Mitochondrial DNA (mtDNA) acts as a damage-associated molecular pattern to activate the stimulator of interferon genes (STING) signaling in macrophages, promoting tissue inflammation. However, its role in acute myocardial infarction (AMI) remains unclear. Macrophage-specific Sting1 knockout mice were used to validate STING's pathological role in AMI. Cardiac and liver mtDNA were used to activate macrophages in co-culture systems with cardiomyocytes to assess fibrosis and hypertrophy. Panaxatriol saponin (PTS) was tested for its ability to block mtDNA-driven macrophage activation and subsequent cardiomyocyte damage. STING-PTS binding ability was analyzed. AMI rats received PTS to evaluate its effects on myocardial inflammation and ventricular remodeling. In vivo, macrophage-specific Sting1 knockout reduced myocardial inflammation and injury after AMI. In vitro, mtDNA-activated macrophages induced cardiomyocyte fibrosis and hypertrophy through STING signaling. PTS suppressed mtDNA-driven macrophage activation by directly binding STING, thereby blocking inflammatory cascades. In AMI rats, PTS treatment attenuated acute inflammation and reversed ventricular remodeling. These findings establish the mtDNA-STING axis in macrophages as a critical driver of post-AMI inflammation and identify pharmacological STING inhibition with PTS as a promising therapeutic strategy. The study bridges genetic validation with translational applications, highlighting macrophage STING as a novel target for ischemic heart disease management.

Acetaminophen (APAP) is the primary cause of drug-induced acute liver failure. Ovarian tumor deubiquitinase 6A (OTUD6A), a recently discovered deubiquitinase of the OTU family, has been primarily studied in tumor contexts. However, its role in APAP-induced liver injury (AILI) remains unclear. Therefore, this study aimed to investigate the involvement of OTUD6A in the pathogenesis of AILI. Our findings demonstrated a substantial upregulation of OTUD6A in both the liver tissue and isolated hepatocytes of mice following APAP stimulation. OTUD6A knockout exacerbated APAP-induced inflammation, hepatocyte necrosis, and liver injury, whereas OTUD6A overexpression alleviated these pathologies. Mechanistically, OTUD6A directly interacted with the enhancer of zeste homolog 2 (EZH2) and selectively removed K48-linked polyubiquitin chains from EZH2, enhancing its stability. This resulted in increased protein levels of EZH2 and H3K27me3, as well as reduced endoplasmic reticulum (ER) stress and cell death in hepatocytes. Collectively, our research uncovers a novel role for OTUD6A in mitigating APAP-induced liver injury by promoting EZH2 stabilization.

Computational approaches, encompassing both physics-based and machine learning (ML) methodologies, have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities. The human dopamine (DA) transporter (hDAT) is the primary therapeutic target of numerous psychiatric medications. However, traditional hDAT-targeting drugs, which interact with the primary binding site, encounter significant limitations, including addictive potential and stimulant effects. In this study, we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape (WHALES) descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs. Initially, WHALES descriptors facilitated a similarity search, employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates. Consequently, from a compound library of 4,921 marketed and clinically tested drugs, we identified 27 candidate atypical inhibitors. Subsequently, ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates, while induced-fit docking (IFD) was performed to estimate their binding affinities. Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities. Among these, three exhibited significant inhibitory potency, with half maximal inhibitory concentration (IC₅₀) values of 0.753 μM, 0.542 μM, and 1.210 μM, respectively. Finally, molecular dynamics (MD) simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation. In conclusion, our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.

Objective : To investigate the effect of long non-coding RNA LUCAT1 (lncRNA LUCAT1) on the biological behavior of MIA PaCa-2 in human pancreatic cancer cells , and to explore the potential role of LUCAT1 in the malignant progression of pancreatic cancer. Methods : The mutation and expression of LUCAT1 in pancreatic cancer were analyzed by GEPIA , the expression levels of LUCAT1 in human pancreatic ductal cells HPNE and hu- man pancreatic cancer cells were detected by q-PCR , and the expression and distribution of LUCAT1 in human pancreatic cancer tissues were detected by FISH . CCK-8 assay and Transwell assay were used to detect the effects of LUCAT1 on the proliferation , apoptosis , drug resistance , and migration of MIA PaCa-2 cells . Gene ensemble enrichment analysis was performed to compare the related signaling pathways involved in LUCAT1 , and Western blot assay was used to verify the protein expression level . Results : The results of GEPIA analysis showed that the expression level of LUCAT1 in human pancreatic cancer tissues was up-regulated , and the expression of LUCAT1 in human pancreatic cancer cells was significantly higher ( P < 0. 05 ) . Knockdown and overexpression of LUCAT1 could affect the proliferation , apoptosis , gemcitabine resistance , migration and invasion of pancreatic cancer cells , and the differences were statistically significant (P < 0. 05) . In addition , LUCAT1 affected p-Akt expression levels in pancreatic cancer and was inhibited after treatment with Akt inhibitor MK-2206 . Conclusion LUCAT1 regulates the malignant progression of MIA PaCa-2 in pancreatic cancer cells through the PI3K-Akt signaling pathway.

Objective To quantitatively analyze the effects of population aging and other risk factors on the burden of colorectal cancer in China from 1990 to 2019. Methods The Global Burden of Disease Study 2019 was used to describe the temporal trend of the burden of colorectal cancer. A decomposition method established by Gupta was applied to quantify the burden related to population growth, aging, age-specific prevalence, and disease severity. Results The age-standardized disability adjusted life years (DALY) rates of colorectal cancer in China showed an overall upward trend from 1990 to 2019. The DALY in 2019 increased by 191.12% compared with that in 1990, with 34.54% of the increase attributed to population growth, 111.36% to population aging, and 77.56% to the rise of age-specific prevalence. Meanwhile, -32.54% benefited from the changes in disease severity. Diet low in milk was the primary risk factor for the disease burden of colorectal cancer in China in 2019, followed by diet low in whole grains and calcium. In the last 30 years, the corresponding risk factor of the most rapid increase in China was high BMI with an average annual percentage of change of 4.14%, and the corresponding risk factor of the most rapid decrease in China was diet low in fiber with an average annual percentage of change of -2.00%. Conclusion Aging population is mainly responsible for the considerable increase in the burden of colorectal cancer in China from 1990 to 2019. The health administrative authorities should take corresponding measures to address the adverse impacts associated with aging.

The incidence of psycho-cardiological diseases， i.e.， cardiovascular diseases combined with psychological disorders， is increasing year by year. Brain-derived neurotrophic factor （BDNF） plays a role in the pathogenesis of such diseases. According to the theory of collateral diseases， our team innovates the concept of regulating mental activity by dredging collaterals in the treatment of psycho-cardiological diseases and summarizes the concepts of "heart of Qi and collaterals" and "heart of vessels and collaterals". We believe that obstructed collaterals and disturbed mental activity run through the whole course of psycho-cardiological diseases， being the core pathogenesis. BDNF closely related to the core pathogenesis can regulate nerve and vascular inflammation， alleviate oxidative stress， and mediate a variety of signaling pathways， thereby promoting the survival and repair of nerve cells and vascular endothelial cells to regulate emotion and protect the heart. Therefore， BDNF is one of the potential biomarkers for clinical treatment of psycho-cardiological diseases. Collateral obstruction caused by blood stasis is specifically manifested as collateral deficiency， blood stasis， and Qi stagnation in collaterals. It can easily lead to inflammation， free radical generation， and antioxidant system changes in the patients with psycho-cardiological diseases， which can cause oxidative stress damage， affect the BDNF level， and result in mental disorders， such as anxiety and depression. Disturbed mental activity is mainly caused by the disturbance in the heart of Qi and collaterals， which is specifically manifested as the disturbance of the mind and liver soul. It is prone to cause anxiety or depression symptoms， which is closely related to the BDNF-mediated abnormal activation of neural circuits， nerve injury， and inflammation. This article elaborates on the theoretical connotation and pathological mechanism of regulating mental activity by dredging collaterals in the treatment of psycho-cardiological diseases from the perspective of BDNF， aiming to provide new ideas for the prevention and treatment of psycho-cardiological diseases and collateral diseases.

Objective: To investigate the relationship between tropomodulin 3(TMOD3) and the malignant biological characteristics of hepatocellular carcinoma, and the predictive potential of TMOD3 as a biomarker for the recurrence and metastasis of hepatocellular carcinoma. Methods: Firstly, the structure of TMOD3 and its subcellular localization in cells and tissues were analyzed using database of Human Protein Atlas. Then explored the differential expression of TMOD3 in hepatocellular carcinoma tissues and normal liver tissues and its impact on clinical pathological characteristics and prognosis using TCGA and GEO datasets. Subsequently, the STRING database was utilized to explore the interacting proteins of TMOD3, followed by enrichment analysis conducted using the Metascape database. Finally, Logistic regression was used to analyze the independent risk factors for metastasis of hepatocellular carcinoma and evaluated the importance of predictive variables using ROC curves and Wald tests. Survival analysis was conducted using the Kaplan-Meier curve and the Log-rank test. Results: TMOD3 was localized to actin filaments in cells, and compared with normal tissues, the expression level of TMOD3 in liver cancer tissues is higher(P<0.05), and high expression of TMOD3 was closely related to lymph node metastasis and distant metastasis of hepatocellular carcinoma patients(P<0.05). Enrichment analysis results revealed that TMOD3 and its interacting proteins mainly function and signaling pathways related to tumor invasion and migration. Logistic regression found that TMOD3 was an independent risk factor for recurrence and metastasis of hepatocellular carcinoma(OR: 4.359, 95%CI: 1.235-15.384,P=0.022). Survival analysis revealed that high expression of TMOD3 was associated with poor OS, DFS, and RFS of hepatocellular carcinoma patients(P<0.05). Both ROC analysis and Wald test indicated that TMOD3 has good predictive characteristics for recurrence and metastasis of hepatocellular carcinoma. Conclusion TMOD3 is closely associated with the invasion and metastasis of hepatocellular carcinoma and is an independent risk factor for the recurrence and metastasis of liver cancer. TMOD3 performs well in predicting the recurrence and metastasis of hepatocellular carcinoma and has the potential to become a biomarker for predicting the recurrence and metastasis of hepatocellular carcinoma.

Purpose To explore the clinical value of quantitative assessment of renal perfusion using ultrasound contrast imaging for the auxiliary diagnosis of type 2 diabetic nephropathy.Materials and Methods This prospective study was conducted from May 2017 to December 2019 at the First Medical Center of Chinese PLA General Hospital.A total of 41 patients with type 2 diabetes and renal function abnormalities,who were scheduled for renal biopsy,underwent contrast-enhanced ultrasound.Differences in contrast imaging parameters,including time to peak in the renal cortex,peak enhancement,mean transit time local,and area under the curve between diabetic nephropathy and focal segmental glomerulosclerosis were compared,and the correlation between imaging parameters and pathological results was analyzed.Results Among 41 patients,30 cases were diagnosed as diabetic nephropathy,and 11 cases were diagnosed as focal segmental glomerulosclerosis.The peak enhancement and area under the curve in the diabetic nephropathy group were significantly lower than those in the focal segmental glomerulosclerosis group[peak enhancement:3 837.16(2 449.16,5 929.16)vs.8 508.00(4 334.88,21 201.00),Z=-2.766,P=0.006;area under the curve:0.14±0.05 vs.0.19±0.05,t=-3.135,P=0.003].In the diabetic nephropathy group,peak enhancement showed a negative correlation with the global glomerulosclerosis rate(r=-0.489,P=0.006).Conclusion Contrast-enhanced ultrasound can quantitatively evaluate renal perfusion and has certain clinical value in assisting the diagnosis of type 2 diabetic nephropathy.

Spontaneous abortion is one of the most common complications of pregnancy， and two or more spontaneous abortions in a row are defined as recurrent spontaneous abortion （RSA）， of which about half of patients have unknown etiology. However， the pathogenesis of unexplained RSA （URSA） has not been elucidated， and the lack of effective treatment has made it one of the key and difficult points in the field of obstetrics and gynecology. This article conducts a literature review of recent research on URSA and finds that the pathogenesis of URSA is related to the imbalance of immune tolerance at the maternal-fetal interface， apoptosis of trophoblast cells， inhibition of angiogenesis， and activation of immune responses. Immunotherapy （including cell therapy， cytokine therapy， and immunosuppressive intervention）， hormone drugs， anticoagulant regimens， and traditional Chinese medicine therapies are commonly used in clinical practice to intervene in URSA， but the safety and effectiveness of some therapies are still controversial.

Objective To determine whether four-and-a-half LIM-only protein 2(FHL2)can affect macrophage foa-ming by regulating nuclear factor kappa-B(NF-κB)signaling pathway.Methods FHL2 over-expression plasmids and siRNA of FHL2 were constructed and transfected into human monocyte/macrophages cell line THP-1.Western blot was used to detect the expression of FHL2.The cells were stimulated with oxidized low density lipoprotein(ox-LDL)and the expression of IL-6,IL-1β,TNF-α and other cytokines were detected by ELISA.Oil red O staining was used to detect the degree of cell foaming.The protein expression of NF-κB signaling pathway was detected by Western blot.Results The expression of FHL2 increased after transfected with FHL2 over-expression plasmids while decreased in si-FLH2 transfected cells.FHL2 down-regulated secretion of inflammatory cytokines.Down-regulation of FHL2 allevi-ated THP-1 macrophage foaming.The down-regulation of FHL2 inhibited activation of NF-κB signaling pathway,while the over-expression FHL2 showed an opposite trend.Conclusions FHL2 down-regulation inhibits the activation of NF-κB signaling pathway,reduces the secretion of inflammatory cytokines and alleviates foaming of macrophages.