Erzhi Pill (EZP), a classical Chinese herbal formula for yin-nourishing and kidney-tonifying, has been traditionally prescribed for insomnia and amnesia, and shows therapeutic potential for Alzheimer's disease (AD). However, its active components and precise mechanisms of action against AD remain elusive. This study aimed to identify the key active components and molecular targets of EZP responsible for improving cognitive dysfunction and to elucidate its underlying mechanisms. Behavioral and histomorphological analyses will be used to validate the efficacy of EZP in ameliorating cognitive impairment in lipopolysaccharide (LPS)-induced models. Untargeted metabolomics characterized metabolic profile alterations in the locus coeruleus (LC), while targeted metabolomics focused on specific metabolic pathways. Microdialysis coupled with high-resolution mass spectrometry (HR-MS) analyzed EZP's chemical components in LC dialysates. Network pharmacology and molecular docking predicted potential targets, with binding affinities validated by surface plasmon resonance (SPR). Molecular biology techniques were employed to investigate relevant signaling pathways. EZP significantly improved learning and memory capabilities in LPS-induced models, accompanied by enhanced neuronal activity. Metabolomic profiling revealed that EZP exerted its effects primarily through modulation of alanine, aspartate, and glutamate metabolism pathways, as well as phenylalanine and tyrosine metabolic networks. Specifically, EZP treatment resulted in decreased tyrosine (Tyr) levels and increased norepinephrine (NE) concentrations in the LC. Western blot analysis further demonstrated upregulated expression of tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DβH) proteins in LC tissues. Phytochemical analysis identified 45 prototype components and 14 metabolites in EZP, among which apigenin and wedelolactone were characterized as potential bioactive ingredients. Network pharmacology combined with molecular docking revealed estrogen receptor β (ERβ) as a critical target mediating EZP's anti-AD effects. SPR validated stronger binding affinity of apigenin and wedelolactone to ERβ compared with G-protein-coupled receptor 30 (GPR30). Mechanistic studies showed that these compounds activated ERβ signaling, restored TFAP2A/TH transcriptional activity, and promoted NE biosynthesis, thereby ameliorating cognitive deficits in AD models. This study not only elucidates that EZP ameliorates cognitive dysfunction in AD)via the ERβ-TFAP2A/TH signaling pathway but also proposes NE augmentation as a novel therapeutic strategy for AD management.

This investigation was conceived to engineer and appraise a pioneering clinical nomogram, crafted to bridge the extant chasm in literature regarding the postoperative risk stratification for deep vein thrombosis (DVT) in the aftermath of lower extremity orthopedic procedures. This novel tool offers a sophisticated and discerning algorithm for risk prediction, heretofore unmet by existing methodologies. In this retrospective observational study, clinical records of hospitalized patients who underwent lower extremity orthopedic surgery were collected at the Wuxi TCM Hospital Affiliated to the Nanjing University of Chinese Medicine between Jan 2017 and Oct 2019. The univariate and multivariate analysis with the backward stepwise method was applied to select features for the predictive nomogram. The performance of the nomogram was evaluated with respect to its discriminant capability, calibration ability, and clinical utility. A total of 5773 in-hospital patients were eligible for the study, with the incidence of deep vein thrombosis being approximately 1 % in this population. Among 31 variables included, 5 of them were identified to be the predictive features in the nomogram, including age, mean corpuscular hemoglobin concentration (MCHC), D-dimer, platelet distribution width (PDW), and thrombin time (TT). The area under the receiver operating characteristic (ROC) curve in the training and validation cohort was 85.9 % (95%CI: 79.96 %-90.04 %) and 85.7 % (95%CI: 78.96 %-90.69 %), respectively. Both the calibration curves and decision curve analysis demonstrated the overall satisfactory performance of the model. Our groundbreaking nomogram is distinguished by its unparalleled accuracy in discriminative and calibrating functions, complemented by its tangible clinical applicability. This innovative instrument is set to empower clinicians with a robust framework for the accurate forecasting of postoperative DVT, thus facilitating the crafting of bespoke and prompt therapeutic strategies, aligning with the rigorous standards upheld by the most esteemed biomedical journals.

Postoperative cognitive dysfunction is a common neurological complication, characterized by impaired learning and memory, that occurs after anesthesia and surgery, especially in elderly patients. The traditional Chinese medicine baicalin is known to have neuroprotective effects. Therefore, we have investigated whether baicalin can improve postoperative cognitive impairment in aged rats after splenectomy. A total of 60 Sprague Dawley rats were randomly divided, equally, into the splenectomy, sham operation (Sham), low-dose baicalin (Baicalin A), medium-dose baicalin (Baicalin B), and high-dose baicalin (Baicalin C) groups. Splenectomy was performed under anesthesia in all groups except for the Sham group, in which an appropriate concentration of saline was administered. The effects of baicalin on learning and memory were examined by the Y-maze behavioral experiments. Although splenectomy had a negative effect on cognitive function in the acute phase, all the rats spontaneously recovered on a postoperative day seven. Nonetheless, in the acute phase, the medium and high doses of baicalin slightly alleviated these effects of the procedure. The protein expression of the inflammatory cytokines tumor necrosis factor- α , Interleukin-6, and Interleukin-1 β was assessed using enzyme-linked immunosorbent assay. Their levels were elevated in the acute phase but were returned to normal with the medium and high dose of baicalin. Real-time PCR analysis of the mRNA expression of the N-methyl-D-aspartic acid receptor TNF- α , which is known to be involved in long-term potentiation, revealed that baicalin promoted its transcription. Thus, the findings indicate that baicalin may improve postoperative cognitive memory dysfunction in postoperative cognitive dysfunction in rats via anti-inflammatory mechanisms and pathways that involve N-methyl-D-aspartate receptor 2B subunit.

Purpose: Ivor Lewis esophagectomy impacts circulatory and cardiac function significantly, often leading to elevated postoperative troponin levels. This study aimed to investigate the effect of low-dose esketamine on postoperative levels of the myocardial injury marker high-sensitivity cardiac troponin T in elderly patients undergoing this procedure. Patients and Methods: 70 elderly patients scheduled for elective Ivor Lewis esophagectomy were randomly assigned using a random number table to the Control group (Group C, n=35) or the Esketamine group (Group K, n=35). In Group K, in addition to conventional anesthetic drugs, intravenous esketamine 0.25 mg/kg was administered during anesthesia induction, followed by continuous intraoperative infusion at 0.125 mg/kg/h as an adjunct to balanced anesthesia. The Control group received conventional anesthesia induction and maintenance. The primary outcome was hs-cTnT concentration at 24 h postoperatively. Results: In Group K, hs-cTnT concentrations were significantly lower than in the control group at 24h (12.1 ± 3.5 vs 18.7 ± 4.7, P < 0.0001) postoperatively, as well as at 6– 12h and 48h postoperatively. Although the incidence of myocardial injury within 2 days postoperatively (11.4% vs 22.9%, P = 0.205) and perioperative severe arrhythmias (2.9% vs 11.4%, P = 0.164) was lower in Group K than in Group C, the differences were not statistically significant. Compared to the control group, Group K indicated more stable hemodynamics. Among postoperative complications, the incidence of dreaming was higher in Group K, with no significant differences in other complications. For postoperative pain, Group K had lower Numerical Rating Scale (NRS) scores at PACU discharge and on postoperative day 1 to day 3. The PACU stay was shorter in Group K. Conclusion: Intraoperative low-dose esketamine effectively reduced hs-cTnT concentrations within 2 days postoperatively in elderly patients undergoing Ivor Lewis esophagectomy, demonstrating a potential beneficial effect in preventing myocardial injury and cardiovascular adverse events.

Respiratory syncytial virus (RSV) remains a major cause of severe lower respiratory tract infections. The high mutability of its RNA genome necessitates novel therapeutics, with the viral fusion (F) protein representing a promising target. This study aimed to identify RSV F protein inhibitors via structure-based virtual screening and to systematically characterize their antiviral efficacy and mechanism of action. A multi-tiered virtual screening of an antiviral compound library was performed against the prefusion RSV F protein structure. Hits were validated for binding using MST and SPR. The mechanism was elucidated through time-of-addition, membrane fusion, and lentiviral pseudotype assays. In vivo efficacy was evaluated in an RSV infected BALB/c mouse model. Screening identified 10 candidate compounds to interact with RSV F protein. Among these, Rhein bound to the prefusion F protein with micromolar affinity. Rhein exhibited potent anti-RSV efficacy with IC₅₀ values of 498.4 nM in HEp-2 cells and 594.0 nM in A549 cells. Further experiments revealed Rhein disrupted RSV membrane fusion by enhancing the conformational stability of the RSV F protein before fusion. Rhein bound to key residues within the central cavity of the RSV F protein at VAL406 and PHE137. Moreover, Rhein demonstrated potent inhibition against the K394R and K272E mutant pseudoviruses, indicating its potential efficacy against RSV variants resistant to Palivizumab and clinical-stage fusion inhibitors. Additionally, acute toxicity and pharmacokinetic studies revealed that Rhein has an LD₅₀ > 2000 mg/kg, along with favorable oral absorption, extensive tissue distribution, and exposure kinetics suitable for antiviral intervention. In an in vivo study, Rhein was shown to alleviate RSV-induced pulmonary pathology by reducing viral titers, mitigating lung injury, and suppressing the inflammatory responses in the lungs. Rhein is a promising RSV fusion inhibitor, and its unique binding mode offers a valuable lead compound for overcoming drug resistance.