Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.

Objective With the widespread of transcatheter aortic valve replacement(TAVR)in patients with severe symptomatic aortic stenosis(AS),the life-cycle management has become a major determinant of prognosis.Methods A total of 408 AS patients who underwent successfully TAVR from June 2021 to August 2023 were consecutively enrolled in Hospital Valve Intervention Center.Patients were assigned to the Usual Care(UC)group between June 2021 and October 2022,while patients were assigned to the Heart Multi-parameter Monitoring(HMM)group between November 2022 and August 2023.The primary endpoint was defined as composite endpoint within 6 months post-TAVR,including all-cause death,cardiovascular death,stroke/transient ischemic attack,conduction block,myocardial infarction,heart failure rehospitalization,and major bleeding events.Secondary endpoints were the time interval(in hours)from event occurrence to medical consultation or advice and patient satisfaction.Statistical analysis was performed using Kaplan-Meier and multivariable Cox proportional hazards models.Results The incidence of primary endpoint in HMM group was significantly lower than that in UC group(8.9％vs.17.7％,P=0.016),the driving event was the rate of diagnosis and recognition of conduction block.The average time intervals from event occurrence to receiving medical advice were 3.02 h in HHM group vs.97.09 h in UC group(P＜0.001).Using cardiac monitoring devices and smart healthcare platforms provided significant improving in patients long-term management(HR 0.439,95％CI 0.244-0.790,P=0.006).Conclusions The utilization of cardiac monitoring devices and smart healthcare platforms effectively alerted clinical events and improved postoperative quality of life during long-term management post TAVR.

Helicobacter pylori(HP),a well-established carcinogenic factor,is implicated in the pathogenesis of gastric ulcer,gastric cancer,and other related diseases.Recent studies have unveiled a significant association between HP infection and an increased prevalence of non-alcoholic fatty liver disease(NAFLD).Furthermore,it has been observed that eradication of HP can ameliorate metabolic disorders and relieve NAFLD.Some studies have explored the possible mechanism,which may be related to energy metabolism disorder and gut microbiota imbalance caused by HP.This review outlined the current research status regarding the association between HP and NAFLD,as well as elucidated the potential mechanisms through which HP promoted the onset and progression of NAFLD.

Background/Aims: Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

A randomized, double-blind, placebo-controlled, multi-center phase Ⅱ clinical trial design was used in this study to recruit subjects who were in line with the syndrome of excess heat and fire toxin, and were diagnosed as recurrent oral ulcers, gingivitis, and acute pharyngitis. A total of 240 cases were included and randomly divided into a placebo group and a Huanglian Jiedu Pills group. The clinical efficacy of Huanglian Jiedu Pills in treating the syndrome of excess heat and fire toxin was evaluated by using the traditional Chinese medicine(TCM) syndrome scale. Enzyme-linked immunosorbent assay(ELISA) was used to determine and evaluate the levels of adenosine triphosphate(ATP), 4-hydroxynonenal(4-HNE), and adrenocorticotropic hormone(ACTH) in plasma of the two groups before and after administration and to predict their application value as clinical biomarkers. The results showed that the disappearance rate of main symptoms in the Huanglian Jiedu Pills group was 69.17%, and that in the placebo group was 50.83%. The comparison between the Huanglian Jiedu Pills group and the placebo group showed that 4-HNE before and after administration was statistically significant(P<0.05). The content of 4-HNE in the Huanglian Jiedu Pills group decreased significantly after administration(P<0.05), but that in the placebo group had no statistical significance and showed an upward trend. After administration, the content of ATP in both Huanglian Jiedu Pills group and placebo group decreased significantly(P<0.05), indicating that the energy metabolism disorder was significantly improved after administration of Huanglian Jiedu Pills and the body's self-healing ability also alleviated the increase in ATP level caused by the syndrome of excess heat and fire toxin to a certain extent. ACTH in both Huanglian Jiedu Pills group and placebo group decreased significantly after administration(P<0.05). It is concluded that Huanglian Jiedu Pills has a significant clinical effect, and can significantly improve the abnormal levels of ATP and 4-HNE in plasma caused by the syndrome of excess heat and fire toxin, which are speculated to be the effective clinical biomarkers for Huanglian Jiedu Pills to treat the syndrome of excess heat and fire toxin.
Humans ; Adrenocorticotropic Hormone ; Hot Temperature ; Medicine, Chinese Traditional ; Adenosine Triphosphate

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

[ Abstract] Objective To explore the role pathway and pattern of the Kruppel-like factor 4 (KLF4) and its mRNA interaction with microRNA (miRNAs) and circular RNA (circRNAs) at 0 hour and the 120 th hour in the rat liver regeneration. Methods The rat 2 / 3 hepatectomy (partial hepatectomy, PH) model was prepared as described by Higgins, the hepatocytes were isolated according to the method of Smedsrod et al, the expression changes of mRNA, miRNA and circRNA together named as competing endogenous RNA (ceRNA) were detected by the large-scale quantitative detection technology, the interaction network of ceRNA was constructed by Cytoscape 3. 2 software, and their correlation in expression and role were analyzed by ceRNA comprehensive analysis. Results It was found that at the 0 hour and the 120th hour PH, the ratio value of KLF4 mRNA showed 1. 00±0. 16 and 3. 14±0. 27, miR-881-3p displays 18. 30±1. 44 and 0. 47±0. 02, circRNA_20298 indicated 0. 32±0. 10 and 4. 24±0. 22, circRNA_14826 showed 0. 42±0. 13 and 0. 61±0. 08. At the same time, the four kinds of cell apoptosis-related genes adrenoceptor beta 2 (ADRB2), dimethylarginine dimethylaminohydrolase 2 (DDAH2), annexin A5 (ANXA5), ect, which were promoted in expression by KLF4, were down-regulated at 0 hour after PH, but the cell apoptosis-related genes synuclein gamma (SNCG), glutathione-disulfide reductase (GSR), FYVE, RhoGEF and PH domain containing 4 (FGD4), ect, which were inhibited in expression by KLF4, were up-regulated at 0 hour after PH. On the other hand, the cell apoptosis-related genes ANXA5 and thymosin beta 10 (TMSB10), which are promoted in expression by KLF4, were up-regulated at the 120th hour after PH, but the cell apoptosis-related genes chloride intracellular channel 4 (CLIC4) and ataxin 3 (ATXN3), ect, which were inhibited in expression by KLF4, were down-regulated at the 120th hour after PH. Conclusion The correlation in expression and role of the miRNAs, which are inhibited by circRNAs, KLF4, its mRNA is inhibited by miRNAs, and the cell apoptosis-related genes, which are regulated by KLF4, are helpful for the hepatocyte to be in active state 0 hour after PH and to be in apoptotic state 120-hour after PH.

Objective To explore the effect of esophageal cancer cell line TE-1 on inhibiting the activation,proliferation,and promoting apoptosis of co-cultured T cells based on the PD-1/PD-L1 signaling pathway.Methods Construct TE-1/PD-L1 cells and TE-1/lock cells through in vitro cell transfection,and detect the expression of PD-L1 after transfection to determine the transfection effect.Four groups of experimental subjects were set up:CD8+T cells+TE-1/PD-L1 cells+IgG antibody group,CD8+T cells+TE-1/mock cells+IgG antibody group,CD8+T cells+TE-1/PD-L1 cells+PD-L1 antibody group,and CD8+T cells+TE-1/PD-L1 cells+PD-1 antibody group.The expression levels of γ-interferon(IFN-γ),tumor necrosis factor-α(TNF-α)and interleukin-10(IL-10)secreted by CD8+T cells were compared by enzyme-linked immunosorbent assay(ELISA)among the 4 groups;the proliferation of CD8+T cells among the 4 groups was compared by cell counting kit-8(CCK-8);the apoptosis of CD8+T cells was detected by caspase-3 activity detection kit among the 4 groups.Results The levels of PD-L1 in TE-1 group,TE-1/mock group and TE-1/PD-L1 group were 4.72±0.68,5.04±0.54 and 12.21±1.35,respectively,indicating a significant increase in PD-L1 expression levels in TE-1/PD-L1 cells after transfection.The expression levels of IFN-γ in the supernatant of CD8+T cells+TE-1/PD-L1 cells+IgG antibody group,CD8+T cells+TE-1/mock cells+IgG antibody group,CD8+T cells+TE-1/PD-L1 cells+PD-L1 antibody group and CD8+T cells+TE-1/PD-L1 cells+PD-1 antibody group were(107.80±4.97),(154.00±10.02),(153.00±9.62)and(145.00±17.28)pg·mL-1;the expression levels of TNF-α were(18.80±2.59),(36.60±4.51),(37.00±4.90)and(36.60±3.21)pg·mL-1;the expression levels of IL-10 were(47.20±16.99),(115.00±6.60),(109.60±5.94)and(116.20±8.79)pg·mL-1,respectively.The above indicators of the CD8+T cells+TE-1/PD-L1 cells+IgG antibody group were statistically significant differences from CD8+T cells+TE-1/mock cells+IgG antibody group,CD8+T cells+TE-1/PD-L1 cells+PD-L1 antibody group,and CD8+T cells+TE-1/PD-L1 cells+PD-1 antibody group(all P＜0.05).Conclusion The esophageal cancer cell line TE-1 inhibits the activation,proliferation,and promotes apoptosis of co cultured T cells through the PD-1/PD-L1 signaling pathway.