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.

OBJECTIVE To investigate the current status of informatization tools applied to antimicrobial stewardship in county hospitals in China， and to provide a reference for promoting the informatization development of antimicrobial stewardship in county hospitals.METHODS From August to September 2025， an online questionnaire survey was conducted among 1 007 county hospitals across 31 provinces（autonomous regions， and municipalities） in China. The survey focused on the application of four types of informatization tools：the real-time monitoring system for antimicrobial use， the pre-prescription review system， the irrational use warning system， and the electronic prescription evaluation system（hereinafter referred to as the “monitoring system”“review system”“warning system”“evaluation system”，respectively）. Correlation analysis and binary Logistic regression analysis were employed to explore the influencing factors.RESULTS Of the county hospitals， 80.83% were equipped with at least one type of informatization tool for antimicrobial stewardship， while 19.17% had no relevant tool. Only 18.87% of the hospitals were equipped with all four types of tools. The monitoring system exhibited the highest equipped rate （70.80%）， whereas the warning system was equipped in only 33.96% of the hospitals. Four types of tools are evenly and adequately deployed in the eastern region， the central and western regions have far lower deployment rates of intervention tools including review system and warning system， accompanied by prominent intra-provincial gaps. The total number of the health technicians， hospital grade， and prescription review rate of outpatient antibacterial drug were significantly and positively correlated with the deployment rates of the four informatization tools （ P ＜0.05）. The results of the Logistic regression model fitting indicated that the model of the review system was rated “excellent” [area under the receiver operating characteristic curve （AUC）＝0.81]， and the model of the warning system was rated “further improvement” （AUC＝0.67）. The total number of health technicians was significantly positively correlated with the deployment rates of all four types of informatization tools （all P ＜0.05）.CONCLUSIONS The informatization of antimicrobial stewardship in county hospitals in China remains in the initial stage of transitioning from “passive statistics” to “active prevention and control”， with challenges such as structural imbalance and regional disparities. In the future， differentiated support strategies should be implemented， the allocation of resources should be optimized， to enhance the level of refined antimicrobial stewardship.

Glaucoma is a multifactorial degenerative optic neuropathy, and its irreversible and blinding pathological characteristics mainly come from the damage to the optic nerve, namely glaucomatous optic neuropathy(GON). The difficulty in the treatment of GON lies in the early intervention, and currently there is no optic neuroprotective drug for the treatment of all types of GON. The death of retinal ganglion cells(RGCs)is the core pathological change caused by various pathogenic mechanisms of GON. Recent studies have found that the widespread second messenger cyclic adenosine 3', 5' -monophosphate(cAMP)and its downstream effector protein kinase A(PKA)signal cascade play an important role in the pathogenesis of GON. It can also inhibit the apoptosis of RGCs and play a protective and therapeutic role in glaucoma. Therefore, this article reviews the role of cAMP/PKA pathway in the pathophysiological development of GON, focusing on its effects on glaucoma intraocular pressure regulation, oxidative stress, neuroinflammation and optic nerve degeneration, in order to find a common central regulatory target for the optic nerve damage caused by different pathological mechanisms of GON and promote the further understanding and clinical treatment of this disease.

Normal heart function depends on complex regulation by the brain, and abnormalities in the brain‒heart axis affect various diseases, such as myocardial infarction and anxiety disorders. However, systematic tracking of the brain regions associated with the input and output of the heart is lacking. In this study, we injected retrograde transsynaptic pseudorabies virus (PRV) and anterograde transsynaptic herpes simplex virus (HSV) into the left ventricular wall of mice to identify the whole-brain regions associated with the input to and output from the heart. We successfully detected PRV and HSV expression in at least 170 brain subregions in both male and female mice. Sex differences were discovered mainly in the hypothalamus and medulla, with male mice exhibiting greater correlation and hierarchical clustering than female mice, indicating reduced similarity and increased modularity of virus expression patterns in male mice. Further graph theory and multiple linear regression analysis of different injection timelines revealed that hub regions of PRV had highly similar clusters, with different brain levels, suggesting a top-down, hierarchically transmitted neural control pattern of the heart. Hub regions of HSV had scattered clusters, with brain regions gathered in the cortex and brainstem, suggesting a bottom-up, leapfrog, multipoint neural sensing pattern of the heart. Both patterns contain many hub brain regions that have been previously overlooked in brain‒heart axis studies. These results provide brain targets for future research and will lead to deeper insight into the brain mechanisms involved in specific heart conditions.
Animals ; Male ; Female ; Heart/physiology* ; Mice ; Herpesvirus 1, Suid ; Brain/physiology* ; Mice, Inbred C57BL ; Brain Mapping ; Efferent Pathways/physiology* ; Afferent Pathways/physiology* ; Simplexvirus ; Sex Characteristics

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Resistance to poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi) presents a considerable obstacle in the treatment of ovarian cancer. F-box and tryptophan-aspartic (WD) repeat domain containing 11 (FBXW11) modulates the ubiquitination of growth-and invasion-related factors in lung cancer, colorectal cancer, and osteosarcoma. The function of FBXW11 in PARPi therapy is still ambiguous. In this study, RNA sequencing (RNA-seq) showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi. FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer (HGSOC) tissues, and low levels of FBXW11 were associated with shorter overall survival (OS) and progression-free survival (PFS) in HGSOC patients. Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi, while knocking down FBXW11 made it less sensitive. The four-dimensional (4D) label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11 (S100A11) and promoted its degradation through ubiquitination. The increased degradation of S100A11 led to less efficient DNA damage repair, which in turn contributed to increased PARPi-induced DNA damage. The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models. In summary, our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.

Cynanchum atratum Bunge (C. atratum) and Cynanchum versicolor Bunge (C. versicolor) are two related species that have been used as "Baiwei" (Cynanchi Atrati Radix Et Rhizoma) in traditional medicine in China and other Asian countries for a long time. However, to date, no comprehensive review of C. atratum and C. versicolor has been published. This review provides a comprehensive summary on the botany, phytochemistry, traditional uses and pharmacology of Baiwei; The authors focus especially on the revision of errors in previous articles and reviews, updating information and providing a comparison of C. atratum and C. versicolor. Furthermore, current research reveals significant disparities in the chemical composition and pharmacological effects between C. atratum and C. versicolor. Up to November 2023, 178 compounds have been isolated from C. atratum and C. versicolor, including C₂₁ steroids, acetophenones, alkaloids and volatile oils. These compounds and extracts have been proven to exhibit significant pharmacological activities, including anti-inflammatory, anti-tumor, anti-virus, anti-fungal, memory-enhancing and anti-pyretic action, immune modulatory effects, reducing blood lipid, inhibition of melanin production, and anti-parasitic effects. Therefore, this review presents new insights into these two herbs used as "Baiwei" and further study is warranted to enhance their clinical application. Please cite this article as: Xie W, Liu XY, Li X, Jin YS. Cynanchum atratum Bunge and Cynanchum versicolor Bunge for Baiwei: An updated review of their botany, phytochemistry, traditional uses and pharmacological activities. J Integr Med. 2025; 23(3): 230-255.
Cynanchum/chemistry* ; Humans ; Drugs, Chinese Herbal/chemistry* ; Phytochemicals/pharmacology* ; Animals ; Medicine, Chinese Traditional ; Plant Extracts/chemistry*

Salvia miltiorrhiza (Danshen) is a traditional Chinese herb that is commonly known for its cardiovascular and hepatoprotective benefits. Recent studies have confirmed that Danshen and its bioactive components can influence gut microbial homeostasis, thereby affecting Helicobacter pylori (HP) colonization in the human stomach. HP is a bacterial pathogen associated with various gastrointestinal diseases. Current HP treatments mainly involve antibiotics and proton pump inhibitors. However, their efficacy is strongly compromised by the rapid emergence of antibiotic resistance in HP and genetic heterogeneity among patients. The interaction between Danshen and gut microbial status provides a novel perspective for HP treatment. Understanding the medical properties of Danshen in altering gut microbiota and eliminating HP, as well as the underlying mechanisms, is important for improving human gastrointestinal healthcare. This review investigates the interaction between Danshen and gut microbiota and its impact on HP infection using databases including Web of Science, PubMed, and Google Scholar. We explored the unconventional intersection between Danshen, gut microbiota, and HP infection, shedding light on their intricate interplay and potential therapeutic implications. A comprehensive understanding of this interaction provides valuable insights into developing novel therapeutic strategies that target the gut microbiota to mitigate HP-associated gastrointestinal disorders. Please cite this article as: Li SJ, Miao JX, Wang F, Wang HY, Ma YW, Jiang Y, Xue X. Salvia miltiorrhiza components and gut microbiota interactions in Helicobacter pylori infection. J Integr Med. 2025; 23(5):462-470.
Salvia miltiorrhiza/chemistry* ; Gastrointestinal Microbiome/drug effects* ; Humans ; Helicobacter Infections/microbiology* ; Helicobacter pylori/drug effects* ; Drugs, Chinese Herbal/therapeutic use*

Microglia, the resident immune cells in the central nervous system (CNS), rapidly transition from a resting to an active state in the acute phase of ischemic brain injury. This active state mediates a pro-inflammatory response that can exacerbate the injury. Targeting the pro-inflammatory response of microglia in the semi-dark band during this acute phase may effectively reduce brain injury. Shionone (SH), an active ingredient extracted from the dried roots and rhizomes of the genus Aster (Asteraceae), has been reported to regulate the inflammatory response of macrophages in sepsis-induced acute lung injury. However, its function in post-stroke neuroinflammation, particularly microglia-mediated neuroinflammation, remains uninvestigated. This study found that SH significantly inhibited lipopolysaccharide (LPS)-induced elevation of inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS), in microglia in vitro. Furthermore, the results demonstrated that SH alleviated infarct volume and improved behavioral performance in middle cerebral artery occlusion (MCAO) mice, which may be attributed to the inhibition of the microglial inflammatory response induced by SH treatment. Mechanistically, SH potently inhibited the phosphorylation of serine-threonine protein kinase B (AKT), mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 (STAT3). These findings suggest that SH may be a potential therapeutic agent for relieving ischemic stroke (IS) by alleviating microglia-associated neuroinflammation.
Animals ; Microglia/immunology* ; Mice ; Male ; Mice, Inbred C57BL ; Brain Ischemia/immunology* ; Neuroinflammatory Diseases/drug therapy* ; Neuroprotective Agents/administration & dosage* ; Interleukin-1beta/genetics* ; STAT3 Transcription Factor/genetics* ; TOR Serine-Threonine Kinases/genetics* ; Tumor Necrosis Factor-alpha/genetics* ; Proto-Oncogene Proteins c-akt/immunology* ; Nitric Oxide Synthase Type II/genetics* ; Lipopolysaccharides

OBJECTIVE: To explore the correlation between chromosome 8 open reading frame 76 (C8orf76) and cyclin-dependent kinase 4 (CDK4) and the potential predictive effect of C8orf76 and CDK4 on the prognosis of colorectal cancer (CRC). METHODS: We constructed a protein-protein interaction network of C8orf76-related genes and analyzed the prognostic signatures of C8orf76 and CDK4. Clinicopathological features of C8orf76 and CDK4 were visualized using a nomogram. RESULTS: C8orf76 and CDK4 levels were positively correlated in two independent human CRC cohorts ( n = 83 and n = 597). A consistent positive correlation was observed between C8orf76 and CDK4 expression in the CRC cell lines. The nomogram included prognostic genes (C8orf76 and CDK4) and pathological N and M stages. The concordance index (C-index) in our cohort was 0.776, which suggests that the ability of the indicators to predict the overall survival of patients with CRC in our cohort was strong. CONCLUSION We found that C8orf76 was positively correlated with CDK4 in both the cohorts as well as in CRC cell lines. Therefore, C8orf76 and CDK4 can be used as potential biomarkers to predict the prognosis of CRC.
Humans ; Colorectal Neoplasms/diagnosis* ; Cyclin-Dependent Kinase 4/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/genetics* ; Aged ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic