Objective To explore the potential mechanism of Polygonum cuspidatum in alleviating silicosis using network pharmacology, molecular docking, and experimental validation. Methods i) The targets of active components of Polygonum cuspidatum and silicosis-related targets were retrieved from multiple databases. The overlapping targets were imported into Venny2.1.0 and STRING platforms. "Polygonum cuspidatum-active components-potential therapeutic targets for silicosis" network was constructed and core targets of Polygonum cuspidatum that can alleviate silicosis were identified using the Cytoscape3.10.2 software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID database, and molecular docking was conducted with AutoDock software. ii) Human embryonic lung fibroblast MRC-5 cells were divided into three groups. Cells in the control group were cultured in high-glucose Dulbecco's modified Eagle's medium containing 10.00% (V/V)fetal bovine serum. Cells in the silica group were treated with silica suspension at a final concentration of 150 μg·cm² (equivalent to 75 mg/L) for 48 hours. Cells in the silica + β-sitosterol group were first treated with silica suspension for 24 hours, then were cultured in medium containing β-sitosterol at a mass concentration of 50 μg/L for another 24 hours. Immunofluorescence assay and Western blotting were used to detect the effects of β-sitosterol, a core component of Polygonum cuspidatum, on the expression of phosphorylated protein kinase B (p-AKT), B-cell lymphoma-2 (BCL-2), and α-smooth muscle actin (α-SMA) in cells. Results i) A total of ten main active components of Polygonum cuspidatum, 840 targets of the active components, and 231 potential therapeutic targets for silicosis were screened through retrieval. A total of 10 core therapeutic targets were further screened, including tumor protein p53, serine/threonine protein kinase B1 (AKT1), heat shock protein 90-α, interleukin (IL)-6 , tumor necrosis factor, Src tyrosine kinase, estrogen receptor 1, epidermal growth factor receptor, BCL-2, and IL-1β. KEGG enrichment analysis yielded 178 related target pathways, among which, the phosphatidylinositol 3-kinase-protein kinase B (PI3K/AKT) signaling pathway was most relevant to silicosis. Molecular docking results showed that the top five compounds of Polygonum cuspidatum with high degree centrality, including quercetin, luteolin, physovenine, rhein, and β-sitosterol, had strong binding affinities with core targets. Among them, β-sitosterol, a key component of Polygonum cuspidatum, ranked high in binding affinity to all core targets. Molecular docking visualization indicated that β-sitosterol ranked high in binding affinitiy with the core target proteins AKT1 and BCL-2. ii) Both immunofluorescence and Western blotting results showed that, the relative expression of p-AKT, BCL-2, and α-SMA proteins increased in MRC-5 cells of the silica group compared with the control group (all P<0.05), except for p-AKT detected by Western blotting. Compared with the silica group, the relative expression levels of p-AKT, BCL-2, and α-SMA proteins in the silica+β-sitosterol group decreased (all P<0.05). Conclusion β-sitosterol, the core component of Polygonum cuspidatum, may alleviate silicosis fibrosis via the PI3K/AKT signaling pathway.

The genome tagging project (GTP) plays a pivotal role in addressing a critical gap in the understanding of protein functions. Within this framework, we successfully generated a human influenza hemagglutinin-tagged sperm-specific protein 411 (HA-tagged Ssp411) mouse model. This model is instrumental in probing the expression and function of Ssp411. Our research revealed that Ssp411 is expressed in the round spermatids, elongating spermatids, elongated spermatids, and epididymal spermatozoa. The comprehensive examination of the distribution of Ssp411 in these germ cells offers new perspectives on its involvement in spermiogenesis. Nevertheless, rigorous further inquiry is imperative to elucidate the precise mechanistic underpinnings of these functions. Ssp411 is not detectable in metaphase II (MII) oocytes, zygotes, or 2-cell stage embryos, highlighting its intricate role in early embryonic development. These findings not only advance our understanding of the role of Ssp411 in reproductive physiology but also significantly contribute to the overarching goals of the GTP, fostering groundbreaking advancements in the fields of spermiogenesis and reproductive biology.
Animals ; Female ; Humans ; Male ; Mice ; Spermatids/metabolism* ; Spermatogenesis/physiology* ; Spermatozoa/metabolism* ; Thioredoxins/genetics*

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

OBJECTIVE: To identify the underlying mechanism by which quercetin (Que) alleviates sepsis-related acute respiratory distress syndrome (ARDS). METHODS: In vivo, C57BL/6 mice were assigned to sham, cecal ligation and puncture (CLP), and CLP+Que (50 mg/kg) groups (n=15 per group) by using a random number table. The sepsisrelated ARDS mouse model was established using the CLP method. In vitro, the murine alveolar macrophages (MH-S) cells were classified into control, lipopolysaccharide (LPS), LPS+Que (10 μmol/L), and LPS+Que+acetylcysteine (NAC, 5 mmol/L) groups. The effect of Que on oxidative stress, inflammation, and apoptosis in mice lungs and MH-S cells was determined, and the mechanism with reactive oxygen species (ROS)/p38 mitogen-activated protein kinase (MAPK) pathway was also explored both in vivo and in vitro. RESULTS: Que alleviated lung injury in mice, as reflected by a reversal of pulmonary histopathologic changes as well as a reduction in lung wet/dry weight ratio and neutrophil infiltration (P<0.05 or P<0.01). Additionally, Que improved the survival rate and relieved gas exchange impairment in mice (P<0.01). Que treatment also remarkedly reduced malondialdehyde formation, superoxide dismutase and catalase depletion, and cell apoptosis both in vivo and in vitro (P<0.05 or P<0.01). Moreover, Que treatment diminished the release of inflammatory factors interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 both in vivo and in vitro (P<0.05 or P<0.01). Mechanistic investigation clarifified that Que administration led to a decline in the phosphorylation of p38 MAPK in addition to the suppression of ROS expression (P<0.01). Furthermore, in LPS-induced MH-S cells, ROS inhibitor NAC further inhibited ROS/p38 MAPK pathway, as well as oxidative stress, inflammation, and cell apoptosis on the basis of Que treatment (P<0.05 or P<0.01). CONCLUSION Que was found to exert anti-oxidative, anti-inflammatory, and anti-apoptotic effects by suppressing the ROS/p38 MAPK pathway, thereby conferring protection for mice against sepsis-related ARDS.
Animals ; Sepsis/drug therapy* ; Quercetin/therapeutic use* ; Respiratory Distress Syndrome/enzymology* ; p38 Mitogen-Activated Protein Kinases/metabolism* ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism* ; Apoptosis/drug effects* ; Male ; Oxidative Stress/drug effects* ; MAP Kinase Signaling System/drug effects* ; Lung/drug effects* ; Mice ; Lipopolysaccharides ; Macrophages, Alveolar/pathology* ; Inflammation/pathology* ; Protective Agents/therapeutic use*

Acute kidney injury(AKI)remains a global public health problem with high incidence,high mortality rates,expensive medical costs,and limited treatment options.AKI can further progress to chronic kidney disease(CKD)and eventually end-stage renal disease(ESRD).Previous studies have shown that trauma,adverse drug reactions,surgery,and other factors are closely associated with AKI.With further in-depth exploration,the role of gut microbiota in AKI is gradually revealed.After AKI occurs,there are changes in the composition of gut microbiota,leading to disruption of the intestinal barrier,intestinal immune response,and bacterial translocation.Meanwhile,metabolites of gut microbiota can exacerbate the progression of AKI.Therefore,elucidating the specific mechanisms by which gut microbiota is involved in the occurrence and development of AKI can provide new insights from the perspective of intestinal microbiota for the prevention and treatment of AKI.

Objective:To investigate the expression of kinase-like gene CT10 regulatory fac-tor(CRKL)in intrahepatic cholangiocarcinoma(ICC)and its effect on the proliferation and invasion of intrahepatic cholangiocarcinoma cells.Methods:qRT-PCR detected CRKL transcription in ICC pa-tient tissues and adjacent tissues.Immunohistochemistry assessed CRKL expression in ICC tissues and adjacent tissues,and analyzed its relationship with clinicopathological features.For the inhibition of CRKL expression in QBC939 cells by siRNA technology,the effect of CRKL silencing on AKT and ERK signaling pathway was measured by Western blot.CRKL's influence on QBC939 cell prolifera-tion and invasion was analyzed by MTT,clonogenesis,and Transwell assays.Results:The expres-sion of CRKL in ICC tissues was up-regulated,and there were statistically significant differences in CRKL expression in ICC with different clinicopathological features such as tumor size,lymph node metastasis and TNM stage.Cellular experiments showed a significant decrease in the phosphoryla-tion of AKT and ERK upon inhibition of CRKL,and the proliferation and invasion ability of ICC cells was significantly diminished(P＜0.05).Conclusion:CRKL promotes ICC cell proliferation and invasion through AKT and ERK pathways,offering new molecular targets and directions for targeted therapy.

Objectives:To investigate the prognostic value of soluble growth stimulation expressed gene 2 protein(sST2)combined with N-terminal pro-brain natriuretic peptide(NT-proBNP)in patients with ST-segment elevation myocardial infarction(STEMI)undergoing primary percutaneous coronary intervention(PCI). Methods:A total of 206 patients who were diagnosed with STEMI for the first time and underwent emergency PCI from August 2020 to February 2021 in the People's Hospital of Liaoning Province were enrolled.Patients were followed up for 3 years and divided into major adverse cardiac event(MACE,a composite endpoint event including cardiac death,stroke,heart failure,and ischemia-driven revascularization)group and MACE-free group.Multivariate cox analysis was performed to determine the independent risk factors for the prognosis of primary PCI in STEMI patients;the predictive value of sST2 and NT-proBNP for the occurrence of MACE in STEMI patients undergoing primary PCI was assessed by ROC analysis and the prediction of MACE by each factor by itself and the combined variables was analyzed with the Delong test. Results:There were 62 cases of MACE during the 3-year follow-up.Compared with the MACE-free group,patients in the MACE group had higher levels of sST2 and NT-proBNP,higher proportion of patients with left anterior descending branch lesions,anterior wall myocardial infarction,lower LVEF,and higher proportion of coronary artery slow flow(all P<0.05).Multivariate Cox analysis showed that sST2(HR=1.018,95%CI:1.012-1.024,P<0.001)and NT-proBNP(HR=1.001,95%CI:1.000-1.010,P<0.001)were independent predictors of MACE.According to the statistical analysis of ROC and Delong test,the AUC of combined sST2 and NT-proBNP in predicting MACE was 0.854,the sensitivity was 64.5%,the specificity was 93.1%,and the combined prediction of prognosis was better than that of individual prediction,with statistically significant difference(Z=2.119,P=0.034;Z=2.178,P=0.029). Conclusions:Serum sST2 and NT-proBNP are valuable predictors of MACE after emergency PCI in patients with STEMI,and the predictive efficacy increases with combined assessment of both sST2 and NT-proBNP.

BackgroundType 1 diabetes is caused by a chronic immune response that destroys islet beta cells， resulting in elevated blood glucose. Mesenchymal stem cells can prevent and treat the development of diabetes and its complications. However， little is known about the effects and potential mechanisms of Gingival mesenchymal stem cells （GMSCs） in preventing diabetes. The aim of this study is to investigate the mechanism of GMSCs in preventing type 1 diabetes in mice and to find targets for clinical treatment of diabetes. MethodsWe injected human GMSCs into NOD mice to observe the trend of blood glucose， observed the survival of pancreatic β-cells by immunohistochemistry， and detected the change of immune cells in the spleen of mice by flow analysis. Finally， the immune cells in NOD mice were transfused into NOD-SCID mice to observe the onset of diabetes in NOD-SCID mice. ResultsGMSCs significantly reduced the incidence of diabetes in NOD mice， with 64% of control mice developing diabetes at 27 weeks of age compared with 35% in the GMSC group， P=0.013. The percentage of Follicular B cells（FO B cell） in the spleen of GMSCs-treated mice decreased from （52.2±4.1）% to （43.2±5.3）%， P=0.008， while other types of immune cells did not change significantly. The immunohistochemical results showed that GMSCs could effectively improve the survival of pancreatic β-cells， which could continuously produce insulin to control blood glucose. Finally， we found the spleen cells transfusion could prevent the development of diabetes in NOD-SCID mice. ConclusionGMSCs can reduce diabetes in mice by reducing FO B cells in the spleen.

Myocardial fibrosis is a common pathological feature in various advanced cardiovascular diseases, and progressive fibrosis is the pathological basis for the development and progression of many cardiac arrhythmias and heart failure. There are no effective reversal drugs for myocardial fibrosis, which is related to the lack of understanding of the molecular mechanisms. Noncoding RNAs are a class of RNAs that do not function as coding proteins, and have been found to be intimately involved in the life cycle of cardiomyocyte differentiation, transcription and apoptosis, and are important regulators of cardiovascular diseases. An increasing number of studies have shown that noncoding RNAs regulate the proliferation and transformation of cardiac fibroblasts through related signaling pathways and can be used as potential biomarkers and novel therapeutic targets for cardiac fibrosis. This article reviews the relationship between noncoding RNAs and cardiac fibrosis.

COVID-19 has been prevalent for three years. The virulence of SARS-CoV-2 is weaken as it mutates continuously. However, elderly patients, especially those with underlying diseases, are still at high risk of developing severe infections. With the continuous study of the molecular structure and pathogenic mechanism of SARS-CoV-2, antiviral drugs for COVID-19 have been successively marketed, and these anti-SARS-CoV-2 drugs can effectively reduce the severe rate and mortality of elderly patients. This article reviews the mechanism, clinical medication regimens, drug interactions and adverse reactions of five small molecule antiviral drugs currently approved for marketing in China, so as to provide advice for the clinical rational use of anti-SARS-CoV-2 in the elderly.