Background/Aims: The pathophysiology of refractory gastroesophageal reflux disease (RGERD), which differs from proton pump inhibitor dependent gastroesophageal reflux disease (DGERD), remains incompletely elucidated. This study aims to compare esophageal motility patterns, transdiaphragmatic pressure gradients (TPG), and reflux profiles between RGERD and DGERD patients, and to delineate dynamic pressure gradient-esophagogastric junction (EGJ) interactions in these patients. Methods: In this retrospective study, 274 patients who underwent 24-hour impedance-pH monitoring and high-resolution manometry, along with an assessment of proton pump inhibitor responsiveness, were classified as RGERD (32.5%), DGERD (54.4%), or non-GERD (13.1%). Clinical characteristics, TPG, esophageal motility, and reflux metrics were compared between RGERD and DGERD patients. Subgroup analysis excluding hiatal hernia (HH) was conducted to investigate the pathophysiology of RGERD. Results: The RGERD group exhibited a significantly higher proportion of chest pain compared to the DGERD group. Regarding reflux profiles, RGERD patients without HH (RGERDHH- group) experienced increased weakly acidic reflux (P < 0.001) and prolonged bolus exposure (P = 0.006) compared to their counterparts (DGERDHH- group). Mechanistically, the RGERDHH- group showed reduced lower esophageal sphincter basal pressure (P = 0.010) and EGJ contractile integral (P = 0.005). Notably, following a wet-swallow, the RGERDHH- group experienced the significant elevation in gastric pressure and TPG. Correlation analyses revealed weakly acidic reflux and bolus exposure were positively correlated with gastric pressure variation, and inversely correlated with lower esophageal sphincter basal pressure. Conclusions Transient gastric pressure elevation and compromised EGJ barrier function drive weakly acidic reflux and esophageal bolus exposure. This pressure gradient-barrier mismatch underpins the refractoriness of RGERD.

ObjectiveTo investigate the protective effect of Qiju Dihuang Wan on diabetic retinopathy （DR） and its regulatory mechanism on the NOD-like receptor protein 3/Cysteinyl aspartate-specific proteinase-1/Gasdermin D （NLRP3/Caspase-1/GSDMD） signaling pathway. MethodsHuman retinal microvascular endothelial cells （HRMEC） were divided into the blank group， model group， and Qiju Dihuang Wan low- and high-dose groups. Except for the blank group， all groups were induced with 40 mmol·L^-1 high glucose， and the treatment groups were supplemented with 6% and 12% Qiju Dihuang Wan-containing serum， respectively， based on the induction. After 24 h of culture， the levels of interleukin （IL）-1β and IL-18 were measured by enzyme-linked immunosorbent assay （ELISA）， pyroptosis-related protein expression was detected by immunofluorescence and Western blot， and the mRNA levels of NLRP3/Caspase-1/GSDMD signaling pathway-related molecules were determined by real-time polymerase chain reaction （Real-time PCR）. The mice were randomly divided into the blank group， model group， Qiju Dihuang Wan low-， medium-， and high-dose groups （11， 22， 44 g·kg^-1·d^-1）， and calcium dobesilate group （0.13 g·kg^-1·d^-1）. Except for the blank group， all groups were intraperitoneally injected with streptozotocin to establish the DR model. After successful modeling， the treatment groups received corresponding doses of Qiju Dihuang Wan crude drug or calcium dobesilate suspension by gavage once daily， while the blank group and model group received an equal volume of normal saline， for 8 consecutive weeks. Fundus changes were examined by optical coherence tomography， optical coherence tomography angiography， and fundus fluorescein angiography. Retinal pathological morphology was observed by hematoxylin-eosin staining. Real-time PCR was used to detect the mRNA levels of NLRP3， Caspase‑1， GSDMD， IL‑1β， and IL‑18 in retinal tissue， and Western blot was used to detect the protein expression of NLRP3， ASC， cleaved Caspase‑1， and GSDMD‑N. ResultsCell experiments showed that compared with the blank group， the model group showed significantly decreased HRMEC viability （P<0.01）， and significantly increased levels of IL-1β， IL-18， as well as increased protein expression of NLRP3， cleaved Caspase-1， and GSDMD-N （P<0.01）. Compared with the model group， the above indicators were significantly reduced in the high-dose Qiju Dihuang Wan groups （P<0.05， P<0.01）. Animal experiments showed that compared with the blank group， the model group had elevated blood glucose （P<0.01）， decreased retinal thickness and vascular density （P<0.01）， up‑regulated mRNA expression of NLRP3， Caspase‑1， GSDMD， IL‑1β and IL‑18 in retinal tissue （P<0.01）， and up‑regulated protein expression of NLRP3， ASC， cleaved Caspase‑1 and GSDMD‑N （P<0.01）. Compared with the model group， the Qiju Dihuang Wan medium- and high‑dose groups showed decreased blood glucose （P<0.01）， increased retinal thickness and vascular density （P<0.01）， alleviated retinal pathological damage， and down‑regulated mRNA expression of NLRP3， Caspase‑1， GSDMD， IL‑1β， IL‑18， as well as protein expression of NLRP3， ASC， cleaved Caspase‑1， and GSDMD‑N （P<0.05， P<0.01）. ConclusionQiju Dihuang Wan may exert protective effects against diabetic retinopathy by inhibiting the activation of the NLRP3/Caspase-1/GSDMD signaling pathway and alleviating high glucose-induced retinal pyroptosis.

ObjectiveTo investigate the protective effect of Qiju Dihuang Wan on diabetic retinopathy （DR） and its regulatory mechanism on the NOD-like receptor protein 3/Cysteinyl aspartate-specific proteinase-1/Gasdermin D （NLRP3/Caspase-1/GSDMD） signaling pathway. MethodsHuman retinal microvascular endothelial cells （HRMEC） were divided into the blank group， model group， and Qiju Dihuang Wan low- and high-dose groups. Except for the blank group， all groups were induced with 40 mmol·L^-1 high glucose， and the treatment groups were supplemented with 6% and 12% Qiju Dihuang Wan-containing serum， respectively， based on the induction. After 24 h of culture， the levels of interleukin （IL）-1β and IL-18 were measured by enzyme-linked immunosorbent assay （ELISA）， pyroptosis-related protein expression was detected by immunofluorescence and Western blot， and the mRNA levels of NLRP3/Caspase-1/GSDMD signaling pathway-related molecules were determined by real-time polymerase chain reaction （Real-time PCR）. The mice were randomly divided into the blank group， model group， Qiju Dihuang Wan low-， medium-， and high-dose groups （11， 22， 44 g·kg^-1·d^-1）， and calcium dobesilate group （0.13 g·kg^-1·d^-1）. Except for the blank group， all groups were intraperitoneally injected with streptozotocin to establish the DR model. After successful modeling， the treatment groups received corresponding doses of Qiju Dihuang Wan crude drug or calcium dobesilate suspension by gavage once daily， while the blank group and model group received an equal volume of normal saline， for 8 consecutive weeks. Fundus changes were examined by optical coherence tomography， optical coherence tomography angiography， and fundus fluorescein angiography. Retinal pathological morphology was observed by hematoxylin-eosin staining. Real-time PCR was used to detect the mRNA levels of NLRP3， Caspase‑1， GSDMD， IL‑1β， and IL‑18 in retinal tissue， and Western blot was used to detect the protein expression of NLRP3， ASC， cleaved Caspase‑1， and GSDMD‑N. ResultsCell experiments showed that compared with the blank group， the model group showed significantly decreased HRMEC viability （P<0.01）， and significantly increased levels of IL-1β， IL-18， as well as increased protein expression of NLRP3， cleaved Caspase-1， and GSDMD-N （P<0.01）. Compared with the model group， the above indicators were significantly reduced in the high-dose Qiju Dihuang Wan groups （P<0.05， P<0.01）. Animal experiments showed that compared with the blank group， the model group had elevated blood glucose （P<0.01）， decreased retinal thickness and vascular density （P<0.01）， up‑regulated mRNA expression of NLRP3， Caspase‑1， GSDMD， IL‑1β and IL‑18 in retinal tissue （P<0.01）， and up‑regulated protein expression of NLRP3， ASC， cleaved Caspase‑1 and GSDMD‑N （P<0.01）. Compared with the model group， the Qiju Dihuang Wan medium- and high‑dose groups showed decreased blood glucose （P<0.01）， increased retinal thickness and vascular density （P<0.01）， alleviated retinal pathological damage， and down‑regulated mRNA expression of NLRP3， Caspase‑1， GSDMD， IL‑1β， IL‑18， as well as protein expression of NLRP3， ASC， cleaved Caspase‑1， and GSDMD‑N （P<0.05， P<0.01）. ConclusionQiju Dihuang Wan may exert protective effects against diabetic retinopathy by inhibiting the activation of the NLRP3/Caspase-1/GSDMD signaling pathway and alleviating high glucose-induced retinal pyroptosis.

With the rapid advancement of medical technology and the increasing complexity of clinical environments, competence in clinical ethical decision-making has become an indispensable core competency for exemplary physicians. However, traditional medical ethics education has long been confronted with the persistent challenges of theory-practice dissociation and the disconnect between pedagogical settings and clinical realities. Thus, how to construct a "Clinical Ethics" curriculum that aligns with the objectives of training high-caliber medical professionals has emerged as a critical and challenging issue in current medical education reform. To effectively address this challenge, the Office of Education at Peking University Third Hospital, since 2021, has assembled a multidisciplinary "Clinical Ethics" teaching and management team comprising faculty from Peking University School of Humanities and key clinical specialists from the hospital. In 2022, the "Clinical Ethics" elective course was formally launched for fourth-year students in the eight-year MD program who had completed coursework in "Medical Ethics" and organ-system-based curricula, with the aim of exploring and operationalizing a pre-clinical ethics education model tailored for senior medical students. The course employs a modular instructional design encompassing "theoretical review-case-based deliberation-clinical workshop", which effectively facilitates the deep integration of medical humanities with clinical practice.Following four years of iterative refinement through the "plan-act-observe-reflect" cycle, the course has demonstrated positive outcomes in enhancing students' ethical awareness and decision-making capabilities, and has preliminarily established a sustainable collaborative mechanism among the multidisciplinary faculty team. This article systematically delineates the course development background, pedagogical model and methodological innovations, and the multidisciplinary collaborative framework, alongside reflections and summaries based on implementation outcomes, with the intent of providing references for the future development of "Clinical Ethics" curricula.

BACKGROUND: Salvianolate is a compound mainly composed of salvia magnesium acetate, which is extracted from the Chinese herb Salvia miltiorrhiza . In recent years, salvianolate injection has been widely used in the treatment of cardiovascular diseases, but the mechanism of how it can alleviate cardiotoxicity remains unclear. METHODS: The cardiac injury model was constructed by treatment with doxorubicin (Dox) or azithromycin (Azi) in zebrafish larvae. Heart phenotype, heart rate, and cardiomyocyte apoptosis were observed in the study. RNA-sequencing (RNA-seq) analysis was used to explore the underlying mechanism of salvianolate treatment. Moreover, cardiomyocyte autophagy was assessed by in situ imaging. In addition, the miR-30a/becn1 axis regulation by salvianolate was further investigated. RESULTS: Salvianolate treatment reduced the proportion of pericardial edema, recovered heart rate, and inhibited cardiomyocyte apoptosis in Dox/Azi-administered zebrafish larvae. Mechanistically, salvianolate regulated the lysosomal pathway and promoted autophagic flux in zebrafish cardiomyocytes. The expression level of becn1 was increased in Dox-induced myocardial tissue injury after salvianolate administration; overexpression of becn1 in cardiomyocytes alleviated the Dox/Azi-induced cardiac injury and promoted autophagic flux in cardiomyocytes, while becn1 knockdown blocked the effects of salvianolate. In addition, miR-30a, negatively regulated by salvianolate, partially inhibited the cardiac amelioration of salvianolate by targeting becn1  directly. CONCLUSION This study has proved that salvianolate reduces cardiomyopathy by regulating autophagic flux through the miR-30a/becn1 axis in zebrafish and is a potential drug for adjunctive Dox/Azi therapy.
Animals ; Zebrafish ; MicroRNAs/genetics* ; Autophagy/drug effects* ; Myocytes, Cardiac/metabolism* ; Cardiomyopathies/metabolism* ; Beclin-1/genetics* ; Apoptosis/drug effects* ; Plant Extracts/therapeutic use* ; Doxorubicin

The inheritance, innovation, and development of traditional Chinese medicine(TCM) need to be based on Chinese medicinal materials. The TCM seed industry is the source of TCM production, which is related to the stable supply and quality safety of TCM. This paper summarizes the basic situation of the TCM seed industry and introduces relevant policies and regulations to TCM seeds in the seed industry and the TCM field. At present, the Management Measures of TCM Seeds and Seedlings has not yet promulgated, and TCM seeds are classified as non-major crops in the category of crops for management. This paper also describes the current situation of TCM seed and seedling system construction, which is in the development stage, from six aspects, including the construction of TCM seed industry technical support system; the establishment of TCM seed standard; the construction of germplasm resource preservation system; TCM seed testing, variety registration, and variety protection; production and management of TCM seeds; TCM seed supervision. According to the development status of the TCM seed industry, four problems are put forward, including imperfect systems and standards relevant to TCM seeds, insufficient supervision and law enforcement regarding TCM seeds, insufficient policy measures and capital investment to promote the development of the industry, and the industry's falling into a low-level cycle.Accordingly, four suggestions are provided, including improving laws, regulations, and policies, perfecting standards and norms,strengthening supervision and law enforcement, and promoting support system construction, in order to boost the high-quality development of the TCM seed industry.
Seeds/chemistry* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/standards* ; Plants, Medicinal/chemistry*

Based on the interleukin-17(IL-17) signaling pathway, this study explores the effect and mechanism of Bufei Decoction on Klebsiella pneumoniae pneumonia in rats. SD rats were randomly divided into the control group, model group, Bufei Decoction low-dose group(6.68 g·kg~(-1)·d~(-1)), Bufei Decoction high-dose group(13.36 g·kg~(-1)·d~(-1)), and dexamethasone group(1.04 mg·kg~(-1)·d~(-1)), with 10 rats in each group. A pneumonia model was established by tracheal drip injection of K. pneumoniae. After successful model establishment, the improvement in lung tissue damage was observed following drug administration. Core targets and signaling pathways were screened using transcriptomics techniques. Real-time fluorescence quantitative polymerase chain reaction was used to detect the mRNA expression of core targets interleukin-6(IL-6), interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), and chemokine CXC ligand 6(CXCL6). Western blot was used to assess key proteins in the IL-17 signaling pathway, including interleukin-17A(IL-17A), nuclear transcription factor-κB activator 1(Act1), tumor necrosis factor receptor-associated factor 6(TRAF6), and downstream phosphorylated p38 mitogen-activated protein kinase(p-p38 MAPK), and phosphorylated nuclear factor-κB p65(p-NF-κB p65). Apoptosis of lung tissue cells was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling(TUNEL). The results showed that, compared with the control group, the model group exhibited significant pathological damage in lung tissue. The mRNA expression of IL-6, IL-1β, TNF-α, and CXCL6, as well as the protein levels of IL-17A, Act1, TRAF6, p-p38 MAPK/p38 MAPK, and p-NF-κB p65/NF-κB p65, were significantly increased, and the number of apoptotic cells was notably higher, indicating successful model establishment. Compared with the model group, both low-and high-dose groups of Bufei Decoction showed reduced pathological damage in lung tissue. The mRNA expression levels of IL-6, IL-1β, TNF-α, and CXCL6, and the protein levels of IL-17A, Act1, TRAF6, p-p38 MAPK/p38 MAPK, and p-NF-κB p65/NF-κB p65, were significantly decreased, with a significant reduction in apoptotic cells in the high-dose group. In conclusion, Bufei Decoction can effectively improve lung tissue damage and reduce inflammation in rats with K. pneumoniae. The mechanism may involve the regulation of the IL-17 signaling pathway and the reduction of apoptosis.
Animals ; Interleukin-17/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Rats ; Male ; Klebsiella pneumoniae/physiology* ; Klebsiella Infections/immunology* ; Humans ; Lung/drug effects*

This study aims to explore the effects and action mechanisms of the active ingredients in Buyang Huanwu Decoction(BYHWD), namely tetramethylpyrazine(TMP) and hydroxy-safflor yellow A(HSYA), on oxygen-glucose deprivation/reglucose-reoxygenation(OGD/R)-induced inflammation and oxidative stress of microglia(MG). Network pharmacology was used to screen the effective monomer ingredients of BYHWD and determine the safe concentration range for each component. Inflammation and oxidative stress models were established to further screen the best ingredient combination and optimal concentration ratio with the most effective anti-inflammatory and antioxidant effects. OGD/R BV2 cell models were constructed, and BV2 cells in the logarithmic growth phase were divided into a normal group, a model group, an HSYA group, a TMP group, and an HSYA + TMP group. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of inflammatory cytokines such as interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), and interleukin-6(IL-6). Oxidative stress markers, including superoxide dismutase(SOD), nitric oxide(NO), and malondialdehyde(MDA), were also measured. Western blot was used to analyze the protein expression of both inflammation-related pathway [Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB)] and oxidative stress-related pathway [nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)]. Immunofluorescence was used to assess the expression of proteins such as inducible nitric oxide synthase(iNOS) and arginase-1(Arg-1). The most effective ingredients for anti-inflammatory and antioxidant effects in BYHWD were TMP and HSYA. Compared to the normal group, the model group showed significantly increased levels of IL-1β, TNF-α, IL-6, NO, and MDA, along with significantly higher protein expression of NF-κB, TLR4, Nrf2, and HO-1 and significantly lower SOD levels. The differences between the two groups were statistically significant. Compared to the model group, both the HSYA group and the TMP group showed significantly reduced levels of IL-1β, TNF-α, IL-6, NO, and MDA, lower expression of NF-κB and TLR4 proteins, higher levels of SOD, and significantly increased protein expression of Nrf2 and HO-1. Additionally, the expression of the M1-type MG marker iNOS was significantly reduced, while the expression of the M2-type MG marker Arg-1 was significantly increased. The results of the HSYA group and the TMP group had statistically significant differences from those of the model group. Compared to the HSYA group and the TMP group, the HSYA + TMP group showed further significant reductions in IL-1β, TNF-α, IL-6, NO, and MDA levels, along with significant reductions in NF-κB and TLR4 protein expression, an increase in SOD levels, and elevated Nrf2 and HO-1 protein expression. Additionally, the expression of the M1-type MG marker iNOS was reduced, while the M2-type MG marker Arg-1 expression increased significantly in the HSYA + TMP group compared to the TMP or HSYA group. The differences in the results were statistically significant between the HSYA + TMP group and the TMP or HSYA group. The findings indicated that the combined use of HSYA and TMP, the active ingredients of BYHWD, can effectively inhibit OGD/R-induced inflammation and oxidative stress of MG, showing superior effects compared to the individual use of either component.
Oxidative Stress/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Animals ; Mice ; Glucose/metabolism* ; Cell Line ; Inflammation/genetics* ; Oxygen/metabolism* ; Pyrazines/pharmacology* ; Microglia/metabolism* ; NF-E2-Related Factor 2/immunology* ; NF-kappa B/immunology* ; Toll-Like Receptor 4/immunology* ; Anti-Inflammatory Agents/pharmacology* ; Humans

OBJECTIVE: To investigate the association of various polycyclic aromatic hydrocarbon (PAH) metabolites with diverse subtypes of cardiovascular disease (CVD) risk. METHODS: A novel predicting risk of cardiovascular disease EVENTs PREVENT equation was used to estimate the 10-year diverse subtypes of CVD risk, and their associations with PAH metabolites were analyzed using multiple logistic regression models, the weighted quantile sum (WQS) model, the quantile g-computation (qgcomp) model, and a stratified analysis of subgroups. RESULTS: For this study, six thousand seven hundred and forty-five participants were selected, and significant positive associations were observed between PAHs, naphthalene (NAP), and fluorene (FLU), and the risks of total CVD, atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF). NAP and FLU were the primary contributors to the effects of PAH mixtures, and their associations with total CVD, ASCVD, and HF risk were significant in younger participants (30 ≤ age < 50 years); however, the associations of phenanthrene (PHEN) with ASCVD, HF, coronary heart disease (CHD), and stroke were dominant in aging participants (age ≥ 50 years). Notably, pyrene (PYR) was negatively associated with the risk of ASCVD, HF, CHD, and stroke. Similarly, negative associations of PYR with the four CVD subtypes were noticeable in aging participants. CONCLUSION Different PAHs metabolites had different impacts on each CVD subtype among different age groups. Notably, the protective effects of PYR on ASCVD, HF, CHD, and stroke were noticeable in aging individuals.
Humans ; Cardiovascular Diseases/chemically induced* ; Middle Aged ; Polycyclic Aromatic Hydrocarbons/metabolism* ; Male ; Female ; Adult ; Aged ; Risk Factors ; China/epidemiology*

Objective To explore the relationship between bedtime procrastination and fear of missing out and the intervention effect of aerobic exercise on bedtime procrastination,so as to provide a theoretical basis and practical reference for remedying bedtime procrastination.Methods Totally 988 students were selected through random sampling and then surveyed with the bedtime procrastination scale and the fear of missing out scale.Correlation and regression analyses were performed to explore the relationship between bedtime procrastination and fear of missing out.A total of 36 students were recruited from the 988 students to participate in the exercise intervention and they were assigned into an exercise group and a control group by the random number table method,with 18 students in each group.The exercise group performed aerobic exercise for 12 weeks,while the control group maintained daily activities.The participants' scores on the bedtime procrastination scale and the fear of missing out scale were recorded before and after the intervention and compared.Results The fear of missing out was positively correlated with bedtime procrastination among college students(r=0.214,P<0.001),and it was an important predictive factor for bedtime procrastination(β=0.241,P<0.001).After the intervention,the scores of bedtime procrastination scale decreased in the exercise group(t=2.277,P=0.036),while there was no significant difference in the scores of the control group before and after intervention(t=-0.787,P=0.442).Conclusions A high level of fear of missing out indicates severe bedtime procrastination.And 12-week exercise intervention could remedy bedtime procrastination.
Humans ; Fear ; Exercise ; Male ; Female ; Procrastination ; Young Adult ; Cross-Sectional Studies ; Students/psychology* ; Adult ; Surveys and Questionnaires ; Adolescent