ObjectiveBased on 16S rDNA technology and molecular biology methods， the molecular mechanism of Shenling Baizhusan in the treatment of diarrhea-predominant irritable bowel syndrome （IBS-D） was investigated. MethodsThe 42 SD rats with SPF were randomly divided into no control group， SLBZS-H， medium （SLBZS-M）， low （SLBZS-L） dose group， positive control group and model group， with 7 rats in each group. The rat model of IBS-D was prepared by ice-cold senna （0.45 g∙mL^-1） gavage （10 mL∙kg^-1） combined with restraint stress for 14 consecutive days. After successful modeling， the corresponding drugs were given to each group with a gavage volume of 10 mL∙kg^-1： The positive group was administered with 2.36 ， 1.18， 0.59 g∙mL^-1 of Shenling Baizhusan in the Positive group and the Model group with the same volume of normal saline for 14 d. The general condition of the rats： Weight， feces， mental state and death were observed and recorded. The body weight， abdominal wall retraction reflex score （AWR） and loose stool rate of rats in each group were measured before （the first day）， after the model （day 14） and after treatment （day 28）. Hematoxylin-eosin staining was used to observe the morphological characteristics of colon tissues of experimental animals. Enzyme-linked immunosorbent assay was used to quantitatively analyze the concentration of inflammatory mediators in the peripheral blood of experimental animals. Western blotting was used to detect the expression levels of key proteins of Toll-like receptor 4 （TLR4）， Toll-like receptor 2 （TLR2）， myeloid differentiation factor 88 （MyD88） and nuclear factor-κB （NF-κB） signaling pathway in rat colon tissue. 16S rDNA technology was used to detect the structural changes of intestinal microbiota in rats. ResultsCompared with Control， the colon of the Model group showed partial mucosal epithelial shedding and inflammatory cell infiltration. The contents of TNF-α， IL-1β， IL-6 and 5-HT in serum increased （P<0.05）， the protein expressions of TLR2， TLR4， MyD88 and NF-κB in colon tissue increased （P<0.05）， the diversity indices of Richness， Chao1， abundance-based coverage estimator（ACE） and Shannon decreased （P<0.05）， and the phylum Firmicutes， Actinobacteria， The relative richness of Bacteroides-H， Lactobacillus and Ligilactobacillus decreased （P<0.05）， while the relative richness of Bacteroidetes， Proteobacteria and Prevotella increased （P<0.05）. Compared with the model group， the colonic structure and organization of the SLBZS-H group， SLBZS-M group， SLBZS-L group and Positive group were clearer， and only a small number of inflammatory cells were present in some areas， and the serum contents of TNF-α， IL-1β， IL-6 and 5-HT were decreased （P<0.05）， TLR2， TLR4， The protein expressions of MyD88 and NF-κB decreased （P<0.05）， and compared with the model group， the diversity indices of Richness， Chao1， ACE and Shannon in the SLBZS-H， SLBZS-M and SLBZS-L groups increased （P<0.05）， and the richness of Firmicutes and Actinobacteria increased （P<0.05）. The richness of Proteobacteria and Prevotella decreased （P<0.05）， and the abundance of Prevotella decreased （P<0.05）， Bacteroides-H， Muribaculum， Lactobacillus and salivarius in the Positive group salivarius （P<0.05）. ConclusionShenling Baizhusan can effectively treat IBS-D， and its molecular mechanism may be to play a therapeutic role by improving intestinal flora and inhibiting the TLRS/MyD88/NF-κB signaling pathway to reduce inflammatory response.

ObjectiveTo investigate the therapeutic effect of Siegesbeckiae Herba water decoction （SWD） at different doses on atherosclerosis （AS） in a mouse model induced by a high-fat diet and analyze its potential mechanism of action. MethodsThirty-six male ApoE^-/- mice were randomly divided into six groups： blank control group， model group， low-dose， medium-dose， and high-dose SWD groups， and positive control group. Firstly， the AS mouse model was created by feeding mice a high-fat diet. After successful modeling， the low-， medium-， and high-dose SWD groups were intragastrically administered with SWD at 0.65， 1.3， 2.6 g·kg^-1， respectively. The positive control group was intragastrically administered with 30 mg·kg^-1 of atorvastatin calcium aqueous solution， while the blank and model groups received an equal volume of 0.9% sodium chloride solution via oral gavage， all administered for 12 weeks. During the administration period， the general condition of the mice was observed and recorded daily. Before sampling， color Doppler ultrasound was performed to observe the pathological changes in atherosclerotic plaques in the aortic wall of mice. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in aortic tissue in mice， and oil red O staining was used to detect the atherosclerotic plaque area in the aorta. Enzyme-linked immunosorbent assay （ELISA） was used to detect the serum lipid indices and the levels of interleukins （IL-1β， IL-4， IL-6， and IL-10） and tumor necrosis factor-α （TNF-α） in mice. Protein expression levels of IKKα， IKKβ， and NF-κB p65 in mouse aortic tissue were detected by Western blot. ResultsCompared with the blank control group， the model group showed a significant increase in body weight. The results of color Doppler ultrasound showed enhanced vascular wall echo， suggesting the presence of atherosclerotic plaques. HE staining showed foam cell aggregation， fibrous connective tissue proliferation， and vascular intima injury in the aortic tissue. Oil red O staining showed a significant increase in the plaque area in the aortic tissue （P<0.01）. ELISA results indicated significantly elevated levels of IL-1β， IL-6， TNF-α， total cholesterol （TC）， triglyceride （TG）， and low-density lipoprotein （LDL） in mouse serum （P<0.01）， as well as significantly decreased levels of IL-4， IL-10， and high-density lipoprotein （HDL） （P<0.01）. Western blot results showed that the expression of IKKα， IKKβ， and NF-κB p65 in mouse aortic tissue increased significantly （P<0.01）. Compared with those in the model group， mice in the middle- and high-dose SWD groups showed significant weight loss. In the high-dose group， the aortic vascular wall echoes were weakened， and the atherosclerotic plaques were reduced. The aortic lesions of mice in the medium- and high-dose SWD groups were significantly alleviated. The plaque area percentage showed an inverse correlation with the administered dose in all groups treated with SWD （P<0.05）. In the medium-dose SWD group， serum levels of IL-1β， IL-6， TNF-α， TC， TG， and LDL were significantly decreased （P<0.05， P<0.01）， while those of IL-4 and IL-10 were significantly increased （P<0.01）. In the high-dose SWD group， levels of IL-1β， IL-6， TNF-α， TC， TG， and LDL were significantly decreased （P<0.01）， while IL-4， IL-10， and HDL were significantly increased （P<0.01）. The IKKα and IKKβ expression was significantly decreased in the low-dose SWD group （P<0.05）， and IKKα， IKKβ， and NF-κB p65 were significantly decreased in the medium- and high-dose SWD groups （P<0.05， P<0.01）. ConclusionSWD may exert therapeutic effects on AS by regulating the expression of related inflammatory factors through the NF-κB signaling pathway， thereby reducing inflammation， plaque area， and lipid content in the body.

ObjectiveTo study the mechanism by which Shexiang Tongxin dropping pills （STDP） ameliorate the dysfunction of coronary microvascular endothelial cells in the rat model of heart failure. MethodsThe heart failure model was established by ligation of the left anterior descending coronary artery in rats， which were then allocated into sham， model， STDP， and telmisartan （TLM） groups and treated for 21 days. The heart function was detected by echocardiography， and the levels of myocardial injury markers， nitric oxide （NO）， endothelin-1 （ET1）， and angiotensinⅡ （AngⅡ） were determined by enzyme-linked immunosorbent assay （ELISA）. The protein levels of endothelial nitric oxide synthase （eNOS） and inducible nitric oxide synthase （iNOS） were determined by Western blot. The model of cardiac microvascular endothelial cell injury was established by AngⅡ induction and then treated with the STDP-containing serum （5%， 10%， and 20%） for 24 h. The levels of NO and ET1 were measured by ELISA. Western blot was employed to determine the protein levels of eNOS， iNOS， angiotensin-converting enzyme 2 （ACE2）， and angiotensinⅡ receptor 2 （AT2）. MLN-4760， an ACE2 inhibitor， was used to explore the mechanism underpinning the regulatory effect of STDP on the ACE2-AT2/MAS pathway. ResultsCompared with the sham group， the model group showed decreases in left ventricular ejection fraction （LVEF） and left ventricular fractional shortening （LVFS） （P<0.05）， a decline in serum NO level， elevations in serum AngⅡ and ET1 levels， a reduction in p-eNOS/eNOS ratio， and up-regulation in iNOS expression （P<0.05）. Compared with the model group， STDP increased LVEF， LVFS， and cardiac output （P<0.05）， raised the level of NO and lowered the levels of AngⅡ and ET1 in the serum （P<0.05）， increased the p-eNOS/eNOS value， and inhibited iNOS expression （P<0.05）. Compared with the AngⅡ group， STDP increased the NO content and decreased the ET1 content in endothelial cells （P<0.05）， increased the p-eNOS/eNOS ratio， and inhibited the iNOS expression （P<0.05）. The ACE2 inhibitor MLN-4760 reversed the regulatory effects of STDP on p-eNOS， eNOS， and iNOS. ConclusionSTDP improves the cardiac function in the rat model of heart failure， enhances the synthesis and release of NO in cardiac microvascular endothelial cells， reduces AngⅡ and ET1 levels， and regulates the expression of p-eNOS and eNOS， thereby ameliorating the dysfunction of microvascular endothelial cells in heart failure. This mechanism is related to the upregulation of the expression of proteins in the ACE2-AT2/MAS pathway.

Objective: To evaluates the association between maternal overweight/obesity during pregnancy and offspring risk of metabolic dysfunction associated steatotic liver disease (MASLD), providing theoretical evidence for early life MASLD prevention. Methods: An online search was conducted across ten databases (CNKI, Wanfang, SinoMed, PubMed, Embase, Web of Science, Cochrane Library, PROSPERO, PQDT Global, ScienceDirect) for research literature on the association between maternal overweight/obesity during pregnancy and the development of MASLD in offspring, with the search period spanning from January 2014 to December 2024. Two researchers independently screened literature, extracted data, and assessed study quality. Statistical analysis was performed using R 4.3.3. Results: Ten studies involving 10 229 participants were included, comprising 4 cohort studies and 6 case control studies. Cohort studies showed that maternal overweight and obesity significantly increased offspring MASLD risk ( RR=1.59, 95%CI=1.06-2.39, P <0.05), with moderate heterogeneity ( I 2=56.9%, P =0.07). Case control studies indicated a positive association between maternal overweight/obesity during pregnancy and offspring risk of MASLD( OR=2.00, 95%CI=1.68-2.39, P < 0.05), with low heterogeneity ( I 2=48.8%, P =0.08). Conclusions Maternal overweight/obesity during pregnancy positively correlates with offspring MASLD risk. Gestational weight management may reduce the risk.

Objective To evaluate the prevention and control effectiveness of four major chronic diseases in Youyang County, and find the weak link of prevention and control, and to provide theoretical support for improving prevention and control strategies. Methods Based on the death data of permanent residents from 2012 to 2020 extracted from the cause-of-death registration and reporting system of Youyang County, a statistical analysis was conducted using SPSS19.0. The annual percentage change (APC) was tested by t-test. Results From 2012 to 2020, the mortality rate of and the standardized mortality rate of the four major chronic diseases and the premature mortality rate of diabetes in males showed an increasing trend (APC was 3.05%, 1.82% and 27.12%, respectively, P < 0.05). The mortality rate of the four chronic diseases in females increased (APC was 2.53%, P < 0.05), while the proportion of premature death of the four chronic diseases and the probability of premature death of cardiovascular and cerebrovascular diseases in females decreased (APC was -2.37%, -5.73%, P < 0.05). The standardized mortality rate and premature death rate of the four major chronic diseases were higher in males than those in females. The mortality rate of the four major chronic diseases and the premature death rate of diabetes in the whole population were on the rise (APC was 2.84% and 12.86%, P < 0.05). It was expected that the early death probability of the four major chronic diseases in Youyang County would be 12.65% in 2030, higher than the target value of 12.59% of ^“Healthy China 2030^”. Conclusion The future focus of Youyang County is to prevent and control malignant tumors and diabetes, especially to strengthen the prevention and control of male diabetes.

Thymocyte selection-associated high mobility group box (TOX), a member of the high mobility group protein super-family, plays an important role in T cell development, functional maintenance, and exhaustion. It has been recently found that TOX exerts critical immunoregulatory functions during pathogen infections, and TOX expression is strongly associated with the intensity and tolerance of host immune responses. This review systematically summarizes the structural and functional features of TOX and focuses on its expression dynamics, mechanisms of action, and immunomodulatory effects during viral, bacterial, and parasitic infections, which provides a theoretical support to better understanding of the role of TOX in infectious diseases and provides new insights into development of potential immunotherapeutic strategies targeting TOX.

BACKGROUND: Skin cancer is a common skin disease whose incidence and mortality rates have been showing yearly increases. In this report, we update the most recent data on skin cancer as obtained from GLOBOCAN 2022. METHODS: The incidence and mortality rates of skin cancer (melanoma of skin and non-melanoma skin cancer) in GLOBOCAN 2022 were reviewed. These data were analyzed and the characteristics of incidence and mortality across five continents and top five countries and regions in each continent are presented. In addition, correlations between Human Development Index (HDI) and age-standardized incidence and mortality rates of these two skin cancers are described. RESULTS: The GLOBOCAN 2022 data indicated that melanoma was the 17th most common cancer. An estimated 331,722 people were diagnosed with melanoma globally and approximately 58,667 died from this disease. For non-melanoma skin cancer, it ranks as the 5th most common cancer, and an estimated 1,234,533 people were diagnosed with non-melanoma skin cancer globally and approximately 69,416 died from this disease. The incidence of skin cancer varies across geographic regions and countries, with a predominance observed in Oceania, North America, and Europe. Australia was ranked first in terms of incidence, while incidence rates in Africa and Asia were very low. Despite these regional differences in incidence, there was little geographic variation in mortality rates. Currently, the number of deaths from non-melanoma skin cancer exceeds that of melanoma of skin. HDI was positively associated with the incidence of both types of skin cancers, with a positive correlation obtained between HDI and mortality from melanoma of skin and a negative correlation between HDI and mortality from non-melanoma skin cancer. CONCLUSIONS Skin cancer remains a major disease burden worldwide. Substantial variations are observed across countries and regions. Further research on skin cancer will be required to provide a rationale for more effective preventions and treatments of this condition.
Humans ; Skin Neoplasms/mortality* ; Incidence ; Melanoma/mortality* ; Prevalence ; Global Health ; Male ; Female

At present, there is no effective drug treatment for obstructive sleep apnea hypopnea syndrome (OSAHS). It is usually treated by mechanical ventilation through a ventilator. In this paper, a non-invasive bi-level breathing therapy system suitable for home scenarios is developed. The system supports single-level and bi-level positive airway pressure therapies, and introduces the function of inspiratory synchronous trigger based on flow monitoring to enhance the synchrony of patient-ventilator synchronization. The test results show that the performance indicators of the system meet expectations. Each ventilation mode can operate normally and can meet the requirements for the use of home non-invasive ventilators.
Humans ; Sleep Apnea, Obstructive/therapy* ; Equipment Design ; Noninvasive Ventilation/instrumentation* ; Respiration, Artificial

Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.