OBJECTIVE To investigate the improvement effect and potential mechanism of Qingxue xiaozhi jiangtang formula on insulin resistance （IR） in type 2 diabetes mellitus （T2DM） rats. METHODS T2DM rat model was established by intraperitoneal injection of 30 mg/kg streptozotocin combined with high-fat and high-sugar diet. The rats were randomly divided into normal control group， model group， Qingxue xiaozhi jiangtang formula low-dose and high-dose groups （6.525， 13.05 g/kg， calculated by raw material） and metformin group （positive control， 0.18 g/kg）， with 8 rats in each group. Administration groups were given relevant medicine intragastrically； normal control group and model group were given constant volume of normal saline intragastrically， once a day， for consecutive 6 weeks. Body mass and fasting blood glucose （FBG） were determined， and oral glucose tolerance test was conducted. Serum fasting insulin （FINS） level was measured to calculate the insulin resistance index （HOMA-IR） and insulin sensitivity index （ISI）. Additionally， the level of serum lipids， liver function， oxidative stress indicators and inflammatory factors were assessed. The phosphorylation levels of kinase R-like endoplasmic reticulum kinase （PERK） and forkhead box O1 （FOXO1） protein in liver tissue of rats were determined. RESULTS Compared with model group， the body weight， ISI， the levels of high-density lipoprotein cholesterol and superoxide dismutase were increased significantly in Qingxue xiaozhi jiangtang formula high-dose group and metformin group （P＜0.05）； FBG， blood glucose level at 120 minutes of glucose loading， area under the curve of glucose， FINS， HOMA-IR， low-density lipoprotein cholesterol， total cholesterol， triglyceride， alanine transaminase， aspartate transaminase， alkaline phosphatase， malondialdehyde， interleukin-6， tumor necrosis factor-α， and C-reactive protein levels were significantly reduced （P＜ Δ0.05）； the pathological damage of liver tissue had significantlyimproved， and the phosphorylation levels of PERK and FOXO1 proteins in liver tissue were significantly decreased （P＜0.05）. CONCLUSIONS Qingxue xiaozhi jiangtang formula can regulate glucose and lipid metabolism， inflammation factor and oxidative stress levels， and alleviate insulin resistance in T2DM rats. Its mechanism of action may be related to the inhibition of the PERK/FOXO1 signaling pathway.

BACKGROUND: Coronary atherectomy is used to treat severely calcified coronary artery lesions which are more frequent with increasing age, but its impact in older adults has not been sufficiently examined. METHODS: We compared adults ≥ 18 years old who underwent coronary atherectomy during inpatient PCI in 2016-2023 from the Vizient Clinical Data Base and compared outcomes in younger (< 65 years), youngest-old (65-74 years), middle-old (75-84 years), and oldest-old (≥ 85 years) adults. Primary outcome was in-hospital mortality, and secondary outcomes included postprocedural complications. RESULTS: Among 47,337 patients who underwent coronary atherectomy, 19,862 (42.0%) were younger adults and 27,475 (58.0%) were older adults, including 13,583 youngest-old, 10,206 middle-old, and 3,686 oldest-old adults. Compared with younger adults, youngest-old adults had higher mortality (adjusted odds ratio [aOR] = 1.37, P < 0.001), ischemic stroke (aOR = 1.35, P = 0.005), gastrointestinal hemorrhage (GIH) (aOR = 1.44, P < 0.001), acute kidney injury (AKI) (aOR = 1.43, P < 0.001), tamponade (aOR = 1.86, P < 0.001), and pericardiocentesis (aOR = 2.32, P < 0.001). Middle-old adults had higher mortality (aOR = 1.80, P < 0.001), GIH (aOR = 1.42, P = 0.002), AKI (aOR = 1.63, P < 0.001), tamponade (aOR = 2.52, P < 0.001), and pericardiocentesis (aOR = 3.13, P < 0.001). Oldest-old adults had the highest odds for mortality (aOR = 2.03, P < 0.001), GIH (aOR = 1.48, P = 0.016), AKI (aOR = 2.26, P < 0.001), tamponade (aOR = 3.86, P < 0.001), and pericardiocentesis (aOR = 4.21, P < 0.001). There was a significant interaction (P-interaction=0.035) between atherectomy and age groups with regard to the odds of in-hospital mortality. CONCLUSIONS In this large claims-based study, in-hospital mortality, GIH, AKI, tamponade, and pericardiocentesis were higher in older adults compared with younger adults, in a stepwise manner by age group.

Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets. Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use, fueling the development of CDK-targeted therapies. With this enthusiasm for finding novel CDK-targeting anti-cancer agents, there have also been exciting advances in the field of targeted protein degradation through innovative strategies, such as using proteolysis-targeting chimera, heat shock protein 90 (HSP90)‍-mediated targeting chimera, hydrophobic tag-based protein degradation, and molecular glue. With a focus on the translational potential of cyclin- and CDK-targeting strategies in cancer, this review presents the fundamental roles of cyclins and CDKs in cancer. Furthermore, it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs, detailing the underlying mechanisms of action for each approach. A comprehensive overview of the structure and activity of existing CDK degraders is also provided. By examining the structure‍‒‍activity relationships, target profiles, and biological effects of reported cyclin/CDK degraders, this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
Humans ; Neoplasms/metabolism* ; Cyclin-Dependent Kinases/antagonists & inhibitors* ; Cyclins/metabolism* ; Proteolysis ; Antineoplastic Agents/pharmacology* ; Molecular Targeted Therapy ; Proteasome Endopeptidase Complex/metabolism* ; Animals

Depressive disorder is a chronic, recurring, and potentially life-endangering neuropsychiatric disease. According to a report by the World Health Organization, the global population suffering from depression is experiencing a significant annual increase. Despite its prevalence and considerable impact on people, little is known about its pathogenesis. One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression. Furthermore, the neural circuit mechanism of depression induced by various factors is particularly complex. Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression, a comparison between the neural circuits of depression induced by various factors is essential for its treatment. In this review, we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression, aiming to provide a theoretical basis for depression prevention.
Animals ; Disease Models, Animal ; Depressive Disorder/psychology* ; Humans ; Behavior, Animal/physiology* ; Nerve Net/physiopathology* ; Brain/physiopathology* ; Neural Pathways/physiopathology*

Myocardial infarction is the most common cause of heart failure,and myocardial remodeling can occur after infarction,thus contributing to the progression of heart failure.The occurrence of post-infarction ventricular remode-ling is closely related to m6A methylation.m6A methylation is a reversible and highly dynamic process.This process is mainly mediated by m6A methylation positive and negative regulatory enzymes and is involved in the occurrence of post-in-farction myocardial remodeling through mechanisms such as cellular autophagy.This article mainly reviews relevant litera-ture in recent years.Firstly,a brief introduction is given to m6A methylation,followed by an introduction to the role of m6A methylase in regulating myocardial remodeling.Finally,a summary analysis is conducted on the mechanism of m6A methylation in regulating myocardial remodeling from the perspectives of autophagy,inflammation,cell apoptosis,calcium ion homeostasis,extracellular matrix remodeling,and ferroptosis.The feasibility of using m6A methylation serological de-tection as a diagnostic tool for myocardial remodeling after myocardial infarction is discussed,in order to provide reference for related research.

BACKGROUND: Tracheal, bronchus, and lung cancer (TBL) is a major cause of mortality and top contributor to productivity loss in large emerging economies such as the BRICS (Brazil, Russia, India, China, and South Africa). We examined the time trends of TBL mortality across the BRICS to better understand the disease burden in these countries and inform public health and healthcare resource allocation. METHODS: TBL mortality-related data between 1990 and 2019 were obtained from the Global Burden of Disease Study 2019 and analyzed using age-period-cohort models. Net drift (local drift) was used to describe the expected age-adjusted TBL mortality rate over time overall (each age group); the longitudinal age curve was used to reflect the age effect; the period rate ratios (RRs) were used to reflect the period effect; and the cohort RR was used to reflect the cohort effect. RESULTS: In 2019, there were 958.3 thousand TBL deaths across the BRICS, representing 46.9% of the global TBL deaths. From 1990 to 2019, the age-standardized mortality rate (ASMR) of TBL decreased in Russia, Brazil, and South Africa while increased in China and India, with the largest reduction reported in Russia (-29.6%) and the largest increase in China (+22.4%). India showed an overall increase (+15.7%) in TBL mortality but the mortality risk decreased among individuals born after 1990 (men) and 1995 (women). Although South Africa and Brazil experienced an overall decline in TBL mortality, their recent birth cohorts, such as Brazilian individuals born after 1985 (men) and 1980 (women), and South African men born after 1995, had an increasing TBL mortality risk. China has experienced an overall increase in TBL mortality, with the mortality risk rising among individuals born after 1995 for both men and women. Russia, which had the highest TBL mortality among the BRICS countries in 1990, has demonstrated significant improvement over the past three decades. CONCLUSIONS Over the past 30 years, the BRICS accounted for an increasing proportion of global TBL mortality. TBL mortality increased in older women in all the BRICS countries except Russia. Among the recent birth cohort, the risk of TBL mortality increased in Brazil, China, and South Africa. More effective efforts are needed in the BRICS to reduce the burden of TBL and help achieve the United Nation's Sustainable Development Goals.
Humans ; Lung Neoplasms/mortality* ; Male ; Female ; China/epidemiology* ; Middle Aged ; Global Burden of Disease ; Aged ; India/epidemiology* ; Adult ; South Africa/epidemiology* ; Cohort Studies ; Russia/epidemiology* ; Brazil/epidemiology* ; Tracheal Neoplasms/mortality* ; Bronchial Neoplasms/mortality* ; Adolescent ; Young Adult ; Aged, 80 and over ; Child

Objective:To explore the effective components and potential mechanisms of Xiefei Lishui Prescription in the treatment of heart failure.Methods:Ultra high-performance liquid chromatography tandem four stage rod time of flight mass spectrometry (UPLC-Q-TOF-MS) technology was used to analyze and identify the active components of Xiefei Lishui Prescription. Drug targets were predicted through the Swiss Target Prediction database, and disease targets were collected from Gene Cards, Dis GENET, and TTD databases. The intersection of drug targets and disease targets was screened using a STRING database for protein interaction to identify core targets. The core targets were included in the DAVID database for GO enrichment and KEGG analysis. Finally, molecular docking validation was performed between the drug components and the corresponding core targets.Results:The results identified 10 active components of Xiefei Lishui Prescription, and 8 potential active components were screened using network pharmacology for the treatment of heart failure with Xiefei Lishui Prescription, corresponding to 160 related action targets. A total of 1 305 disease-related targets were collected, and a total of 51 targets ad 17 core targets were included in the string database for protein interaction analysis. GO functional enrichment and KEGG analysis indicated that the mechanism of Xiefei Lishui Prescription in treating heart failure may be related to pathways such as protein binding, ATP binding, and negative regulation of the VEGF signaling pathway and T cell receptor pathway during apoptosis. The molecular docking results showed that baicalin exhibited good binding activity with ESR1, sorghum isoflavones with ESR1, and quercetin with AKT1, EGFR, IL2, and ABCB1.Conclusion:Xiefei Lishui Prescription may exert therapeutic effects on heart failure through multiple pathways by targeting ESR1, AKT1, EGFR, and other targets.

Myocardial fibrosis is characterized by pathological remodeling of extracellular matrix,which is a common pathological change during the development of various cardiovascular diseases.Qi transformation dysfunction in the zang-fu organs,subtle substance accumulation,and endogenous turbid evil production lead to the occurrence of diseases.The theory of turbid blood is widely used to elucidate the pathological changes of diseases and guide the prevention and treatment.Turbid blood,as a special pathogenic factor and pathological product,plays a crucial role in the oxidative stress process of myocardial fibrosis.Qi deficiency of the heart and spleen,stagnation of turbid blood,impaired blood circulation in the heart,and the inability to maintain the oxidative-reductive system balance of myocardial cells are the root causes of disease onset.Accumulation of turbid blood,intermingled phlegm and blood stasis,blockage of heart vessels,and accumulation of metabolic waste products contribute to disease progression.Prolonged turbidity accumulation leads to cardiac enlargement,scattered mental state,and pathological remodeling of the extracellular matrix,indicating a severe disease stage.Early treatment focuses on strengthening the vital qi and spleen,reducing turbidity and recovering clarity.In the middle stage,the key is to resolve phlegm,eliminate stasis,and promote clarity while removing turbidity.In the late stage,detoxification,turbidity elimination,and restoring clarity are emphasized.By adhering to the characteristics of the pathological mechanism and using traditional Chinese medicine intervention,it is possible to suppress oxidative stress,prevent pathological remodeling of the extracellular matrix,and improve myocardial fibrosis.

Background: For anatomic total arthroscopic repair, cementless humeral fixation has recently gained popularity. However, few studies have compared clinical, radiographic, and patient-reported outcomes between cemented and press-fit humeral fixation, and none have performed follow-up for longer than 5 years. In this study, we compared long-term postoperative outcomes in patients receiving a cemented versus press-fit humeral stem anatomic arthroscopic repair. Methods: This study retrospectively analyzed 169 shoulders that required primary anatomic total shoulder arthroplasty (aTSA). Shoulders were stratified by humeral stem fixation technique: cementation or press-fit. Data were collected pre- and postoperatively. Primary outcome measures included range of motion, patient reported outcomes, and radiographic measures. Results: One hundred thirty-eight cemented humeral stems and 31 press-fit stems were included. Significant improvements in range of motion were seen in all aTSA patients with no significant differences between final cemented and press-fit stems (forward elevation: P=0.12, external rotation: P=0.60, and internal rotation: P=0.77). Patient reported outcome metrics also exhibited sustained improvement through final follow-up. However, at final follow-up, the press-fit stem cohort had significantly better overall scores when compared to the cemented cohort (visual analog score: P=0.04, American Shoulder and Elbow Surgeon Score: P<0.01, Simple Shoulder Test score: P=0.03). Humeral radiolucency was noted in two cemented implants and one press-fit implant. No significant differences in implant survival were observed between the two cohorts (P=0.75). Conclusions In this series, we found that irrespective of humeral fixation technique, aTSA significantly improves shoulder function. However, within this cohort, press-fit stems provided significantly better outcomes than cemented stems in terms of patient reported outcome scores.Level of evidence: III.

Methods: Among the patients who underwent TSA, 119 shoulders were retrospectively analyzed. Preoperative and postoperative clinical outcome data were collected. Linear regression analysis (univariate and multivariate) was conducted to evaluate the associations of clinical outcomes with age. Kaplan-Meier curves and Cox regression analyses were performed to evaluate implant survival. Results: At final follow-up, patients of all ages undergoing aTSA experienced significant and sustained improvements in all primary outcome measures compared with preoperative values. Based on multivariate analysis, age at the time of surgery was a significant predictor of postoperative outcomes. Excellent implant survival was observed over the course of this study, and Cox regression survival analysis indicated age and sex to not be associated with an increased risk of implant failure. Conclusions When controlling for sex and follow-up duration, older age was associated with significantly better patient-reported outcome measures. Despite this difference, we noted no significant effects on range of motion or implant survival.Level of evidence: IV.