ObjectiveTo investigate the possible mechanism of action of Xibining Formula （膝痹宁） for cartilage damage in knee osteoarthritis （KOA） through the cyclic guanosine-adenosine monophosphate synthase （cGAS）- stimulator of interferon genes （STING） signaling pathway. MethodsFifty C57BL/6J mice were randomly divided into five groups （10 per group）， sham operation group， KOA model group， low-dose Xibining Formula group， high-dose Xibining Formula group， and high-dose Xibining Formula + agonist group. The KOA models were constructed using the destabilization of the medial meniscus （DMM） method in all groups but the sham surgery group. Two weeks after surgery， the low- and high-dose Xibining Formula groups were administered Xibining Formula at doses of 3.58 g/（kg·d） and 14.32 g/（kg·d） respectively via gavage. The high-dose Xibining Formula + agonist group received 14.32 g/（kg·d） of Xibining Formula via gavage followed by an intraperitoneal injection of Vadimezan （DMXAA） at 25 mg/kg. The sham surgery group and the KOA model group mice were given an equivalent volume of normal saline at 5 ml/（kg·d） via gavage， once daily for four consecutive weeks. Serum levels of tumor necrosis factor-alpha （TNF-α）， interleukin-1β （IL-1β）， and interleukin-6 （IL-6） were measured by ELISA； pathological changes in cartilage tissue were observed using hematoxylin-eosin （HE） staining and Safranin O-Fast Green staining. Pathological changes were scored according to the Mankin scoring system； the levels of cartilage tissue matrix regulation-related indicators such as matrix metalloproteinase 3 （MMP3）， matrix metalloproteinase 13 （MMP13）， a disintegrin and metalloproteinase with thrombospondin motifs 5 （ADAMTS）， type-Ⅱ collagen （CⅡ） and aggregated proteoglycan （Aggrecan）， and also cGAS-STING pathway-related protein and mRNA expression levels were detected by Western blot and qPCR methods. ResultsCompared with the sham surgery group， the KOA model group showed severe cartilage edge destruction， significantly increased Mankin scores， significantly decreased protein and mRNA expression levels of COLⅡ and Aggrecan， and significantly increased protein and mRNA expression levels of cGAS， STING， MMP3， MMP13， and ADAMTS5 （P＜0.01）. Compared with the control group， serum level of IL-6， IL-1β， TNF-α in all the intervented groups decreased （P＜0.01）， while compared with high-dose Xibining Formula group， level of IL-6， IL-1β， and TNF-α in low-dose Xibining Formula group and high-dose Xibining Formula + agonist group increased （P＜0.01）. Compared with the KOA model group， all the intervention groups exhibited alleviated cartilage pathological changes， signi-ficantly reduced Mankin scores， significantly increased protein and mRNA expression levels of COLⅡ and Aggrecan， and significantly decreased protein and mRNA expression levels of cGAS， STING， MMP3， MMP13， and ADAMTS5 （P＜0.01）. Compared with high-dose Xibining Formula group， high-dose Xibining Formula + agonist group showed cartilage edge destruction， significantly increased Mankin scores， significantly decreased protein and mRNA expression levels of COLⅡ and Aggrecan， and increased protein and mRNA expression levels of cGAS， STING， MMP3， MMP13， and ADAMTS5 （P＜0.01）. ConclusionXibining Formula may improve KOA cartilage damage by inhibiting the cGAS-STING signaling pathway， decreasing matrix degradation-related proteins， and elevating matrix composition-related proteins.

Intestinal mucositis is a common complication induced by chemotherapy in malignant tumors， which severely compromises the efficacy of chemotherapy and reduces patients’ quality of life. This article systematically reviews the pathological mechanisms underlying chemotherapy-induced intestinal mucositis， encompassing oxidative damage， inflammatory injury， apoptotic damage， disruption of the intestinal barrier， and intestinal dysbiosis. Additionally， it provides a comprehensive summary of current therapeutic strategies for intestinal mucositis， including chemical agents and composite materials， natural products， compound prescription of traditional Chinese medicine， growth factors， blood products， and fecal microbiota transplantation. Future efforts should strengthen multidisciplinary cross-innovation， integrating animal models and large-scale clinical trials to develop highly effective and low-toxicity therapeutic drugs that balance chemotherapy toxicity and antitumor efficacy.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Identifying drug-drug interactions (DDIs) is essential to prevent adverse effects from polypharmacy. Although deep learning has advanced DDI identification, the gap between powerful models and their lack of clinical application and evaluation has hindered clinical benefits. Here, we developed a Multi-Dimensional Feature Fusion model named MDFF, which integrates one-dimensional simplified molecular input line entry system sequence features, two-dimensional molecular graph features, and three-dimensional geometric features to enhance drug representations for predicting DDIs. MDFF was trained and validated on two DDI datasets, evaluated across three distinct scenarios, and compared with advanced DDI prediction models using accuracy, precision, recall, area under the curve, and F1 score metrics. MDFF achieved state-of-the-art performance across all metrics. Ablation experiments showed that integrating multi-dimensional drug features yielded the best results. More importantly, we obtained adverse drug reaction reports uploaded by Xiangya Hospital of Central South University from 2021 to 2023 and used MDFF to identify potential adverse DDIs. Among 12 real-world adverse drug reaction reports, the predictions of 9 reports were supported by relevant evidence. Additionally, MDFF demonstrated the ability to explain adverse DDI mechanisms, providing insights into the mechanisms behind one specific report and highlighting its potential to assist practitioners in improving medical practice.

OBJECTIVE: To investigate whether the G protein-coupled estrogen receptor (GPER) can attenuates acute lung injury in mice with exertional heat stroke (EHS) by inhibiting ferroptosis. METHODS: Sixty SPF-grade male C57BL/6 mice were randomly divided into four groups: normal control group (control group), EHS model group (EHS group), dimethyl sulfoxide (DMSO) solvent group (EHS+DMSO group), and GPER-specific agonist G1 group (EHS+G1 group), with 15 mice in each group. All mice underwent 14 days of adaptive training at 24-26 centigrade before modeling, and the EHS model was established using a high-temperature treadmill device. After successful modeling, the mice were allowed to cool naturally at room temperature. In the EHS+G1 group, 40 μg/kg of the GPER-specific agonist G1 was slowly injected intraperitoneally immediately after modeling. In the EHS+DMSO group, 40 μg/kg of DMSO was slowly injected intraperitoneally immediately after modeling. The control group received no treatment. Five hours after modeling, abdominal aortic blood was collected, and lung tissues were harvested after euthanasia. The lung coefficient was calculated to evaluate lung injury. Lung histopathological changes were observed under a light microscope after hematoxylin-eosin (HE) staining, and a lung histopathological score was assigned. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), malondialdehyde (MDA), and Fe²⁺ in lung tissue. Immunofluorescence was used to detect the expression of glutathione peroxidase 4 (GPX4). Real-time polymerase chain reaction (RT-PCR) was used to detect the mRNA expression of GPX4, ferroportin 1 (FPN1), and ferritin heavy chain 1 (FTH1). Western blotting was performed to detect the protein expression of GPX4, FPN1, and FTH1. RESULTS: Compared with the control group, the lung coefficient and lung histopathological score were significantly increased in the EHS group. HE staining showed significant thickening and unevenness of the alveolar septa and alveolar walls, partial alveolar collapse, and extensive erythrocyte, inflammatory cell, and plasma-like material extravasation in the alveolar spaces. Serum levels of TNF-α, IL-1β, MDA, and Fe²⁺ were significantly elevated. Immunofluorescence staining showed a significant decrease in GPX4-positive expression in lung tissue. Western blotting and RT-PCR showed significantly reduced protein and mRNA expression of GPX4, FPN1, and FTH1 in lung tissue. Compared with the EHS group, the EHS+G1 group showed a significant reduction in lung coefficient and lung histopathological score [lung coefficient (mg/g): 3.9±0.1 vs. 4.6±0.3, lung histopathological score: 4.2±0.2 vs. 6.9±0.2, both P < 0.05]. HE staining revealed reduced severity of lung tissue fluid extravasation, inflammatory infiltration, decreased hemorrhage, and less severe alveolar structural damage. Serum levels of TNF-α, IL-1β, MDA, and Fe²⁺ were significantly reduced [TNF-α (ng/L): 44.3±0.2 vs. 64.6±0.3, IL-1β (ng/L): 69.3±0.4 vs. 97.8±0.2, MDA (nmol/L): 2.8±0.3 vs. 3.6±0.5, Fe²⁺ (nmol/L): 0.021±0.004 vs. 0.028±0.004, all P < 0.05]. Immunofluorescence staining showed a significant decrease in GPX4-positive expression in lung tissue (fluorescence intensity: 35.53±2.41 vs. 16.45±0.31, P < 0.05). RT-PCR and Western blotting showed significantly increased mRNA and protein expression of GPX4, FPN1, and FTH1 in lung tissue [mRNA expression: GPX4 mRNA (2^-ΔΔCt): 0.44±0.05 vs. 0.09±0.01, FPN1 mRNA (2^-ΔΔCt): 0.77±0.17 vs. 0.42±0.14, FTH1 mRNA (2^-ΔΔCt): 0.75±0.04 vs. 0.58±0.01; protein expression: GPX4/β-actin: 0.96±0.11 vs. 0.24±0.04, FPN1/β-actin: 1.26±0.21 vs. 0.44±0.14, FTH1/β-actin: 0.27±0.12 vs. 0.15±0.07; all P < 0.05]. However, there were no statistically significant differences in any of the above indicators between the EHS+DMSO group and the EHS group. CONCLUSION Activation of GPER can attenuate EHS-related lung injury in mice, and its mechanism may be related to the activation of the GPX4 signaling pathway and inhibition of ferroptosis.
Animals ; Mice, Inbred C57BL ; Male ; Mice ; Heat Stroke/metabolism* ; Receptors, G-Protein-Coupled ; Ferroptosis ; Receptors, Estrogen ; Acute Lung Injury/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-1beta/metabolism* ; Lung Injury ; Lung/metabolism*

Objective:To explore the application of C-reactive protein(CRP) to prealbumin (PA) ratio(CRP/PA) for diagnosis and prognosis evaluation of sepsis.Methods:By a retrospective study, a total of 95 sepsis patients (sepsis group) and 100 local infection patients(non-sepsis group) treated in Dongying People′s Hospital from September 2021 to September 2022 were enrolled. Sepsis patients were divided into survival group(57 cases) and death group (38 cases) according to the 28-day outcome. The clinical data were collected and CRP/PA was calculated. Multivariate Logistic regression and Cox regression were used to analyze the relationship between various indicators and the occurrence and prognosis of sepsis, and receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic and prognostic value of CRP/PA for sepsis. Kaplan-Meier survival analysis was used to evaluate the prognostic value of different CRP/PA ratios for patients with sepsis.Results:The systolic blood pressure, diastolic blood pressure, prealbumin were lower and heart rate, respiratory rate, CRP, CRP/PA, procalcitonin were higher in the sepsis group compared to the non-sepsis group: (117.27 ± 11.65) mmHg (1 mmHg = 0.133 kPa) vs. (123.26 ± 10.71) mmHg, (69.42 ± 8.58) mmHg vs. (75.44 ± 6.53) mmHg, (174.09 ± 24.77) g/L vs. (207.13 ± 34.31) g/L, (97.87 ± 12.73) bpm vs. (86.90 ± 10.19) bpm, 22.0(20.00, 25.00) times/min vs. 21.00(19.00, 23.00) times/min, (93.96 ± 19.64) mg/L vs. (77.56 ± 22.54) mg/L, 0.54(0.44, 0.65) vs. 0.37(0.28, 0.46), 3.35(2.16, 4.17) μg/L vs. 1.52(0.81, 2.16) μg/L, there were statistical differences ( P<0.05). Multivariate Logistic regression analysis showed that CRP/PA and procalcitonin were risk factors for sepsis ( P<0.05). The results of ROC curve showed that the area under the curve (AUC) of CRP/PA in diagnosis of sepsis was 0.821, the specificity and sensitivity was 76.0% and 93.7%, respectively. The diastolic blood pressure, prealbumin, neutrophil were higher and the heart rate, respiratory rate, CRP, CRP/PA, lymphocytes, procalcitonin were lower in the survival group compared to the death group: (71.76 ± 8.86) mmHg vs. (67.86 ± 8.10) mmHg, (181.46 ± 24.35) g/L vs. (163.05 ± 21.28) g/L, (63.46 ± 9.88) × 10 9/L vs.(57.13 ± 8.64) × 10 9/L, (95.68 ± 13.48) times/min vs. (101.16 ± 10.88) times/min, 22.00(19.50, 24.00) times/min vs. 24.00(20.00, 28.00) times/min, (88.09 ± 19.35) mg/L vs. (102.76 ± 16.75) mg/L, 0.46(0.41, 0.58) vs. 0.63(0.55, 0.72), 21.00(16.00, 30.00) ×10 9/L vs. 29.50(18.00, 37.30) ×10 9/L, 2.94(2.10, 3.97) μg/L vs. 3.82(2.21, 4.77) μg/L, there were statistical differences ( P<0.05). Multivariate Cox regression analysis showed that CRP/PA and procalcitonin were independent risk factors for the prognosis of sepsis ( P<0.05). The AUC of CRP/PA in predicting the prognosis of sepsis was 0.827, the specificity and sensitivity was 92.1% and 63.8%, respectively. Grouped by the cut-off of CRP/PA (0.48), the 28-day mortality rate of patients in the CRP/PA>0.48 was significantly higher than that of patients in the CRP/PA≤0.48, there was statistical difference ( P<0.01). Conclusions:CRP/PA ratio can be used as an index for diagnosis and prognosis evaluation of sepsis.

Asia-Pacific Association for the Study of the Liver published the guidelines on management of ascites in liver disease in May 2023， which introduces the diagnosis， differential diagnosis， and treatment of ascites， hyponatremia， hepatic hydrothorax， and hepatorenal syndrome in patients with liver cirrhosis and acute-on-chronic liver failure. This article summarizes the main recommendations in the guidelines， so as to provide a reference for the treatment of ascites in patients with liver diseases in China.

Existing studies have underscored the pivotal role of N-acetyltransferase 10 (NAT10) in various cancers. However, the outcomes of protein-protein interactions between NAT10 and its protein partners in head and neck squamous cell carcinoma (HNSCC) remain unexplored. In this study, we identified a significant upregulation of RNA-binding protein with serine-rich domain 1 (RNPS1) in HNSCC, where RNPS1 inhibits the ubiquitination degradation of NAT10 by E3 ubiquitin ligase, zinc finger SWIM domain-containing protein 6 (ZSWIM6), through direct protein interaction, thereby promoting high NAT10 expression in HNSCC. This upregulated NAT10 stability mediates the enhancement of specific tRNA ac⁴C modifications, subsequently boosting the translation process of genes involved in pathways such as IL-6 signaling, IL-8 signaling, and PTEN signaling that play roles in regulating HNSCC malignant progression, ultimately influencing the survival and prognosis of HNSCC patients. Additionally, we pioneered the development of TRMC-seq, leading to the discovery of novel tRNA-ac⁴C modification sites, thereby providing a potent sequencing tool for tRNA-ac⁴C research. Our findings expand the repertoire of tRNA ac⁴C modifications and identify a role of tRNA ac⁴C in the regulation of mRNA translation in HNSCC.
Humans ; DNA-Binding Proteins ; Head and Neck Neoplasms/genetics* ; N-Terminal Acetyltransferases ; RNA, Transfer ; Serine ; Signal Transduction ; Squamous Cell Carcinoma of Head and Neck

Insulin resistance （IR） is an important pathological and physiological mechanism of type 2 diabetes （T2DM）， and the treatment of IR has become the key to the prevention and treatment of T2DM. IR is a state of insensitivity or reduced sensitivity of insulin-stimulated tissue cells to glucose， resulting in cells that are unable to efficiently take up glucose in the bloodstream and thus causing hyperglycemia. Adenosine monophosphate-activated protein kinase （AMPK） is an energy-sensing enzyme that can regulate multiple metabolic pathways and maintain the stability of adenosine triphosphate （ATP） in the cell. In recent years， traditional Chinese medicine （TCM） has played an increasingly important role in the prevention and treatment of T2DM. The research on exploring the AMPK signaling pathway of TCM intervention in the progress of T2DM has gradually increased. Many pharmacological studies have shown that TCM has advantages such as safety and high efficiency in the prevention and treatment of T2DM. AMPK signaling pathway is one of the key pathways for the active ingredients of TCM and TCM extracts to improve IR. Active ingredients such as phenols， flavonoids， polysaccharides， alkaloids， and saponins， as well as other herbal extracts can improve IR by activating the AMPK signaling pathway cascade response， thereby improving IR by regulating glucolipid metabolism， inhibiting inflammatory response， anti-oxidative stress and maintaining mitochondrial homeostasis. Based on this， this paper reviews the pharmacological and experimental research results of TCM intervening the AMPK signaling pathway to improve IR in recent years， expecting to provide reference for further research， development and application of TCM in intervening IR and treating T2DM.