Aim To investigate the therapeutic effects of a newly developed Tadalafil tablet on pulmonary fi-brosis induced by paraquat(PQ)in rats,as well as its impact on histone acetylation levels in epithelial cells.Methods SD rats were randomly divided into four groups:the control group(control),the model group(PQ),the Tadalafil new tablet treatment group(N-Tad,1 mg·kg-1),and the positive control drug treatment group(Cialis,5 mg·kg-1).The model group and treatment group rats were intraperitoneally injected with PQ(30 mg·kg-1).Two hours after the initial treatment,the rats in the treatment group re-ceived N-Tad or Cialis via gavage,while the control and model groups were administered an equal volume of physiological saline by gavage once daily for 28 days.The weight gain rate and lung tissue index for each group of rats were calculated.Additionally,the effects of N-Tad treatment on lung tissue structural damage and collagen deposition in rats with PQ-in-duced pulmonary fibrosis were observed using HE stai-ning,Masson trichrome staining,and immunohisto-chemical techniques.By employing the Western blot technique,the effects of Tadalafil intervention on the expression of the epithelial marker E-cadherin(E-Cad),the stromal marker fibronectin(Fn),and the histone acetylation marker acetylated histones(Ac-his-tones)in A549 cells were observed.Results Com-pared to the control group,rats with PQ-induced pul-monary fibrosis exhibited a significant decrease in the rate of body weight growth,an increase in lung tissue index(P＜0.05),and a notable increase in the expression and distribution of the fibrosis marker alpha-smooth muscle actin(α-SMA)in lung tissue.The structure of the lung tissue was disrupted,accompanied by the deposition of interstitial collagen fibers.Both N-Tad and Cialis treatments could significantly enhance the rate of weight gain,decrease the lung tissue index,inhibit the expression of α-SMA,and reduce the depo-sition of interstitial collagen in the lung tissue of rats with pulmonary fibrosis.Notably,low-dose N-Tad treatment was comparable to high-dose Cialis treat-ment.At the cellular level,Tadalafil significantly in-hibited the high expression of Fn induced by transfor-ming growth factor beta 1(TGF-β1)in A549 cells.It also upregulated the expression of E-cadherin and sig-nificantly increased the levels of acetylated histones(P＜0.05).Conclusions N-Tad promotes histone acetylation in alveolar epithelial cells,significantly in-hibits epithelial-mesenchymal transition,increases E-cadherin expression,and improves lung tissue structur-al damage and collagen deposition caused by PQ.Ad-ditionally,it offers the advantage of a lower effective dose compared to Cialis,providing a new option for the treatment of pulmonary fibrosis.

Aim To investigate the therapeutic effects of a newly developed Tadalafil tablet on pulmonary fi-brosis induced by paraquat(PQ)in rats,as well as its impact on histone acetylation levels in epithelial cells.Methods SD rats were randomly divided into four groups:the control group(control),the model group(PQ),the Tadalafil new tablet treatment group(N-Tad,1 mg·kg-1),and the positive control drug treatment group(Cialis,5 mg·kg-1).The model group and treatment group rats were intraperitoneally injected with PQ(30 mg·kg-1).Two hours after the initial treatment,the rats in the treatment group re-ceived N-Tad or Cialis via gavage,while the control and model groups were administered an equal volume of physiological saline by gavage once daily for 28 days.The weight gain rate and lung tissue index for each group of rats were calculated.Additionally,the effects of N-Tad treatment on lung tissue structural damage and collagen deposition in rats with PQ-in-duced pulmonary fibrosis were observed using HE stai-ning,Masson trichrome staining,and immunohisto-chemical techniques.By employing the Western blot technique,the effects of Tadalafil intervention on the expression of the epithelial marker E-cadherin(E-Cad),the stromal marker fibronectin(Fn),and the histone acetylation marker acetylated histones(Ac-his-tones)in A549 cells were observed.Results Com-pared to the control group,rats with PQ-induced pul-monary fibrosis exhibited a significant decrease in the rate of body weight growth,an increase in lung tissue index(P＜0.05),and a notable increase in the expression and distribution of the fibrosis marker alpha-smooth muscle actin(α-SMA)in lung tissue.The structure of the lung tissue was disrupted,accompanied by the deposition of interstitial collagen fibers.Both N-Tad and Cialis treatments could significantly enhance the rate of weight gain,decrease the lung tissue index,inhibit the expression of α-SMA,and reduce the depo-sition of interstitial collagen in the lung tissue of rats with pulmonary fibrosis.Notably,low-dose N-Tad treatment was comparable to high-dose Cialis treat-ment.At the cellular level,Tadalafil significantly in-hibited the high expression of Fn induced by transfor-ming growth factor beta 1(TGF-β1)in A549 cells.It also upregulated the expression of E-cadherin and sig-nificantly increased the levels of acetylated histones(P＜0.05).Conclusions N-Tad promotes histone acetylation in alveolar epithelial cells,significantly in-hibits epithelial-mesenchymal transition,increases E-cadherin expression,and improves lung tissue structur-al damage and collagen deposition caused by PQ.Ad-ditionally,it offers the advantage of a lower effective dose compared to Cialis,providing a new option for the treatment of pulmonary fibrosis.

Objective This study aimed to explore the relationships between residential greenness and cardiometabolic risk factors among rural adults in Xinjiang Uygur Autonomous Region(Xinjiang)and thus provide a theoretical basis and data support for improving the health of residents in this region. Methods We recruited 9,723 adult rural residents from the 51st Regiment of the Third Division of the Xinjiang Production and Construction Corps in September 2016.The normalized difference vegetation index(NDVI)was used to estimate residential greenness.The generalized linear mixed model(GLMM)was used to examine the association between residential greenness and cardiometabolic risk factors. Results Higher residential greenness was associated with lower cardiometabolic risk factor prevalence.After adjustments were made for age,sex,education,and marital status,for each interquartile range(IQR)increase of NDVI500-m,the risk of hypertension was reduced by 10.3%(OR=0.897,95%CI=0.836-0.962),the risk of obesity by 20.5%(OR=0.795,95%CI=0.695-0.910),the risk of type 2 diabetes by 15.1%(OR=0.849,95%CI=0.740-0.974),and the risk of dyslipidemia by 10.5%(OR=0.895,95%CI=0.825-0.971).Risk factor aggregation was reduced by 20.4%(OR=0.796,95%CI=0.716-0.885)for the same.Stratified analysis showed that NDVI500-m was associated more strongly with hypertension,dyslipidemia,and risk factor aggregation among male participants.The association of NDVI500-m with type 2 diabetes was stronger among participants with a higher education level.PM10 and physical activity mediated 1.9%-9.2%of the associations between NDVI500-m and obesity,dyslipidemia,and risk factor aggregation. Conclusion Higher residential greenness has a protective effect against cardiometabolic risk factors among rural residents in Xinjiang.Increasing the area of green space around residences is an effective measure to reduce the burden of cardiometabolic-related diseases among rural residents in Xinjiang.

Background: The initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) typically leads to a reversible initial dip in estimated glomerular filtration rate (eGFR). The implications of this phenomenon on clinical outcomes are not well-defined. Methods: We searched MEDLINE, Embase, and Cochrane Library from inception to March 23, 2023 to identify randomized controlled trials and cohort studies comparing kidney and cardiovascular outcomes in patients with and without initial eGFR dip after initiating SGLT2i. Pooled estimates were calculated using random-effect meta-analysis. Results: We included seven studies in our analysis, which revealed that an initial eGFR dip following the initiation of SGLT2i was associated with less annual eGFR decline (mean difference, 0.64; 95% confidence interval [CI], 0.437 to 0.843) regardless of baseline eGFR. The risk of major adverse kidney events was similar between the non-dipping and dipping groups but reduced in patients with a ≤10% eGFR dip (hazard ratio [HR], 0.915; 95% CI, 0.865 to 0.967). No significant differences were observed in the composite of hospitalized heart failure and cardiovascular death (HR, 0.824; 95% CI, 0.633 to 1.074), hospitalized heart failure (HR, 1.059; 95% CI, 0.574 to 1.952), or all-cause mortality (HR, 0.83; 95% CI, 0.589 to 1.170). The risk of serious adverse events (AEs), discontinuation of SGLT2i due to AEs, kidney-related AEs, and volume depletion were similar between the two groups. Patients with >10% eGFR dip had increased risk of hyperkalemia compared to the non-dipping group. Conclusion Initial eGFR dip after initiating SGLT2i might be associated with less annual eGFR decline. There were no significant disparities in the risks of adverse cardiovascular outcomes between the dipping and non-dipping groups.

Objective: Murine CD19 chimeric antigen receptor T-cell (CAR-T) products have been approved for the treatment of refractory/relapsed (R/R) B-cell acute lymphocytic leukemia (B-ALL) ; moreover, humanized products are also undergoing clinical trials. This study aimed to explore the differences in safety and short- and long-term follow-up efficacy between humanized and murine CD19 CAR-T-cells for treating relapsed and refractory B-ALL. Methods: Clinical data of 80 patients with R/R B-ALL treated with CD19-targeted CAR-T-cells at the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology between May 2016 and March 2023 were analyzed, which included 31 patients with murine CAR-T and 49 with humanized products. Results: The proportion of patients with cytokine-release syndrome (CRS) in the murine and humanized groups was 63.1% and 65.3%, respectively. Moreover, a higher proportion of patients suffered from severe CRS in the murine group than in the humanized CAR-T group (19.4% vs 8.2%, P=0.174). Furthermore, one patient per group died of grade 5 CRS. The incidence of grade 1-2 immune effector cell-associated neurotoxicity syndrome (ICANS) was 12.9% and 6.1%, respectively; severe ICANS were not observed. Among patients receiving murine CAR-T-cells, an overall response (OR) was observed in 74.2%. Conversely, the OR rate of patients receiving humanized CAR-T-cells was 87.8%. During the median follow-up time of 10.5 months, the median recurrence-free survival (RFS) of patients with murine CAR-T-cells was 12 months, which was as long as that of patients with humanized CAR-T-cells. The median overall survival (OS) were not reached in both groups. Of the 45 patients with a bone marrow burden over 20% at baseline, humanized CAR-T therapy was associated with a significantly improved RFS (43.25% vs 33.33%, P=0.027). Bridging transplantation was an independent factor in prolonging OS (χ(2)=8.017, P=0.005) and PFS (χ(2)=6.584, P=0.010). Common risk factors, such as age, high proportion of bone marrow blasts, and BCR-ABL fusion gene expression, had no significant effect on patients' long-term follow-up outcomes. Three patients reached complete remission after reinfusion of humanized CAR-T-cells. However, one patient relapsed one month after his second infusion of murine CAR-T-cells. Conclusions: The results indicate that humanized CAR-T therapy showed durable efficacy in patients with a higher tumor burden in the bone marrow without any influence on safety. Moreover, it could overcome immunogenicity-induced CAR-T resistance, providing treatment options for patients who were not treated successfully with CAR-T therapies.
Animals ; Humans ; Mice ; Antigens, CD19 ; Burkitt Lymphoma/drug therapy* ; Cell- and Tissue-Based Therapy ; Follow-Up Studies ; Immunotherapy, Adoptive ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Receptors, Chimeric Antigen

The vagina contains at least a billion microbial cells,dominated by lactobacilli.Here we perform metagenomic shotgun sequencing on cervical and fecal samples from a cohort of 516 Chinese women of reproductive age,as well as cervical,fecal,and salivary samples from a second cohort of 632 women.Factors such as pregnancy history,delivery history,cesarean section,and breastfeeding were all more important than menstrual cycle in shaping the microbiome,and such information would be necessary before trying to interpret differences between vagino-cervical micro-biome data.Greater proportion of Bifidobacterium breve was seen with older age at sexual debut.The relative abundance of lactobacilli especially Lactobacillus crispatus was negatively associated with pregnancy history.Potential markers for lack of menstrual regularity,heavy flow,dysmenor-rhea,and contraceptives were also identified.Lactobacilli were rare during breastfeeding or post-menopause.Other features such as mood fluctuations and facial speckles could potentially be predicted from the vagino-cervical microbiome.Gut and salivary microbiomes,plasma vitamins,metals,amino acids,and hormones showed associations with the vagino-cervical microbiome.Our results offer an unprecedented glimpse into the microbiota of the female reproductive tract and call for international collaborations to better understand its long-term health impact other than in the settings of infection or pre-term birth.

Objective:To construct and evaluate a predictive diagnosis model of Alzheimer′s disease(AD) based on serum microRNA (miRNA).Methods:Downloaded the serum miRNA chip data of 1 021 AD patients and 288 healthy controls from the gene expression omnibus (GEO) database, a total of 1 309 samples were obtained. Matched AD patients and healthy controls by age, and screened out 494 samples for training and verifying the diagnostic model. Sorted the miRNA expression value from high to low and selected the top 1 000 probes for the next step. According to the ratio of 7∶3, all 494 samples were randomly divided into a training group and a validation group. LASSO regression was used to screen miRNAs, combined with gender, APOE4 genotype and miRNA data, stepwise regression was used to further screen independent variables and construct a multi-factor diagnostic model. Receiver operating characteristic (ROC) curves and calibration curves were used to verify the accuracy of the model in the training group, validation group, training group+validation group, and 1 309 total samples; A Nomogram was drawn for actual case prediction.Results:The area under the Curve of ROC of the multi-factorial diagnostic model in the training group, the validation group, the training+validation group and the total samples of 1 309 cases were 0.870, 0.831, 0.842 and 0.826, respectively, showing high predictive effectiveness. An AD case was used to show an example of applying the method and its predicted results (the total score of the patient was 521, and the probability of predicted NC was 0.022 8, indicating that the sample was AD, which was consistent with the actual diagnosis).Conclusions:The diagnostic model based on 11 serum miRNA, gender, and apolipoprotein E (ApoE4) genotypes can well predict AD and may provide the possibility for clinical prediction of AD.

Objective:To construct and evaluate a predictive diagnosis model of Alzheimer′s disease(AD) based on serum microRNA (miRNA).Methods:Downloaded the serum miRNA chip data of 1 021 AD patients and 288 healthy controls from the gene expression omnibus (GEO) database, a total of 1 309 samples were obtained. Matched AD patients and healthy controls by age, and screened out 494 samples for training and verifying the diagnostic model. Sorted the miRNA expression value from high to low and selected the top 1 000 probes for the next step. According to the ratio of 7∶3, all 494 samples were randomly divided into a training group and a validation group. LASSO regression was used to screen miRNAs, combined with gender, APOE4 genotype and miRNA data, stepwise regression was used to further screen independent variables and construct a multi-factor diagnostic model. Receiver operating characteristic (ROC) curves and calibration curves were used to verify the accuracy of the model in the training group, validation group, training group+validation group, and 1 309 total samples; A Nomogram was drawn for actual case prediction.Results:The area under the Curve of ROC of the multi-factorial diagnostic model in the training group, the validation group, the training+validation group and the total samples of 1 309 cases were 0.870, 0.831, 0.842 and 0.826, respectively, showing high predictive effectiveness. An AD case was used to show an example of applying the method and its predicted results (the total score of the patient was 521, and the probability of predicted NC was 0.022 8, indicating that the sample was AD, which was consistent with the actual diagnosis).Conclusions:The diagnostic model based on 11 serum miRNA, gender, and apolipoprotein E (ApoE4) genotypes can well predict AD and may provide the possibility for clinical prediction of AD.

BackgroundMicroRNAs (miRNAs) have been reported to play vital roles in liver regeneration. Previous studies mainly focused on the functions of intracellular miRNAs, while the functions of circulating exosomal miRNAs in liver regeneration remain largely unknown. The aim of this study was to identify the key exosomal miRNA that played vital roles in liver regeneration.

MethodsThe Sprague-Dawley male rats were assigned to 70% partially hepatectomized group (n = 6) and sham surgery group (n = 6). The peripheral blood of both groups was collected 24 h after surgery. The exosomal miRNAs were extracted, and microarray was used to find out the key miRNA implicated in liver regeneration. Adenovirus was used to overexpress the key miRNA in rats, and proliferating cell nuclear antigen (PCNA) staining was applied to study the effect of key miRNA overexpression on liver regeneration. Western blotting was used to validate the predicted target of the key miRNA.

ResultsExosomal miR-10a was upregulated more than nine times in hepatectomized rats. The level of miR-10a was increased in the early phase of liver regeneration, reached the top at 72 h postsurgery, and decreased to perioperative level 168 h after surgery. Moreover, enforced expression of miR-10a by adenovirus facilitated the process of liver regeneration as evidenced by immunohistochemical staining of PCNA. Erythropoietin-producing hepatocellular receptor A4 (EphA4) has been predicted to be a target of miR-10a. The protein level of EphA4 was decreased in the early phase of liver regeneration, reached the bottom at 72 h postsurgery, and rose to perioperative level 168 h after surgery, which was negatively correlated with miR-10a, confirming that EphA4 served as a downstream target of miR-10a. Moreover, inhibition of EphA4 by rhynchophylline could promote the proliferation of hepatocytes by regulating the cell cycle.

ConclusionExosomal miR-10a might accelerate liver regeneration through downregulation of EphA4.

A questionnaire survey of 1 000 clinicians having experience in treating uncomplicated lower urinary tract infections from different levels of hospitals was conducted to mainly evaluate the applicability and effectiveness of clinical application of clinical practice guideline on traditional Chinese medicine therapy alone or combined with antibiotics for uncomplicated lower urinary tract infection(hereinafter referred to as Guideline). The research was conducted with the three-level quality control strictly throughout the process, and the data was real and reliable. The survey's results showed that: most clinicians considered that the Guideline had good clinical applicability. The availability and price of the recommended medicine were moderate. Traditional Chinese medicine had obvious features and advantages in treating lower urinary tract infection for it could reduce the usage of antibiotics and shorten the course of antibiotic application. In the recommendation section, clinicians proposed increasing medication guidance, updating the Guideline timely, as well as increasing treating methods and techniques, strengthen propaganda and promotion, and improve the use of evidence-based methods. In the evaluation of effectiveness, the majority of clinicians agreed that the definition in both traditional Chinese medicine (TCM) and Western medicine and differential diagnosis in the Guideline were accurately described and the basic principle of treatment as well as the treating method of TCM were recommended appropriately. The TCM formulas and Chinese patent medicine had good effect. Some clinicians suggested refining the syndrome differentiation of stranguria. Some clinicians considered that the formulas and herbs recommended in Guideline didn't have obvious effect and some had doubts about the manipulation of fumigation and washing in the part of other methods recommended in Guideline. Moreover, specification and procedure of manipulation of fumigation and washing using herbs and the acupuncture included in characteristic TCM therapy treating uncomplicated lower urinary tract infection remained to be developed.
Acupuncture Therapy ; Anti-Bacterial Agents ; Diagnosis, Differential ; Drugs, Chinese Herbal ; Humans ; Medicine, Chinese Traditional ; Urinary Tract Infections