Hepatocellular carcinoma (HCC) is one of the fastest growing cancers in the world, ranking fourth among the causes of cancer-induced death in the world. At present, the field of HCC treatment is developing rapidly, and immunotherapy has been recognized as a promising treatment method, in which T cells play a key role in HCC immunotherapy. However, in the case of virus infection or in tumor microenvironment (TME), T cells will be continuously stimulated by antigens and then fall into the state of T cell exhaustion (Tex). This state will not only reduce the immunity of patients but also lead to poor efficacy of immunotherapy. Therefore, to deeply analyze the mechanism of Tex and to explore effective strategies to reverse Tex is the key point in the immunotherapy for HCC. This review aims to summarize the mechanism of Tex in HCC patients, and the current situation and shortcomings of drug research and development to reverse Tex at this stage, in order to provide theoretical basis for the optimization of immunotherapy regimen for HCC patients.
Humans ; Carcinoma, Hepatocellular/therapy* ; Liver Neoplasms/therapy* ; Immunotherapy/methods* ; T-Lymphocytes/immunology* ; Tumor Microenvironment/immunology* ; Animals ; T-Cell Exhaustion

Urticarial vasculitis is a skin disease with urticaria-like lesions and a histopathological pattern of leukocytoclastic vasculitis. It is considered a "hidden rash" in traditional Chinese medicine. Xuanfu is the portal that regulates qi, blood, fluid, and the ascending, descending, exiting, and entering of nutrition qi and defensive qi. Collaterals are the pathways for the circulation of qi and blood. The two accompany each other, connecting zang-fu organs, reaching the surfaces of the skin, hair, and external body, circulating qi and fluid, and moistening and protecting the skin. Based on the theory of Xuanfu-collateral, this study aimed to clarify the etiology, pathogenesis, and treatment method of urticarial vasculitis. External assault by wind and Xuanfu blockage are believed to be the initiating factors of this disease. The malnutrition of Xuanfu and collaterals and accumulated dampness-heat are important links in the occurrence and development of urticarial vasculitis. It spreads from Xuanfu to the collaterals, and blockage of the collaterals is the immanent trend of this disease. Clinically, by closely adhering to the core pathogenesis of blockage of Xuanfu-collateral, treatment method such as using wind medicinals to open Xuanfu with pungent and dispersing properties, using the method of supplement deficiency and removing the blockage, and using medicinals to promote blood circulation and remove blood stasis to unblock the blocked collaterals. The herbs are flexibly added or subtracted to unblock Xuanfu and collaterals, harmonize qi and blood, thus all symptoms can be relieved. We hope that this study will provide new ideas for the treatment of urticarial vasculitis with traditional Chinese medicine.

This study investigated the regulatory potential of salidroside (SAL), a primary active compound in Rhodiola rosea L., on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha (HIF-1a) pathway in osteoblasts. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were employed to validate whether the receptor activator of nuclear factor-?B ligand (RANKL) is the downstream target gene of HIF-1a in osteoblasts. The study also utilized lipopolysaccharide (LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo. Furthermore, conditioned medium (CM) from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1a pathway. Hypoxic condition-induced overexpression of HIF-1a upregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells. In vivo, SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1a by downregulating the expression of RANKL, vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), and angiopoietin-like 4 (ANGPTL4). In the paracrine experiment, conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. RANKL emerges as the downstream target gene regulated by HIF-1a in osteoblasts. SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.
Animals ; Osteoblasts/cytology* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Glucosides/administration & dosage* ; Cell Differentiation/drug effects* ; Phenols/administration & dosage* ; Mice ; Osteoclasts/metabolism* ; RANK Ligand/genetics* ; Rhodiola/chemistry* ; Osteogenesis/drug effects* ; Signal Transduction/drug effects* ; Interleukin-6/genetics* ; Male ; RAW 264.7 Cells ; Osteolysis/genetics* ; Humans ; Mice, Inbred C57BL

Osteosarcoma,which primarily affects children and adolescents,is a highly malignant bone tumor with high rates of disability and mortality.Therefore,the exploration of biological markers related to its occurrence,development,and prognosis is crucial.Genome-wide association studies have revealed the vital role of genetic polymorphisms in the pathogenesis of osteosarcoma.This study aims to provide new insights into reliable biomarkers of osteosarcoma through the analysis of the functional single-nucleotide polymor-phisms of tumor-related genes.

Objective To explore the independent risk factors that affect the overall survival(OS)of elderly patients with hepatocellular carcinoma(HCC,≥60 years old)and build a nomogram prediction model.Methods Clinical data of all elderly patients with HCC from the SEER database from 2005 to 2020 were downloaded from SEER database.In accordance with the inclusion and exclusion criteria,the screened patients were randomly assigned to a training group(70%)and a validation group(30%).The independent risk factors of elderly patients with HCC were determined by univariate and multivariate Cox regression analyses and further validated by Kaplan-Meier survival analysis.On the basis of the determined variables,nomograms were developed and verified to predict the OS of elderly patients with HCC at 6,12,and 24 months.The consistency index(C index),calibration curve,receiver's operating characteristic(ROC)curve,and area under curve(AUC)were used to evaluate the prediction efficiency and discrimination ability of the prediction model,and decision curve analysis(DCA)was used to evaluate the potential clinical application value of the nomogram.Results A total of 1134 elderly patients with HCC were included,with 793 in the training group and 341 in the validation group.Seven variables,including age,clinical grade,clinical stage,M stage,tumor size classification,and radiotherapy,were identified as independent prognostic factors of this population.The constructed nomogram shows excellent prediction performance,with C indices of 0.745 in the training group and 0.704 in the validation group.The AUC values of the training group at 6,12,and 24 months were 0.785,0.788,and 0.798,respectively,and those of the validation group were 0.780,0.725,and 0.607,respectively.The calibration curve shows good consistency from the predicted survival probability to the actual probability.The ROC curve and DCA show that the nomogram proposed in this study has good prediction ability.Conclusion Age,clinical grade,clinical stage,M stage,tumor size classification,and radiotherapy are important influencing factors for the survival of elderly patients with HCC.The prediction model of prognosis nomogram constructed in this study has good predictive value,and it can be used to predict the OS of elderly patients with HCC,which could be helpful for individualized survival assessment and clinical management of these patients.

Objective: To analyze the relationship between new surrogate marks of insulin resistance (IR) and bone mineral content (BMC) in adolescents, and predictive value of the new surrogate marks on low bone mass, so as to provide scientific basis for early identification and prevention of skeletal related diseases in adolescents. Methods: A total of 1 594 adolescents aged 12-18 years in Yinchuan City were selected by convenience sampling and stratified cluster random sampling from September 2017 to September 2020, and triglyceride and glucose index (TyG), triglyceride glucose-body mass index (TyG-BMI) and triglyceride/high density lipoprotein cholesterol (TG/HDL-C) were calculated as new simplified IR index. The correlation between different simplified IR indexes and BMC level was analyzed by partial correlation. Binary Logistic regression was used to analyze the relationship between IR index and low bone mass, and receiver operating characteristic (ROC) curve was constructed to analyze its evaluation effect on low bone mass. Results: After adjusting for confounding factors such as gender, age, smoking, drinking, family history of hypertension, systolic blood pressure (SBP) and diastolic blood pressure (DBP), the new surrogate marks of IR were positively correlated with BMC level (TyG: r =0.11, TyG-BMI: r =0.58, TG/HDL-C: r =0.21, P <0.01). After further adjustment of body mass index (BMI), fat mass (FM) and lean mass (LM), the relationship between IR indexes and BMC turned into negative correlation (TyG: r =-0.20, TyG-BMI: r =-0.18, TG/HDL-C: r=-0.14, P <0.01). After adjusting for confounding factors such as gender, age, smoking, drinking, family history of hypertension, SBP and DBP, Logistic regression results showed that the increase of TyG, TyG-BMI and TG/HDL-C levels reduced the possibility of low bone mass in adolescents (TyG: OR=0.63, 95%CI = 0.40-0.98, TyG-BMI: OR=0.94, 95%CI =0.93-0.96, TG/HDL-C: OR=0.31, 95%CI=0.17-0.58, P <0.01). After adjusting BMI, FM and LM, the above results were completely reversed. Girls with high TyG and TG/HDL-C levels were 4.95 and 4.38 times more likely to have low bone mass than those with low TyG and TG/HDL-C levels (TyG: OR=4.95, 95%CI =1.29- 18.95 , TG/HDL-C: OR=4.38, 95%CI=1.04-18.50, P <0.05). ROC curve showed that TyG-BMI had the best predictive value on low bone mass (AUC=0.80, 95% CI=0.77-0.83, P <0.01). Conclusion The new surrogate marks of IR in adolescents are negatively correlated with adolescent BMC, of which TyG-BMI is the best for assessing of low bone mass and can serving as a reliable indicator for early identification of low bone mass.

Objective To explore the mechanism of Juanxiao decoction in regulating type 3 innate lymphoid cells(ILC3s)in treating obese asthma.Methods Sixty male BALB/c mice were randomly divided into a normal group,model group(high-fat diet+OVA),Juanxiao decoction groups(low,middle,and high doses of 8.5,17,and 34 g/kg,respectively),and dexamethasone group(1 mg/kg)with 10 mice in each group.Except for the normal group,the other groups were fed a high-fat diet for 12 weeks,and OVA sensitization by inhalation of an atomized OVA solution was used to establish the obese asthma model.From the first inhalation,the low-,medium-,and high-dose groups of Juanxiao decoction and the dexamethasone group were administered corresponding drugs by gavage,whereas normal and model groups were administered equal amounts of saline by gavage for 7 days.The state of mice and changes in typical symptoms of obese asthma were observed.At 24 hours after the last challenge,a fully automated biochemical analyzer was used to assess four blood lipids and count inflammatory cells in alveolar lavage fluid(BALF).Hematoxylin-eosin staining was used to observe morphological changes in lung tissue and abdominal fat.Enzyme-linked immunosorbent assays were used to measure the immunoglobulin E in BALF and serum,and interleukin(IL)-1β,IL-13,and mouse thymus activation regulating chemokine(CCL17)in lung tissue.IL-17A+ILC3 and IL-22+ILC3 in lung tissue and peripheral blood were analyzed by flow cytometry.Western blot was used to detect expression of P-STAT3 protein in lung tissue.Results Compared with the normal group,model group mice showed infiltration of airway inflammatory cells and thickening of airway walls.However,compared with the model group,lung inflammation in dexamethasone and Juanxiao decoction groups was improved,especially in middle-and high-dose groups.Compared with the normal group,IL-1β,IL-17A+ILC3,IL-13,and CCL17 in lung tissue of the model group were significantly increased(P＜0.05),whereas the proportion of IL-22+ILC3 and expression of P-STAT3 were significantly decreased(P＜0.01,P＜0.05).Compared with the model group,IL-1β,IL-17A+ILC3,IL-13,and CCL17 in lung tissue were significantly decreased and the proportion of IL-22+ILC3 and expression of P-STAT3 were significantly increased in middle-and high-dose Juanxiao decoction groups(P＜0.05,P＜0.01,P＜0.001).Conclusions Juanxiao decoction improves the inflammatory environment of obese asthmatic mice and alleviates lung inflammatory and allergic reactions.Its mechanism may be related to regulating secretion of cytokines by ILC3s.

Objective:To investigate effect of Yiqi Huoxue Huazhuo Jiedu Prescription(YHHJP)on inflammatory factors of brain tissues,tight junction between brain and colon tissues,intestinal flora and bacterial metabolites in cerebral ischemia reperfusion injury(CIRI)rats based on brain-gut axis.Methods:Fifty male SD rats of SPF grade were randomly divided into sham-operation group(Sham),model group(MCAO),low,medium,high doses YHHJP groups(TCM-L/TCM-M/TCM-H).Middle cerebral artery occlusion model was established according to Zea Longa methods.Neurological function defects were detected 3 days after administra-tion.TTC staining was used to calculate infarct size of brain tissue.Pathological changes of brain tissue were observed by Nissl staining,and pathological changes of brain and colon tissues were observed by HE staining.IL-1β,IL-6,TNF-α in brain tissue and LPS con-tent in serum were detected by ELISA,and D-LA content in serum was detected by biochemical method.Gene expressions of ZO-1 and Claudin-5 in brain tissue and gene expressions of ZO-1,Claudin-1 in colon tissue were studied by Real-time fluorescent quantita-tive PCR.Intestinal flora were detected by 16S rDNA high-throughput sequencing.Results:Compared with Sham group,pathological damage of brain and colon tissue were serious in MCAO group,intestinal flora structure was significantly different,neural function im-pairment was aggravated,infarct size was increased,IL-1β,IL-6,TNF-α contents in brain tissue,and LPS,D-LA contents in serum were increased,gene expressions of ZO-1 and Claudin-5 in brain tissue and gene expressions of ZO-1 and Claudin-1 in colon tissue were decreased significantly(P<0.05).Compared with MCAO group,pathological damage of brain and colon tissue of rats were relieved in TCM-L,TCM-M,TCM-H groups,disturbance of intestinal microflora microecology was improved,neurological function impairment and infarct size were markedly decreased,IL-1β,IL-6,TNF-α contents in brain tissue were decreased,gene expressions of ZO-1 and Claudin-1 in colon tissue were increased significantly(P<0.05);LPS and D-LA contents in serum were decreased in YH-HJP medium and high doses groups,while gene expressions of ZO-1 and Claudin-5 in brain tissue were increased significantly(P<0.05).Conclusion:YHHJP has a good effect on improving CIRI,whose mechanism may be related to regulating diversity of intestinal flora,reducing release of intestinal bacterial metabolites LPS and D-LA,increasing gene expressions of tight junction proteins ZO-1,Claudin-5 and Claudin-1,and down-regulating secretion of proinflammatory cytokine.

Objective:To apply the best evidence for nutritional management in patients with chronic heart failure (CHF) into clinical practice and evaluate its effectiveness.Methods:Totally 80 CHF patients admitted to the Department of Cardiology at the Affiliated Hospital of Chengde Medical University from October 2022 to March 2023 and 23 nurses involved in the project were selected by convenience sampling. The 40 CHF patients admitted from October to December 2022 formed the baseline group, while those admitted from January to March 2023 constituted the evidence application group. Evidence-based nursing methods were implemented in four stages: evidence retrieval, current status review, evidence implementation, and effectiveness evaluation. The compliance rates of review indicators, nurses' knowledge of nutritional management for CHF patients, and patient outcomes related to nutrition status and readmission rates were compared before and after evidence-based practice.Results:After evidence-based practice, the compliance rates of review indicators increased from 0-60.87% to 80.00%-100.00%. Nurses' scores on nutritional management knowledge for CHF patients increased significantly from (48.48±13.09) to (91.30±4.82), with a statistically significant difference ( P<0.05). The NRS 2002 scores of CHF patients decreased from (3.05±0.50) to (2.10±0.44), MNA-HF scores increased from (18.20±2.64) to (21.24±2.94), and albumin levels increased from (37.33±4.98) g/L to (39.24±3.29) g/L, all with statistically significant differences ( P<0.05). The 3-month readmission rate for CHF patients in the evidence application group was 10.00% (4/40), significantly lower than the 27.50% (11/40) in the baseline group ( P<0.05) . Conclusions:Evidence-based nursing practice for nutritional management in CHF patients can enhance nurses' knowledge, improve patients' nutritional status, reduce readmission rates, and improve the quality of nursing care.

Objective To explore the effect of formononetin on alleviating inflammatory injury of C28/I2 cell,and to explain its mechanism of alleviating inflammatory injury of chondrocytes via NF-κB signaling pathway.Methods The treating concentrations of formononetin were screened,and the model of LPS-induced inflammatory injury in C28/I2 cells was established.Experimental group:normal control group,LPS group,low-dose group(12.5 μmol·L-1),medium-dose group(25 μmol·L-1),and high-dose group(50 μmol·L-1).The cell counting kit 8(CCK-8)was used to detect the effect of formononetin on chondrocyte viability.Enzyme-linked immunosorbent assay(ELISA)was used to detect the levels of inflammatory cytokine interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)in the supernatant of C28/I2 cell culture.Western blotting assay was used to measure the protein expressions of nuclear factor kappa B inhibitory protein α(IκBα),phospho-nuclear factor kappa B inhibitory protein α(p-IκBα),nuclear factor kappa B p65(NF-κB p65)and phospho-nuclear factor kappa B p65(p-NF-κB p65)in C28/I2 cells.Results The results of CCK-8 assay showed the chondrocyte viability decreased in the 10 μg·mL-1 LPS group and increased in formononetin group(P<0.01).The results of ELISA experiments showed that the administration of formononetin could reduce the levels of IL-6 and TNF-α in the supernatant of C28/I2 cells(P<0.01 or 0.05)when compared with the LPS group.The results of Western blotting showed that compared with the LPS group,the phosphorylation level of the NFκB pathway could be down-regulated in a dose-dependent way(P<0.01 or 0.05).Conclusion The formononetin can alleviate the inflammatory injury of C28/I2 cell,which is related to the modulation of the phosphorylation activation of NF-κB signal pathway.