Background/Aims: Regorafenib is recommended by guidelines and trials as a sequential second-line therapy following progression on first-line sorafenib or lenvatinib in hepatocellular carcinoma (HCC). However, efficacy is limited, highlighting the urgent need to screen suitable patients and develop sensitization strategies. Methods: Acquired sorafenib- or lenvatinib-resistant (SR or LR) HCC cell lines and organoids were established. Genome-wide CRISPR library screen was performed in SR or LR cell strains to identify synthetic lethal targets of regorafenib. RNA-seq and FITC-regorafenib efflux assay were used to elucidate ERBB3-driven downstream signaling. Preclinical mouse models of cell line- and patient-derived xenografts and clinical cohorts of HCC patients were employed to validate the efficacy of ERBB3-guided patient stratification. Results: Screening with CRISPR library, we showed that inhibition of ERBB3 was synthetic lethal with regorafenib in SR or LR cell strains and organoids. Mechanistically, SR or LR triggered feedback activation of ERBB3 signaling and mediated regorafenib efflux via ERBB3-HIF1A-ABCB1 cascade pathway, limiting sensitivity to regorafenib. Moreover, ERBB3-low tumors following SR or LR exhibited significant sensitivity to regorafenib, suggesting its potential as a predictive biomarker to screen optimal candidates for sequential therapy. Seribantumab, an ERBB3-targeting monoclonal antibody, inhibited ERBB3-HIF1A-ABCB1 cascade, and its combination with regorafenib exerted marked synergistic anti-tumor effects on ERBB3-high tumors resistant to sorafenib or lenvatinib both in vitro and in vivo. Conclusions This study revealed that ERBB3 was a key resistance factor driving limited efficacy to sequential regorafenib, but also an effective therapeutic target whose inhibition enhanced regorafenib sensitivity after SR or LR.

This study aimed to investigate the protective effects of Huangqi Guizhi Wuwu decoction (HGWD) against cerebral ischemic injury and the underlying mechanisms. A middle cerebral artery occlusion (MCAO) model was established in C57BL/6 mice to evaluate the effects of HGWD on neurobehavioral scores, cerebral infarction rate, brain water content, and oxidative stress and inflammatory markers. The mRNA and protein expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein (Bax) in brain tissue were assessed. In addition, Nrf2 knockout mice were used to verify the role of Nrf2 in the protective effects of HGWD against MCAO-induced injury. Additionally, an oxygen-glucose deprivation/reperfusion (OGD/R) model in primary neuronal cells was employed to further confirm the pharmacological effects of HGWD in vitro. The results showed that HGWD significantly ameliorated cerebral ischemic injury in MCAO mice, alleviated oxidative stress, suppressed the release of inflammatory factors, and markedly upregulated the expression of Nrf2, HO-1, and Bcl-2 while downregulating Bax expression, with consistent trends being observed at both mRNA and protein levels. The protective effects of HGWD were significantly attenuated in Nrf2 knockout mice, indicating the pivotal role of Nrf2 in HGWD-mediated protection against cerebral ischemic injury. In vitro experiments revealed that HGWD significantly increased neuronal cell viability, reduced lactate dehydrogenase(LDH) leakage, and decreased apoptosis in OGD/R-treated cells, accompanied by upregulation of Nrf2, HO-1, and Bcl-2 and downregulation of Bax. In conclusion, HGWD protects against cerebral ischemic injury by activating the Nrf2/HO-1 pathway to enhance antioxidant capacity and modulating the Bcl-2/Bax signaling pathway to inhibit apoptosis, thereby protecting brain cells from ischemic damage.

This study aimed to investigate the effects of zidovudine (AZT) on high-fat diet (HFD)-induced metabolic disturbances in rats and its underlying mechanisms. The HFD rat model was established, and the animals were divided into the control group, the model group, and the AZT-treated group at low (25 mg/kg) and high (50 mg/kg) doses. Metabolic phenotype, hepatic lipid deposition, oxidative stress, mitochondrial function, and peroxisome proliferator-activated receptor (PPAR) signaling were evaluated. AZT treatment significantly mitigated HFD-induced body weight gain and reduced both the mass and adipocyte size of inguinal and epididymal white adipose tissues; it also enhanced metabolic flexibility and improved glucose tolerance without elevating blood lactate levels. High-dose AZT further lowered hepatic triglyceride accumulation, ameliorated steatosis, and additionally, attenuated hepatic oxidative stress by increasing superoxide dismutase (SOD) activity and decreasing malondialdehyde (MDA) levels. Western blot analysis revealed that AZT upregulated hepatic PPARα and carnitine palmitoyltransferase 1α (CPT1α), while downregulating PPARγ expression. In conclusion, AZT effectively ameliorates HFD-induced metabolic disorders without inducing mitochondrial toxicity, which may be related to the promotion of fatty acid oxidation, the reduction of oxidative stress, and the modulation of both the PPAR signaling pathway and pyrimidine metabolism.

By exploring theories related to yin-yang， body and spirit， and the relationship between nature and human beings， this study proposed the holistic functional perspective in Traditional Chinese Medicine （TCM） rehabi-litation. This perspective emphasizes the influence of various internal and external factors on the body's function and health status， with the integration of form and spirit as its core concept. It integrates the principles of correspondence between nature and human beings， as well as the unity of individuals and society， positioning holistic function as the key focus in TCM rehabilitation practice. It guides the prevention， assessment， and rehabilitation treatment of functional disorders， ultimately achieving the goal of comprehensive recovery of health. Additionally， the study reviewed the current application status of the holistic functional perspective in clinical TCM rehabilitation， clarified its integration throughout the entire TCM rehabilitation process， with the goal of providing a theoretical and practical foundation for further research and application in TCM rehabilitation.

Objective To explore the characteristics of latent profiles of ego depletion in patients with heart failure,and analyze the impacts of these profiles on patients' self-management behavior.Methods 280 heart failure patients who were hospitalized in a tertiary grade A hospital were conveniently selected in Nanjing from April to October 2024 as study subjects.The investigation utilized a general information questionnaire,the Ego-Depletion Scale for Heart Failure Patients,the Self-Management Scale of Heart Failure Patients,and the Chronic Disease Self-Efficacy Scale.The latent profile categories of ego depletion was explored in heart failure patients.Univariate analysis and multiple Logistic regression analysis were used to investigate the influencing factors of different latent profile categories and the impact of each category on patients' self-management levels.Results The ego depletion of 255 heart failure patients could be classified into 3 latent profiles:self-adaptive low depletion group(35.29％),symptom distressed moderate depletion group(43.53％),and social life change high depletion group(21.18％).Multiple Logistic regression analysis showed that residence,primary caregiver,education level,New York Heart Association cardiac function grade,and self-efficacy score were factors influencing the potential profile of ego depletion in heart failure patients(P＜0.05).The comparison of self-management scores among patients in different latent profiles of ego depletion showed statistically significant differences(P＜0.05).Conclusion The level of ego depletion in patients with heart failure is high with significant heterogeneity.Medical staff should pay attention to the heterogeneity and influencing factors of ego depletion in patients with heart failure in time,and develop personalized comprehensive intervention strategies to alleviate ego depletion and improve their self-management levels.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

ObjectiveTo establish a model that can quickly identify the aroma components in different parts of Nardostachys jatamansi， so as to provide a quality control basis for the market circulation and clinical use of N. jatamansi. MethodsHeadspace solid-phase microextraction-gas chromatography-mass spectrometry（HS-SPME-GC-MS） combined with Smart aroma database and National Institute of Standards and Technology（NIST） database were used to characterize the aroma components in different parts of N. jatamansi， and the aroma components were quantified according to relative response factor（RRF） and three internal standards， and the markers of aroma differences in different parts of N. jatamansi were identified by orthogonal partial least squares-discriminant analysis（OPLS-DA） and cluster thermal analysis based on variable importance in the projection（VIP） value >1 and P<0.01. The odor data of different parts of N. jatamansi were collected by Heracles Ⅱ Neo ultra-fast gas phase electronic nose， and the correlation between compound types of aroma components collected by the ultra-fast gas phase electronic nose and the detection results of HS-SPME-GC-MS was investigated by drawing odor fingerprints and odor response radargrams. Chromatographic peak information with distinguishing ability≥0.700 and peak area≥200 was selected as sensor data， and the rapid identification model of different parts of N. jatamansi was established by principal component analysis（PCA）， discriminant factor alysis（DFA）， soft independent modeling of class analogies（SIMCA） and statistical quality control analysis（SQCA）. ResultsThe HS-SPME-GC-MS results showed that there were 28 common components in the underground and aboveground parts of N. jatamansi， of which 22 could be quantified and 12 significantly different components were screened out. Among these 12 components， the contents of five components（ethyl isovalerate， 2-pentylfuran， benzyl alcohol， nonanal and glacial acetic acid，） in the aboveground part of N. jatamansi were significantly higher than those in the underground part（P<0.01）， the contents of β-ionone， patchouli alcohol， α-caryophyllene， linalyl butyrate， valencene， 1，8-cineole and p-cymene in the underground part of N. jatamansi were significantly higher than those in the aboveground part（P<0.01）. Heracles Ⅱ Neo electronic nose results showed that the PCA discrimination index of the underground and aboveground parts of N. jatamansi was 82， and the contribution rates of the principal component factors were 99.94% and 99.89% when 2 and 3 principal components were extracted， respectively. The contribution rate of the discriminant factor 1 of the DFA model constructed on the basis of PCA was 100%， the validation score of the SIMCA model for discrimination of the two parts was 99， and SQCA could clearly distinguish different parts of N. jatamansi. ConclusionHS-SPME-GC-MS can clarify the differential markers of underground and aboveground parts of N. jatamansi. The four analytical models provided by Heracles Ⅱ Neo electronic nose（PCA， DFA， SIMCA and SQCA） can realize the rapid identification of different parts of N. jatamansi. Combining the two results， it is speculated that terpenes and carboxylic acids may be the main factors contributing to the difference in aroma between the underground and aboveground parts of N. jatamansi.

Objective To analyze the imaging features of cerebral small vessel disease in patients with type 2 diabetes mellitus by multimodal MRI.Methods The clinical data of 160 patients with cerebral small vessel disease admitted to our hospital from January to December 2020 were retrospectively analyzed.According to whether they were complicated with type 2 diabetes mellitus,they were divided into the diabetic group and the non-diabetic group,with 80 cases in each group.Both groups underwent multimodal MRI scans.And the severity of lacunar infarction,the severity of subcortical and periventricular white matter lesions,white matter integral and cerebral microbleeds of patients in the two groups were compared.Results The severity of lacunar infarction(χ2=34.076,P=0.001),subcortical white matter lesions(χ2=25.000,P=0.001),periventricular white matter lesions(χ2=22.895,P=0.001)and white matter integral(t=12.370,P=0.001)of patients in the diabetic group were significantly higher than those in the non-diabetic group.No cerebral microbleeds were detected in either group of patients.Conclusion Patients with cerebral small vessel disease and type 2 diabetes mellitus show characteristic multimodal MRI changes.The increase in the number of lacunar infarction lesions and the aggravation of white matter lesions can be used as the characteristic imaging basis for the diagnosis of type 2 diabetes mellitus related cerebral small vessel disease.

Objective:To explore the effect and mechanism of CD147 on differentiation of circulating fibrocytes and its pro-inflammatory and pro-fibrotic function.Methods:Circulating fibrocytes were extracted from peripheral blood of asthma patients,stimu-lated with CD147,and intervened with CD147 antagonist AP-9 or p38/MAPK inhibitor SB203580.Cell viability was detected by CCK-8 method,cell migration was assessed by Transwell method,expressions of collagen type Ⅰ(COL-Ⅰ),CD45 and α-SMA were detected by immunofluorescence staining.Levels of cytokines such as TGF-β1,IL-4,IL-5 and IL-13 were detected by ELISA,and expression levels of COL-Ⅰ,fibronectin(FN),α-SMA,p-TAK1,p-P38 and other proteins were detected by Western blot.Results:Low dose of CD147 increased cell viability of circulating fibrocytes.CD147 significantly promoted migration of circulating fibrocytes and induces their differentiation into myofibrocytes.CD147 significantly increased secretion of cytokines such as TGF-β1,IL-4,IL-5 and IL-13 in circulating fibrocytes.CD147 significantly increased expressions of COL-Ⅰ,FN,α-SMA,p-TAK1,p-P38 in circulating fibrocytes.AP-9 or SB203580 significantly inhibited effect of CD147 on circulating fibrocytes.Conclusion:CD147 can promote proliferation,mi-gration,differentiation and pro-inflammatory and profibrotic function of circulating fibrocytes in vitro,and TAK1-p38/MAPK signaling pathway is involved in CD147-mediated regulation of circulating fibrocytes.