (IL-17A), an important pro-inflammatory cytokine, has recently attracted increasing attention in studies of RILI. IL-17A regulates immune responses through multiple signaling pathways-not only promoting the recruitment of neutrophils during the acute phase of RILI, but also accelerating pulmonary fibrosis during the chronic phase by enhancing the activity of fibrogenic factors. Thus, IL-17A is considered a promising new therapeutic target for RILI. This review summarizes the mechanisms of IL-17A in RILI, discusses the prospects and challenges of targeting IL-17A for RILI treatment, and provides a theoretical basis for optimizing clinical intervention strategies.

BACKGROUND:The relationship between rheumatoid arthritis and coronary atherosclerosis has received extensive attention.Inflammation is related to rheumatoid arthritis and coronary atherosclerosis,indicating that there may be a common pathophysiological pathway between the two diseases.However,observational studies have not yet clarified the causal relationship.OBJECTIVE:To explore whether there is a causal relationship between rheumatoid arthritis and coronary atherosclerosis,as well as the potential causal relationship with 1 400 serum metabolites and 91 inflammatory factors through a Mendelian randomization analysis.METHODS:Coronary atherosclerosis data are from Finngen database,rheumatoid arthritis data are from IEU OpenGWAS database,serum metabolites data are from Canadian Longitudinal Study on Aging,Augsburg Cooperative Health Research and British Twin Project Research,and data of 91 inflammatory proteins are from research published in Nature Immunology in 2023.Mendelian randomization analysis was performed using data from genome-wide association studies,and causal effects were evaluated using inverse variance weighting,MR-Egger regression,weighted median,weighted model,and simple model methods,with inverse variance weighting being the primary analysis method.To enhance robustness,Cochran's Q-test MR-Egger intercept was used for sensitivity analysis.RESULTS AND CONCLUSION:(1)Inverse variance weighting results showed that rheumatoid arthritis was positively correlated with the increased relative risk of coronary atherosclerosis(odds ratio=1.002,95％confidence interval=1.001-1.003,P=0.003).There was no reverse causal relationship between coronary atherosclerosis and rheumatoid arthritis.In addition,96 serum metabolites and 9 inflammatory factors were found to have causal relationships with coronary atherosclerosis.There was a causal relationship between 51 serum metabolites and 7 inflammatory factors and rheumatoid arthritis.(2)This study provided epidemiological evidence between rheumatoid arthritis and coronary atherosclerosis,and emphasized the potential role of serum metabolites and inflammatory factors in the pathogenesis of these diseases.These findings may contribute to the development of new treatment strategies.Due to the limited inclusion of data from Asian populations,most contemporary studies used international databases and European population analyses.By collecting and analyzing the health data of European populations,it is conducive to a better understanding of the effects and potential role of Chinese medicine in Europe,and to further promote the practice of modern integration of Western and Chinese medicine.Meanwhile,through the comparative study with the European databases,it is possible to reveal the genetic differences and susceptibility to diseases among different populations,providing more dimensions and perspectives for global health research.

The clinical diagnosis and treatment of urinary tract infection has long faced the challenges of insufficient standardization of diagnosis and treatment pathways,irrational use of antimicrobial drugs and high recurrence rate.How to optimize the hierarchical diagnosis and treatment pathway of urinary tract infection,standardize the use of antimicrobial drugs,and reduce the recurrence rate have always been the focus of clinical attention.There is significant heterogeneity in the existing diagnostic criteria for urinary tract infection,which seriously affects the comparability and evidence integration of clinical and research studies.In order to solve the above problems,a consensus on global multidisciplinary diagnostic criteria for urinary tract infection has been formed by international multidisciplinary experts after three rounds of Delphi method.Breaking through the traditional classification framework,the consensus innovatively established a four-dimensional quantitative scoring system including local symptoms and signs,systemic inflammatory response,quantitative analysis of pyuria and urine culture results,and established a hierarchical standard for stepwise urinary tract diagnosis according to the scoring threshold.Based on the key citations related to the consensus,this paper interprets in detail the basis for the selection of core indicators and the establishment of thresholds for the diagnosis of urinary tract infection in the consensus,and focuses on the key issues and implementation paths of the consensus in localization practice.This consensus provides a unified standard for standardizing the clinical diagnosis and treatment of urinary tract infection,improving the homogeneity of clinical research through standardized diagnostic processes,and promoting the standardization of UTI drug research and development and the rational use of antibiotics and precision.