ObjectiveTo investigate the mechanism of Yangxin Tongmai Formula （养心通脉方， YTF） in trea-ting coronary heart disease with blood stasis syndrome based on DNA methylation. MethodsSeventy-two SD rats were randomly divided into a control group （n=12） and a modeling group （n=60）. The modeling group was subjected to a high-fat diet， intragastric administration of vitamin D3， and subcutaneous injection of isoprenaline to establish the rat model of coronary heart disease with blood stasis syndrome. Forty-one successfully modeled rats were then randomly allocated into model group， YTF low-， medium-， and high-dose groups， and the atorvastatin calcium group， with 8 rats in each group and 1 rat reserved. The YTF low-， medium-， and high-dose groups received YTF at 6， 12， and 18 g/（kg·d） by gavage， respectively. The atorvastatin calcium group received atorvastatin calcium tablets at 1.8 mg/（kg·d） by gavage. The control group and the model group received 0.9% sodium chloride injection at 4 ml/（kg·d） by gavage. All administrations were performed once daily for 3 weeks. Twenty-four hours after the last administration， serum lipid levels including total cholesterol （TC）， triglycerides （TG）， low-density lipoprotein cholesterol （LDL-C）， and high-density lipoprotein cholesterol （HDL-C）， myocardial enzymes including cardiac troponin T （cTnT）， creatine kinase MB （CK-MB）， and lactate dehydrogenase （LDH）， and inflammatory factors including interleukin-1β （IL-1β） and interleukin-10 （IL-10） were detected by ELISA. Pathological changes in myocardial tissue were observed via HE staining. Whole blood DNA methylation sequencing was used to analyze differential methylation gene expression among the control group， model group， and YTF high-dose group. Western Blotting was used to verify the protein levels of the key genes and downstream signaling pathways. ResultsCompared to the control group， the model group showed increased levels of TC， TG， LDL-C， cTnT， CK-MB， LDH， and IL-1β， along with decreased levels of HDL-C and IL-10 （P＜0.05 or P＜0.01）. Compared to the model group， all treatment groups exhibited decreased levels of TC， LDL-C， CK-MB， and LDH， along with increased IL-10 levels. Among these， the high-dose YTF group demonstrated superior efficacy in reducing cTnT levels compared to the other TCM groups （P＜0.05 or P＜0.01）. HE staining indicated that the YTF high-dose group ameliorated myocardial cell swelling， disordered arrangement， pyknosis， and disappearance of nuclei， thereby reducing myocardial cell damage. Whole blood DNA methylation sequencing identified 240 differentially methylated genes shared by the control group， model group， and YTF high-dose group， including 109 hypermethylated and 131 hypomethylated genes； eif2ak3 was identified as a key differentially methylated gene. Compared to the control group， the model group exhibited increased protein levels of eukaryotic translation initiation factor 2 alpha kinase 3 （eIf2ak3）， phosphorylated protein kinase RNA-like endoplasmic reticulum kinase （p-PERK）， activating transcription factor 4 （ATF4）， C/EBP homologous protein （CHOP）， and Bax， along with a decreased level of B-cell lymphoma-2 （Bcl-2） protein （P＜0.05 or P＜0.01）. Compared to the model group， the YTF high-dose group showed decreased protein levels of eIf2ak3， p-PERK， ATF4， CHOP， and Bax， and an increased level of Bcl-2 protein （P＜0.05 or P＜0.01）. ConclusionYTF may regulate key differentially methylated genes such as eIf2ak3 and the PERK/ATF4/CHOP signaling pathway， thereby inhibiting endoplasmic reticulum stress， reducing myocardial cell apoptosis， and exerting therapeutic effects in coronary heart disease blood stasis syndrome.

Fibrosis, the pathological scarring of vital organs, is a severe and often irreversible condition that leads to progressive organ dysfunction. It is particularly pronounced in organs like the liver, kidneys, lungs, and heart. Despite its clinical significance, the full understanding of its etiology and complex pathogenesis remains incomplete, posing substantial challenges to diagnosing, treating, and preventing the progression of fibrosis. Among the various molecular players involved, platelet-derived growth factor-C (PDGF-C) has emerged as a crucial factor in fibrotic diseases, contributing to the pathological transformation of tissues in several key organs. PDGF-C is a member of the PDGFs family of growth factors and is synthesized and secreted by various cell types, including fibroblasts, smooth muscle cells, and endothelial cells. It acts through both autocrine and paracrine mechanisms, exerting its biological effects by binding to and activating the PDGF receptors (PDGFRs), specifically PDGFRα and PDGFRβ. This binding triggers multiple intracellular signaling pathways, such as JAK/STAT, PI3K/AKT and Ras-MAPK pathways. which are integral to the regulation of cell proliferation, survival, migration, and fibrosis. Notably, PDGF-C has been shown to promote the proliferation and migration of fibroblasts, key effector cells in the fibrotic process, thus accelerating the accumulation of extracellular matrix components and the formation of fibrotic tissue. Numerous studies have documented an upregulation of PDGF-C expression in various fibrotic diseases, suggesting its significant role in the initiation and progression of fibrosis. For instance, in liver fibrosis, PDGF-C stimulates hepatic stellate cell activation, contributing to the excessive deposition of collagen and other extracellular matrix proteins. Similarly, in pulmonary fibrosis, PDGF-C enhances the migration of fibroblasts into the damaged areas of lungs, thereby worsening the pathological process. Such findings highlight the pivotal role of PDGF-C in fibrotic diseases and underscore its potential as a therapeutic target for these conditions. Given its central role in the pathogenesis of fibrosis, PDGF-C has become an attractive target for therapeutic intervention. Several studies have focused on developing inhibitors that block the PDGF-C/PDGFR signaling pathway. These inhibitors aim to reduce fibroblast activation, prevent the excessive accumulation of extracellular matrix components, and halt the progression of fibrosis. Preclinical studies have demonstrated the efficacy of such inhibitors in animal models of liver, kidney, and lung fibrosis, with promising results in reducing fibrotic lesions and improving organ function. Furthermore, several clinical inhibitors, such as Olaratumab and Seralutinib, are ongoing to assess the safety and efficacy of these inhibitors in human patients, offering hope for novel therapeutic options in the treatment of fibrotic diseases. In conclusion, PDGF-C plays a critical role in the development and progression of fibrosis in vital organs. Its ability to regulate fibroblast activity and influence key signaling pathways makes it a promising target for therapeutic strategies aiming at combating fibrosis. Ongoing research into the regulation of PDGF-C expression and the development of PDGF-C/PDGFR inhibitors holds the potential to offer new insights and approaches for the diagnosis, treatment, and prevention of fibrotic diseases. Ultimately, these efforts may lead to the development of more effective and targeted therapies that can mitigate the impact of fibrosis and improve patient outcomes.

Guided by the theory of turbid pathogen disturbing clarity， this paper holds that the pathogenesis of otolith disorders involves the failure of clear yang to ascend and the internal generation of phlegm-turbidity as the initiating factors. The clinical manifestations are characterized by the intermingling of phlegm and fluid， as well as the disturbance between turbid and clear substances， while the root lies in spleen-kidney deficiency and depletion of primordial qi. Treatment strategies are formulated according to the different stages of the disease： in the acute phase， therapy focuses on warming and resolving phlegm-fluid retention， using a modified combination of Linggui Zhugan Decoction （苓桂术甘汤） and Zexie Decoction （泽泻汤）； in the residual phase， the approach shifts to tonifying qi and uplifting clear yang， with a modified combination of Shengxian Decoction （升陷汤） and Shengmai Power （生脉散）； in the consolidation phase， therapy aims to tonify the kidney and replenish essence， employing a modified version of Qiju Dihuang Pill （杞菊地黄丸）.

BACKGROUND: While emotional distress, encompassing anxiety and depression, has been associated with negative clinical outcomes, its impact across various clinical departments and general hospitals has been less explored. Previous studies with limited sample sizes have examined the effectiveness of specific treatments (e.g., antidepressants) rather than a systemic management strategy for outcome improvement in non-psychiatric inpatients. To enhance the understanding of the importance of addressing mental health care needs among non-psychiatric patients in general hospitals, this study retrospectively investigated the impacts of emotional distress and the effects of early detection and management of depression and anxiety on hospital length of stay (LOS) and rate of long LOS (LLOS, i.e., LOS >30 days) in a large sample of non-psychiatric inpatients. METHODS: This retrospective cohort study included 487,871 inpatients from 20 non-psychiatric departments of a general hospital. They were divided, according to whether they underwent a novel strategy to manage emotional distress which deployed the Huaxi Emotional Distress Index (HEI) for brief screening with grading psychological services (BS-GPS), into BS-GPS ( n = 178,883) and non-BS-GPS ( n = 308,988) cohorts. The LOS and rate of LLOS between the BS-GPS and non-BS-GPS cohorts and between subcohorts with and without clinically significant anxiety and/or depression (CSAD, i.e., HEI score ≥11 on admission to the hospital) in the BS-GPS cohort were compared using univariable analyses, multilevel analyses, and/or propensity score-matched analyses, respectively. RESULTS: The detection rate of CSAD in the BS-GPS cohort varied from 2.64% (95% confidence interval [CI]: 2.49%-2.81%) to 20.50% (95% CI: 19.43%-21.62%) across the 20 departments, with a average rate of 5.36%. Significant differences were observed in both the LOS and LLOS rates between the subcohorts with CSAD (12.7 days, 535/9590) and without CSAD (9.5 days, 3800/169,293) and between the BS-GPS (9.6 days, 4335/178,883) and non-BS-GPS (10.8 days, 11,483/308,988) cohorts. These differences remained significant after controlling for confounders using propensity score-matched comparisons. A multilevel analysis indicated that BS-GPS was negatively associated with both LOS and LLOS after controlling for sociodemographics and the departments of patient discharge and remained negatively associated with LLOS after controlling additionally for the year of patient discharge. CONCLUSION Emotional distress significantly prolonged the LOS and increased the LLOS of non-psychiatric inpatients across most departments and general hospitals. These impacts were moderated by the implementation of BS-GPS. Thus, BS-GPS has the potential as an effective, resource-saving strategy for enhancing mental health care and optimizing medical resources in general hospitals.
Humans ; Retrospective Studies ; Male ; Length of Stay/statistics & numerical data* ; Female ; Middle Aged ; Adult ; Psychological Distress ; Inpatients/psychology* ; Aged ; Anxiety/diagnosis* ; Depression/diagnosis*

This study aims to investigate the antipyretic effects and mechanisms of ethanol extracts from Arisaematis Rhizoma fermented with bile from different sources on a rat model of fever induced by a dry-yeast suspension. The rat model of fever was established by subcutaneous injection of 20% dry-yeast suspension into the rat back. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6) in the serum, as well as prostaglandin E_2(PGE_2) and cyclic adenosine monophosphate(cAMP) in the hypothalamus, were determined by ELISA. Metabolomics analysis was then performed on serum and hypothalamus samples based on UPLC-Q-TOF MS to explore the potential biomarkers and metabolic pathways. The results showed that the body temperatures of rats significantly rose 4 h after modeling. After oral administration of high-dose ethanol extracts of Arisaematis Rhizoma fermented with bovine bile(NCH) and porcine bile(ZCH), the body temperatures of rats declined(P<0.05), and the NCH group showed better antipyretic effect than the ZCH group. Additionally, compared with the model group, the NCH and ZCH groups showed lowered levels of IL-1β, IL-6, TNF-α, PGE_2, and cAMP(P<0.01). The results of serum and hypothalamus metabolomics analysis indicated that both NCH and ZCH exerted antipyretic effects by regulating phenylalanine metabolism, sphingolipid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis. Collectively, both NCH and ZCH can play an obvious antipyretic role in the rat model of dry yeast-induced fever, and the underlying mechanism might be closely associated with inhibiting inflammation and regulating metabolic disorders. Moreover, NCH demonstrates better antipyretic effect.
Animals ; Rats ; Male ; Fermentation ; Rats, Sprague-Dawley ; Rhizome/metabolism* ; Drugs, Chinese Herbal/chemistry* ; Bile/chemistry* ; Antipyretics/chemistry* ; Fever/metabolism* ; Cattle ; Swine ; Tumor Necrosis Factor-alpha/metabolism* ; Ethanol/chemistry* ; Interleukin-6/blood* ; Interleukin-1beta/blood*

Based on the high-fat diet-induced hyperlipidemia rat model, this study aimed to evaluate the lipid-lowering effect of Arisaema Cum Bile and explore its mechanisms, providing experimental evidence for its clinical application. Biochemical analysis was used to detect serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein cholesterol(LDL-C), triglycerides(TG), and total cholesterol(TC) to assess the lipid-lowering activity of Arisaema Cum Bile. Additionally, 16S rDNA sequencing and metabolomics techniques were employed to jointly elucidate the lipid-lowering mechanisms of Arisaema Cum Bile. The experimental results showed that high-dose Arisaema Cum Bile(PBA-H) significantly reduced serum ALT, AST, LDL-C, TG, and TC levels(P<0.01), and significantly increased HDL-C levels(P<0.01). The effect was similar to that of fenofibrate, with no significant difference. Furthermore, Arisaema Cum Bile significantly alleviated hepatocyte ballooning and mitigated fatty degeneration in liver tissues. As indicated by 16S rDNA sequencing results, PBA-H significantly enhanced both alpha and beta diversity of the gut microbiota in the model rats, notably increasing the relative abundance of Akkermansia and Subdoligranulum species(P<0.01). Liver metabolomics analysis revealed that PBA-H primarily regulated pathways involved in arachidonic acid metabolism, vitamin B_6 metabolism, and steroid biosynthesis. In summary, Arisaema Cum Bile significantly improved abnormal blood lipid levels and liver pathology induced by a high-fat diet, regulated hepatic metabolic disorders, and improved the abundance and structural composition of gut microbiota, thereby exerting its lipid-lowering effect. The findings of this study provide experimental evidence for the clinical application of Arisaema Cum Bile and the treatment of hyperlipidemia.
Animals ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Metabolomics ; Hyperlipidemias/microbiology* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Hypolipidemic Agents/pharmacology* ; Liver/metabolism* ; Humans ; Alanine Transaminase/metabolism* ; Triglycerides/metabolism* ; Aspartate Aminotransferases/metabolism*

OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

Objective To evaluate the relationship between anxiety levels and clinicopathological characteristics in patients with papillary thyroid carcinoma (PTC). Methods Among the patients who underwent surgical treatment in our center from July 2022 to September 2023, 304 patients completed the Hamilton anxiety rating scale (HAM-A) questionnaire. The clinical and pathological characteristics of these patients and their association with anxiety levels were investigated. Results Among the 304 patients, 271 were pathologically confirmed to have PTC. Of the 271 patients, 75 had higher levels of anxiety (according to HAM-A scoring system, a score ≥14 indicates clinically significant anxiety) and were assigned to the anxiety group. Univariate statistical analysis showed that the proportion of patients with elevated thyroid peroxidase antibody (TPOAb) in the anxiety group was higher than that in the non-anxiety group (34.7% vs. 16.8%, P=0.002 4). Moreover, the proportion of patients with multifocal tumors in the anxiety group was also higher than that in the non-anxiety group (33.3% vs. 16.7%, P=0.004 4). Multivariate Logistic regression confirmed that anxiety levels were associated with elevated TPOAb (P=0.005 6) and tumor multifocality (P=0.001 9). Conclusions Anxiety levels may be related to elevated TPOAb and tumor multifocality in PTC patients.

Objective:To investigate the effect of Xuebijing injection against blood-brain barrier(BBB)damage in the mice with anti-N-methyl-D-aspartate receptor(NMDAR)encephalitis,and to elucidate its regulatory effect on the imbalance of helper T cells 17(Th17)/regulatory T cells(Treg).Methods:The active immunization models of anti-NMDAR encephalitis in the mice were established using glutamate receptor N1 subunit(GluN1)356-385 antigen peptide,and the serum anti-NMDAR immunoglobulin G(IgG)antibody levels were detected by enzyme-linked immunosorbent assay(ELISA).The healthy mice without modeling were served as control group,and the mice with successful modeling were randomly divided into model group,low dose of Xuebijing injection(XBJ-L)group,and high dose of Xuebijing injection(XBJ-H)group,with 10 mice in each group.After modeling,the mice in XBJ-L and XBJ-H groups were intraperitoneally injected with 5 and 10 mL·kg-1 Xuebijing injection,respectively.The Longa score was used to assess the neurological impairment of the mice in various groups;evans blue(EB)staining was used to determine the BBB permeability;immunofluorescence staining was used to detect the expressions of zonula occludens 1(ZO-1)and Occludin in cerebral cortex of the mice in various groups;Western blotting method was used to determine the expression levels of ZO-1,Occludin,Claudin-5,and neuron-specific nuclear protein(NeuN)in cerebral cortex of the mice in various groups;ELISA method was used to determine the levels of Th17-and Treg-related cytokines including interleukin(IL)-17,IL-22,and IL-10 in serum of the mice;flow cytometry was used to determine the percentages of Th17 and Treg cells in peripheral blood of the mice in various groups,and the Th17/Treg ratio was calculated.Results:The serum of the mice induced with the GluN1 356-385 antigen peptide was positive for NMDAR IgG antibodies,indicating that the models were successfully established.Compared with control group,the neurological impairment score of the mice in model group was significantly increased(P＜0.05),and the EB level in brain tissue was significantly increased(P＜0.05);the fluorescence staining intensities of ZO-1 and Occludin in the cerebral cortex were decreased,and the expression levels of ZO-1,Occludin,Claudin-5,and NeuN proteins in the cerebral cortex were significantly decreased(P＜0.05);the serum levels of IL-17 and IL-22 were significantly increased(P＜0.05),while the IL-10 level was significantly decreased(P＜0.05);the percentage of Th17 cells in peripheral blood was significantly increased(P＜0.05),while the percentage of Treg cells was significantly decreased(P＜0.05),and the Th17/Treg ratio was significantly increased(P＜0.05).Compared with model group,the neurological impairment scores of the mice in XBJ-L and XBJ-H groups were significantly decreased(P＜0.05),the EB levels in brain tissue were significantly decreased(P＜0.05),the fluorescence staining intensities of ZO-1 and Occludin in cerebral cortex were increased,and the expression levels of ZO-1,Occludin,Claudin-5,and NeuN proteins were significantly increased(P＜0.05);the levels of IL-17 and IL-22 in serum were significantly decreased(P＜0.05),and the level of IL-10 was significantly increased(P＜0.05);the percentages of Th17 cells in peripheral blood were significantly decreased(P＜0.05),the percentages of Treg cells were significantly increased(P＜0.05),and the Th17/Treg ratios were significantly decreased(P＜0.05).Compared with XBJ-L group,the neurological function injury score of the mice in XBJ-H group was significantly decreased(P＜0.05),the EB level in brain tissue was significantly decreased(P＜0.05);the fluorescence staining intensities of ZO-1 and Occludin in the cerebral cortex were increased,and the expression levels of ZO-1,Occludin,Claudin-5,and NeuN proteins were significantly increased(P＜0.05);the serum levels of IL-17 and IL-22 were significantly decreased(P＜0.05),and the level of IL-10 was significantly increased(P＜0.05);the percentage of Th17 cells in peripheral blood was significantly decreased(P＜0.05),the percentage of Treg cells was significantly increased(P＜0.05),and the Th17/Treg ratio was significantly decreased(P＜0.05).Conclusion:Xuebijing injection can improve BBB injury,regulate Th17/Treg balance,and thereby alleviate the neurological functional damage in anti-NMDAR encephalitis.