ObjectiveTo investigate the role of sphingosine-1-phosphate （S1P） in abnormal ossification in ankylosing spondylitis （AS）， clarify the relationship between S1P and “angiogenesis-osteogenesis” coupling， and provide new strategies for AS treatment. MethodsFemoral heads from AS patients and patients undergoing routine hip replacement were collected for immunohistochemical （IHC） staining to evaluate osteogenesis and H-type vessel formation. In vitro， ELISA was used to quantify the synthesis of S1P and analyze the expression changes of S1P signaling pathway-related molecules during the osteogenic differentiation of mesenchymal stem cells derived from patients with ankylosing spondylitis （ASMSCs） and those from healthy donors （HDMSCs）， to evaluate the activation status of S1P pathway during osteogenesis. Sphingosine kinase 1 （SK1） expression was knocked down in MSCs， and the S1P receptor inhibitor FTY720 was applied to block S1P signaling. Alkaline phosphatase （ALP） activity and Alizarin Red S （ARS） quantification were used to assess the effect of S1P on ASMSCs osteogenesis. Conditioned medium from osteogenically induced MSCs was used to treat human umbilical vein endothelial cells （HUVECs） to evaluate the effect of S1P on angiogenesis. An AS mouse model （SKG mice） was treated with FTY720 or the SK1 inhibitor PF-543 citrate. IHC staining and micro-CT scanning were used to assess abnormal ossification and spinal fusion， and immunofluorescence was used to evaluate H-type vessel formation. ResultsCompared with Osteonecrosis of the Femoral Head（ONFH） patients， AS patients exhibited excessive osteogenesis and H-type vessel formation （OCN P＜0.001， CD31 P＜0.001， EMCN P＜0.001）. During osteogenic differentiation， S1P expression and secretion were significantly higher in ASMSCs than in HDMSCs （P=0.0179）. Inhibition of S1P signaling with FTY720 or SK1 knockdown significantly suppressed osteogenic differentiation （compared with ASMSC， ARS： HDMSC P=0.001 8， FTY720 P＜0.001， si-SK1 P＜0.001； ALP： HDMSC P=0.032 8， FTY720 P=0.001 6， si-SK1 P＜0.001） of ASMSCs and the angiogenesis of HUVEC（compared with ASMSC， cell-covered area， total loops， total tube length and total branch points P＜0.001）. Treatment with FTY720 or PF-543 markedly inhibited abnormal ossification and spinal fusion（compared with Curdlan， arthritis index score， P＜0.001； OCN：control P=0.002， PF-543 P=0.010 7， FTY720 P=0.015 9 ） in AS mice and reduced H-type vessel formation （CD31⁺EMCN⁺： compared with curdlan， control P＜0.001， PF-543 P=0.001 7， FTY720 P=0.002 1）. ConclusionIncreased S1P synthesis in ASMSCs promotes osteogenic differentiation via autocrine mechanisms and further enhances ossification by facilitating H-type angiogenesis. Inhibiting S1P secretion in ASMSCs significantly suppresses abnormal ossification in AS.

Silent mutations within the RAS  gene have garnered increasing attention for their potential roles in tumorigenesis and therapeutic strategies. Kirsten-RAS ( KRAS ) mutations, predominantly oncogenic, are pivotal drivers in various cancers. While extensive research has elucidated the molecular mechanisms and biological consequences of active KRAS  mutations, the functional significance of silent mutations remains relatively understudied. This review synthesizes current knowledge on KRAS  silent mutations, highlighting their impact on cancer development. Silent mutations, which do not alter protein sequences but can affect RNA stability and translational efficiency, pose intriguing questions regarding their contribution to tumor biology. Understanding these mutations is crucial for comprehensively unraveling KRAS -driven oncogenesis and exploring novel therapeutic avenues. Moreover, investigations into the clinical implications of silent mutations in KRAS -mutant tumors suggest potential diagnostic and therapeutic strategies. Despite being in early stages, research on KRAS  silent mutations holds promise for uncovering novel insights that could inform personalized cancer treatments. In conclusion, this review underscores the evolving landscape of KRAS  silent mutations, advocating for further exploration to bridge fundamental biology with clinical applications in oncology.
Humans ; Mutation/genetics* ; Neoplasms/genetics* ; Proto-Oncogene Proteins p21(ras)/genetics* ; Animals

Traditional Chinese medicine formula (TCMF) represents a fundamental component of Chinese medical practice, incorporating medical knowledge and practices from both Han Chinese and various ethnic minorities, while providing comprehensive insights into health and disease. The foundation of TCMF lies in its holistic approach, manifested through herbal compatibility theory, which has emerged from extensive clinical experience and evolved into a highly refined knowledge system. Within this framework, Chinese herbal medicines exhibit intricated characteristics, including multi-component interactions, diverse target sites, and varied biological pathways. These complexities pose significant challenges for understanding their molecular mechanisms. Contemporary advances in artificial intelligence (AI) are reshaping research in traditional Chinese medicine (TCM), offering immense potential to transform our understanding of the molecular mechanisms underlying TCMFs. This review explores the application of AI in uncovering these mechanisms, highlighting its role in compound absorption, distribution, metabolism, and excretion (ADME) prediction, molecular target identification, compound and target synergy recognition, pharmacological mechanisms exploration, and herbal formula optimization. Furthermore, the review discusses the challenges and opportunities in AI-assisted research on TCMF molecular mechanisms, promoting the modernization and globalization of TCM.
Artificial Intelligence ; Drugs, Chinese Herbal/pharmacokinetics* ; Humans ; Medicine, Chinese Traditional ; Animals

OBJECTIVES: To investigate the therapeutic mechanism of Sangma Zhike Formula (SMZKF) for relieving cough sensitivity and airway inflammation in rats with postinfectious cough (PIC). METHODS: Male SD rat models were established by cigarette smoke exposure with intranasal LPS instillation and capsaicin aerosol inhalation. From day 19 following the start of PIC modeling, the rats received daily treatment with saline (model group), low-, medium-, and high-dose SMZKF, and compound methoxyphenamine (ASM) via gavage for 10 consecutive days (n=8). The assessments included behavioral changes, cough sensitivity (latency and frequency), lung histopathology, inflammatory cell counts and cytokine/mediator levels in the bronchoalveolar lavage fluid (BALF), oxidative stress markers in the lung tissue, and expressions of proteins related with cough hypersensitivity and pyroptosis. RESULTS: The rat models of PIC exhibited reduced mental alertness, accelerated respiration, and pronounced symptoms such as coughing, sneezing, and facial scratching with significantly shortened cough latency and increased 5-min cough frequency. Histopathological analysis revealed collapsed alveolar structures, thickened alveolar septa, and extensive inflammatory cell infiltration in the bronchi and peribronchial regions, accompanied by elevated bronchial and alveolar inflammation scores of the rat models. In the BALF, inflammatory cell counts and the levels of IL-1β, TNF-α, IL-6, COX-2, PGE-2, and TXA-2 were all markedly elevated, and the pulmonary oxidative stress markers (ROS and MDA) and myeloperoxidase (MPO) activity were also significantly increased. The pulmonary expressions of cough hypersensitivity-related proteins (TRPV1, SP, CGRP, and NK1R) and pyroptosis-associated markers (P-NF-κB, NLRP3, ACS, cleaved caspase-1, cleaved IL-1β, and GSDMD-N) were significantly upregulated in the model group. SMZKF interventions significantly ameliorated these pathological changes in the rat models, and high-dose SMZKF produced a similar therapeutic efficacy to that of ASM. CONCLUSIONS SMZKF alleviates cough sensitivity and airway inflammation in PIC rats possibly by inhibiting TRPV1-mediated SP/NK1R signaling and the NLRP3/caspase-1/GSDMD pyroptosis pathway.
Animals ; Cough/metabolism* ; Rats, Sprague-Dawley ; Pyroptosis/drug effects* ; Male ; TRPV Cation Channels/metabolism* ; Rats ; Drugs, Chinese Herbal/pharmacology* ; Inflammation ; Signal Transduction

Programmed death 1 (PD-1)/PD-1 ligand (PD-L1) are important signaling molecules that mediate immunosuppression. This signaling pathway leads to the evading of tumor cells from immune surveillance and plays an adverse affect on anti-tumor immunity. For grafts, the activation of PD-1/PD-L1 signaling pathway also plays an important role in the its evasion from host immune attack and the formation of immune tolerance. PD-1/PD-L1 has been shown to regulate immune tolerance in corneal, heart and lung transplantation. Its role in liver transplantation, however, has yet to be elaborated. This article reviews the potential of PD-1/PD-L1 as a marker of immune tolerance after liver transplantation.

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal cavity. However, no reliable method is currently available to assess its impact on delivery performance. In this study, a biomimetic nasal model based on three-dimensional (3D) reconstruction and three-dimensional printing (3DP) technology was developed for visualizing the deposition of drug powders in the nasal cavity. The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females. The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test. The experimental device produced the most satisfactory results with five spray times. Furthermore, particle sizes and spray angles were found to significantly affect the experimental device's performance and alter drug distribution, respectively. Additionally, mometasone furoate (MF) nasal spray (NS) distribution patterns were investigated in a goat nasal cavity model and three male goat noses, confirming the in vitro and in vivo correlation. In conclusion, the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.

Objective:To evaluate the effect of s-ketamine on perioperative myocardial injury in patients undergoing liver transplantation.Methods:This was a prospective randomized controlled study. Sixty American Society of Anesthesiologists Physical Status classification Ⅲ or Ⅳ patients, aged 18-64 yr, with New York Heart Association classⅠ-Ⅲ, undergoing elective liver transplantation with general anesthesia in our hospital from May to October 2023, were divided into 2 groups ( n=30 each) using a random number table method: s-ketamine group (group S) and control group (group C). In group S, s-ketamine was intravenously injected at a dose of 0.5 mg/kg after induction of anesthesia, followed by an infusion of 0.5 mg·kg -1·h -1 until the end of surgery. The equal volume of normal saline was given instead in group C. Central venous blood samples were collected after induction of anesthesia (T 0), at 30 min of anhepatic phase (T 1), 30 min of neopepatic phase (T 2), abdominal closure (T 3), 24 h after operation (T 4) and 72 h after operation (T 5) for determination of the concentrations of serum high-sensitivity cardiac troponin I, creatine kinase-MB isoenzyme, N-terminal pro-B-type natriuretic peptide, tumor necrosis factor-α, interleukin-6 (IL-6), IL-10 and high-mobility group protein B1 by enzyme-linked immunosorbent assay. The occurrence of adverse cardiac events during surgery and within 24 h after surgery, postoperative mechanical ventilation time, time of intensive care unit stay, and postoperative length of hospital stay were recorded. Results:Compared with group C, the concentrations of serum high-sensitivity cardiac troponin I, creatine kinase-MB isoenzyme, N-terminal pro-B-type natriuretic peptide, tumor necrosis factor-α and IL-6 at T 2-5 and high-mobility group protein B1 at T 2-4 were significantly decreased, the concentrations of serum IL-10 were increased at T 2-5, the incidence of myocardial ischemia was decreased, the mechanical ventilation time was shortened ( P<0.05), and no significant change was found in the time of intensive care unit stay and postoperative length of hospital stay in S group ( P>0.05). Conclusions:Intraoperative usage of s-ketamine can inhibit the inflammatory responses and reduce perioperative myocardial injury in the patients undergoing liver transplantation.

Objective:To explore the effect of esketamine on inflammatory cytokines and myocardial injury markers in children undergoing living-donor liver transplantation (LT).Methods:Considering the inclusion criteria, 50 children with biliary atresia were selected for living donor LT. They were equally randomized into two groups of control (C) and esketamine (E) (25 cases each). Esketamine 0.5 mg/kg was administered to group E during induction and continued at a dose of 0.5 mg·kg –1·h -1 after an induction of anesthesia. Group C provided the same dose of 0.9% sodium chloride injection during induction and then continued to pumping until the end of the procedure. Basic profiles of two groups were recorded. Hemodynamic parameters, such as heart rate (HR), mean arterial pressure (MAP) and central venous pressure (CVP), were monitored at 5 min of anesthesia induction (T 0), 30 min of anhepatic phase (T 1), immediately after repercussion (T 2), 30 min of neohepatic phase (T 3) and end of surgery (T 4) in both groups. Central venous blood samples were collected at T 0, T 1, T 3 and T 4. Serum levels of cardiac troponin I (cTnI), creatine kinase isoenzyme-MB (CK-MB) ,tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were measured. The incidence of adverse cardiac events, postoperative mechanical ventilation time, ICU stay and hospitalization length were compared. Results:As compared with T 0, mean arterial pressure (MAP) at T 2 declined markedly in group E [(48.6±12.7) mmHg (1 mmHg=0.133 kPa) vs (55.6±10.7) mmHg, P<0.001] and C [(39.3±8.0) mmHg vs (53.2±9.4) mmHg, P<0.001 ] ;As compared with T 0, the TNF-α and IL-6 spiked at T 3 in group C [169.0 (207.1) ng/L vs 43.8 (26.4) ng/L, (132.63±51.75) ng/L vs (51.79±17.83) ng/L, P<0.001] and E [78.5 (138.8) ng/L vs 43.8 (26.4) ng/L, (87.44±32.17) ng/L vs (51.79±17.83) ng/L, P<0.001 ] ; In group C, the concentration of myocardial injury markers CK-MB and cTnI rose at T 3/T 4 compared with T 0[T 3 vs T 0: 5.7 (5.4) μg/L vs 4.0 (3.5) μg/L, 0.09 (0.08) μg/L vs 0.02 (0.02) μg/L; T 4 vs T 0: 5.3 (5.0) μg/L vs 4.0 (3.5) μg/L, 0.07 (0.08) μg/L vs 0.02 (0.02) μg/L, P<0.001 ]. In group E, the levels of CK-MB and cTnI were higher at T 3/T 4 than those at T 0[T 3 vs T 0: 7.0 (5.0) μg/L vs 4.6 (2.1) μg/L, 0.06 (0.09) μg/L vs 0.03 (0.04) μg/L; T 4 vs T 0: 5.4 (4.9) μg/L vs 4.6 (2.1) μg/L, 0.03 (0.06) μg/L vs 0.03 (0.04) μg/L; P<0.001]. Compared with group C, the MAP of E rose at T 1/T 2/T 3 [(58.8±10.3) mmHg vs (53.3±8.6) mmHg, P=0.048; (48.6±12.7) mmHg vs (39.3± 8.0) mmHg, P=0.003; (55.8±7.4) mmHg vs (51.5±7.3) mmHg, P=0.044]. Compared with group C, TNF-α and IL-6 decreased in E at T 3/T 4[T 3: 78.5 (138.8) ng/L vs 169.0 (207.1) ng/L, P=0.010; (87.44±32.17) ng/L vs (132.63±51.75) ng/L, P=0.017. T 4: 62.3 (118.3) ng/L vs 141.3 (129.2) ng/L, P=0.001; (74.34±26.38) ng/L vs (100.59±30.40) ng/L, P=0.002]. Compared with group C, cTnI decreased in E at T 3/T 4[0.06 (0.09) μg/L vs 0.09 (0.08) μg/L, P=0.014; 0.03 (0.06) μg/L vs 0.07 (0.08) μg/L, P=0.003]. Compared with group C, the mechanical ventilation time in group E decreased [195 (120) min vs 315 (239) min, P<0.001]. Compared with group C, the incidence of severe hypotension [16%(4/25) vs 48% (12/25), P=0.015 ], bradycardia [12% (3/25) vs 36 % (9/25), P=0.047 ], myocardial ischemia [4 % (1 /25) vs 24 % (6/25), P=0.042 ] and premature ventricular contractions [0 vs 4 %(1/25), P=0.312 ] decreased in group E. Conclusion:Intraoperative dosing of esketamine may suppress inflammatory reactions and alleviate perioperative myocardial injury in children undergoing living-donor LT.

Objective:To analyze hip joint movement during the swing phase of the strides of stroke survivors with hemiplegia and foot drop.Methods:Thirty stroke survivors with hemiplegia and foot drop formed the observation group, while thirty matched healthy counterparts were the control group. A three-dimensional gait analysis system was used to compare the hip and ankle joint kinematics on the hemiplegic side of the observation group members with those on the corresponding side of a matched control. Pearson correlation related the maximum plantar flexion angle of the ankle and hip joints in the observation group.Results:Compared with the control group, there was a significant increase in the maximum abduction and external rotation of the hip joint during the swing phase, but a significant decrease in the maximum extension, flexion, adduction, internal rotation. The range of motion of the hip joint in the sagittal, frontal and horizontal planes was significantly smaller, as was the maximum dorsiflexion and sagittal range of motion of the ankle joint. The maximum plantar flexion angle of the ankle was positively correlated with the hip joint′s maximum flexion, maximum external rotation and sagittal joint motion, but negatively correlated with the hip′s horizontal motion.Conclusion:In stroke survivors with hemiplegia and ptosis, significant changes are observed in the three-dimensional motion during the swing phase of a stride. The mode of hip joint compensation changes depending on the severity of the foot drop.