This study aims to explore the mechanism through which Yishen Jiangtang Decoction(YSJTD) regulates endoplasmic reticulum stress(ERS)-mediated NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome to improve diabetic nephropathy(DN) in db/db mice. Thirty db/db mice were randomly divided into the model group, YSJTD group, ERS inhibitor 4-phenylbutyric acid(4-PBA) group, with 10 mice in each group. Additionally, 10 db/m mice were selected as the control group. The YSJTD group was orally administered YSJTD at a dose of 0.01 mL·g~(-1), the 4-PBA group was orally administered 4-PBA at a dose of 0.5 mg·g~(-1), and the control and model groups were given an equal volume of carboxylmethyl cellulose sodium. The treatments were administered once daily for 8 weeks. Food intake, water consumption, and body weight were recorded every 2 weeks. After the intervention, fasting blood glucose(FBG), glycosylated hemoglobin(HbA1c), urine microalbumin(U-mALB), 24-hour urine volume, serum creatinine(Scr), and blood urea nitrogen(BUN) were measured. Inflammatory markers interleukin-1β(IL-1β) and interleukin-18(IL-18) were detected using the enzyme-linked immunosorbent assay(ELISA). Renal pathology was assessed through hematoxylin-eosin(HE), periodic acid-Schiff(PAS), and Masson staining, and transmission electron microscopy(TEM). Western blot was used to detect the expression levels of glucose-regulated protein 78(GRP78), C/EBP homologous protein(CHOP), NLRP3, apoptosis-associated speck-like protein containing CARD(ASC), cysteinyl aspartate-specific proteinase(caspase-1), and gasdermin D(GSDMD) in kidney tissues. The results showed that compared to the control group, the model group exhibited poor general condition, increased weight and food and water intake, and significantly higher levels of FBG, HbA1c, U-mALB, kidney index, 24-hour urine volume, IL-1β, and IL-18. Compared to the model group, the YSJTD and 4-PBA groups showed improved general condition, increased body weight, decreased food intake, and lower levels of FBG, U-mALB, kidney index, 24-hour urine volume, and IL-1β. Specifically, the YSJTD group showed a significant reduction in IL-18 levels compared to the model group, while the 4-PBA group exhibited decreased water intake and HbA1c levels compared to the model group. Although there was a decreasing trend in water intake and HbA1c in the YSJTD group, the differences were not statistically significant. No significant differences were observed in BUN, Scr, and kidney weight among the groups. Renal pathology revealed that the model group exhibited more severe renal damage compared to the control group. Kidney sections from the model group showed diffuse mesangial proliferation in the glomeruli, tubular edema, tubular dilation, significant inflammatory cell infiltration in the interstitium, and increased glycogen staining and blue collagen deposition in the basement membrane. In contrast, the YSJTD and 4-PBA groups showed varying degrees of improvement in renal damage, glycogen staining, and collagen deposition, with the YSJTD group showing more significant improvements. TEM analysis indicated that the model group had extensive cytoplasmic edema, homogeneous thickening of the basement membrane, fewer foot processes, and widening of fused foot processes. In the YSJTD and 4-PBA groups, cytoplasmic swelling of renal tissues was reduced, the basement membrane remained intact and uniform, and foot process fusion improved.Western blot results indicated that compared to the control group, the model group showed upregulation of GRP78, CHOP, GSDMD, NLRP3, ASC, and caspase-1 expression. In contrast, both the YSJTD and 4-PBA groups showed downregulation of these markers compared to the model group. These findings suggest that YSJTD exerts a protective effect against DN by alleviating NLRP3 inflammasome activation through the inhibition of ERS, thereby improving the inflammatory response in db/db DN mice.
Animals ; Endoplasmic Reticulum Stress/drug effects* ; Diabetic Nephropathies/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Inflammasomes/drug effects* ; Male ; Kidney/pathology* ; Endoplasmic Reticulum Chaperone BiP ; Humans ; Interleukin-18/genetics* ; Mice, Inbred C57BL

Objective The aim of this study was to explore the predictive value of the systemic inflammatory immune nutri-tion score(SIINS)for the prognosis of immunotherapy for advanced gastric cancer.Methods A retrospective analysis was conducted on the clinical data of 202 patients with advanced gastric cancer who received treatment with programmed death-1(PD-1)inhibitors at the Harbin Medical University Cancer Hospital from October 2018 to July 2022.The LASSO regression analysis was used to screen prognostic indicators,construct SIINS indicator,determine the optimal cutoff value for predicting prognosis using subject operating characteristic curves,and divide patients into the high SIINS and low SIINS groups.Independent prognostic factors for overall survival(OS)were determined using univariate and multivariate Cox regression analyses.Results Four indicators,including lymphocyte count,lactate dehydrogenase,and neutrophil lymphocytes,were selected to construct the SIINS index.The prognosis of patients in the high SIINS group was significantly lower than that in the low SIINS group(P<0.05).The results of the multifactorial Cox regression a-nalysis showed that the Eastern Cooperative Oncology Group(ECOG)score,Geriatric Nutritional Risk Index(GNRI),SIINS,treatment regimen,and number of treatment lines(P<0.05)could serve as the independent predictive prognosis of immunotherapy for advanced gastric cancer.Conclusion SIINS can predict the prognosis of patients with advanced gastric cancer treated with PD-1 inhibitors.

Biomolecular condensates are formed through phase separation of biomacromolecules such as proteins and RNAs. These condensates exhibit liquid-like properties that can futher transition into more stable material states. They form complex internal structures via multivalent weak interactions, enabling precise spatiotemporal regulations. However, the use of inconsistent and non-standardized terminology has become increasingly problematic, hindering academic exchange and the dissemination of scientific knowledge. Therefore, it is necessary to discuss the terminology related to biomolecular condensates in order to clarify concepts, promote interdisciplinary cooperation, enhance research efficiency, and support the healthy development of this field.

OBJECTIVE: To observe the effect of moxibustion on small intestinal mucosal immune barrier in rats with diarrhea-predominant irritable bowel syndrome (IBS-D) and explore its underlying mechanisms. METHODS: Of 38 newborn rats from 4 healthy SPF pregnant rats, 12 neonatal rats were randomly selected in a normal group. IBS-D model was prepared by the combined measures for the rest rats, including neonatal maternal separation, acetic acid enema and chronic restraint stress. Twenty-four successfully-modeled rats were randomized into a model group and a moxibustion group, 12 rats in each one. In the moxibustion group, suspending moxibustion was delivered at bilateral "Tianshu" (ST25) and "Shangjuxu" (ST37), 20 min each time, once daily and for 7 consecutive days. Separately, before acetic acid enema (aged 35 days), after modeling (aged 45 days) and after intervention (aged 53 days), the body mass, loose stool rate (LSR) and and the minimum volume threshold when abdominal withdrawal reflex (AWR) scored 3 were observed in the rats of each group. After intervention (aged 53 days), using HE and PAS staining, the morphology of duodenum was observed, the length of villus and the depth of crypt were measured, the ratio of the length of villus to the depth of crypt was calculated; and the numbers of mucosal intraepithelial lymphocytes (IELs) and goblet cells were counted. With ELISA adopted, the contents of γ-interferon (IFN-γ), interleukin-4 (IL-4) and secretory immunoglobulin A (sIgA) in duodenal mucosa of rats were detected. The proportion of T cell subsets in duodenal mucosa was detected using flow cytometry. The microvilli and tight junctions of duodenal mucosal epithelial cells were observed by transmission electron microscopy, and the integrity of duodenal mucosa observed by scanning electron microscopy. RESULTS: Compared with the normal group, for the rats in the model group, the body mass, the minimum volume threshold when AWR scored 3, the length of duodenal villus and the the ratio of the length of villus to the depth of crypt, as well as the proportion of CD₈⁺ T subset were all reduced (P<0.01, P<0.05), the counts of goblet cells in duodenal mucosa decreased (P<0.01); LRS, the proportion of CD₄⁺ T subset and CD₄⁺/CD₈⁺, as well as the contents of IFN-γ, IL-4 and sIgA in duodenal mucosa and IFN-γ/IL-4 were all elevated (P<0.01); and the numbers of IELs rose (P<0.01). The morphology of duodenal mucosa was irregular, the villi got shorter, sparse and scattered, with uneven density. The morphology of epithelial cells was destroyed and the tight junctions damaged, with larger spaces. When compared with the model group, in the moxibustion group, the body mass, the minimum volume threshold when AWR scored 3, the length of duodenal villus and the ratio of the length of villus to the depth of crypt, as well as the counts of goblet cells in duodenal mucosa increased (P<0.01); LRS, the proportion of CD₄⁺ T subset, and CD₄⁺/CD₈⁺, as well as the contents of IFN-γ, IL-4 and sIgA in duodenal mucosa and IFN-γ/IL-4 were reduced (P<0.01); and the numbers of IELs was dropped (P<0.01). The morphology of duodenal mucosa was more regular, the villi were grew, got longer and arranged regularly, with even density. The morphology of epithelial cells was slightly destroyed, and the tight junctions partially damaged. CONCLUSION Moxibustion at "Tianshu" (ST25) and "Shangjuxu" (ST37) can reduce visceral hypersensitivity in IBS-D rats and relieve abdominal pain, diarrhea and other symptoms. Its effect mechanism may be related to the repair of small intestinal mucosal immune barrier and the improvement in the immune function in IBS-D.
Animals ; Irritable Bowel Syndrome/immunology* ; Rats ; Moxibustion ; Intestinal Mucosa/immunology* ; Female ; Diarrhea/therapy* ; Intestine, Small/immunology* ; Male ; Humans ; Rats, Sprague-Dawley ; Disease Models, Animal

Japanese spotted fever(JSF)is an infectious disease caused by Rickettsia japonica,with nonspecific clinical symptoms and a high risk of misdiagnosis.We reported a case of JSF,in which Rickettsia japonica was detected in blood cells by metagenomic next-generation sequencing.The patient recovered after treatment with doxycycline.This report provides a reference for the clinical diagnosis and treatment of JSF.
Humans ; High-Throughput Nucleotide Sequencing ; Metagenomics ; Rickettsia/isolation & purification* ; Spotted Fever Group Rickettsiosis/microbiology*

Chimeric antigen receptor gene-modified T lymphocytes(CAR-T cells)have made significant progress in the treatment of hematologic malignancies.However,the uncertainties and lack of controllability associated with their in vivo behavior remain major limitations to their clinical application.Uncontrolled or inappropriate activation of CAR-T cells at unintended locations can lead to reduced antitumor efficacy or unpredictable adverse reactions.Enabling CAR-T cells to exhibit predictable and controllable behavior in vivo,with activation occurring at the right location and at the appropriate intensity,holds the potential to significantly enhance their antitumor effectiveness and minimize adverse effects.This article systematically reviews recent strategies for"remotely controlling"CAR-T cell activity in vivo through innovative designs that allow precise regulation of CAR-T cell activity and behavior.Achieving safe,targeted,and efficient antitumor responses represents one of the key directions for the future development of CAR-T cell therapies.

Objective The aim of this study was to explore the predictive value of the systemic inflammatory immune nutri-tion score(SIINS)for the prognosis of immunotherapy for advanced gastric cancer.Methods A retrospective analysis was conducted on the clinical data of 202 patients with advanced gastric cancer who received treatment with programmed death-1(PD-1)inhibitors at the Harbin Medical University Cancer Hospital from October 2018 to July 2022.The LASSO regression analysis was used to screen prognostic indicators,construct SIINS indicator,determine the optimal cutoff value for predicting prognosis using subject operating characteristic curves,and divide patients into the high SIINS and low SIINS groups.Independent prognostic factors for overall survival(OS)were determined using univariate and multivariate Cox regression analyses.Results Four indicators,including lymphocyte count,lactate dehydrogenase,and neutrophil lymphocytes,were selected to construct the SIINS index.The prognosis of patients in the high SIINS group was significantly lower than that in the low SIINS group(P<0.05).The results of the multifactorial Cox regression a-nalysis showed that the Eastern Cooperative Oncology Group(ECOG)score,Geriatric Nutritional Risk Index(GNRI),SIINS,treatment regimen,and number of treatment lines(P<0.05)could serve as the independent predictive prognosis of immunotherapy for advanced gastric cancer.Conclusion SIINS can predict the prognosis of patients with advanced gastric cancer treated with PD-1 inhibitors.

Objective:To evaluate the gene mutation profile and prognostic significance of adult cytogenetically normal acute myeloid leukemia (CN-AML) with CEBPA-bZIP mutation. Methods:Targeted sequencing was implemented on the diagnostic bone marrow DNA samples of 141 adult CN-AML subjects with CEBPA-bZIP mutation. The nomogram model for leukemia-free survival (LFS) rate was generated by combining genetic abnormalities and clinical data. Risk stratification was conducted based on prognostic variables and the effect of risk-adjusted consolidation therapy was investigated by Kaplan-Meier method. Results:Four variables were finally included in our nomogram model after multivariate Cox analysis,and an equation for risk score calculation was obtained,risk score=1.3002×white blood cell (WBC) (≥18.77×109/L)+1.4065×CSF3R mutation positive+2.6489×KMT2A mutation positive+1.0128×DNA methylation-related genes mutation positive. According to the nomogram model,patients were further divided into low-risk group (score=0,n=46) and high-risk group (score>0,n=95). Prognostic analysis showed that the 5-year LFS rate,5-year overall survival (OS) rate,and 5-year cumulative incidence of relapse (CIR) of patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the high-risk group were 93.5％,97.1％,and 3.5％,while those in patients who received maintenance chemotherapy were 32.9％,70.5％,and 63.4％,respectively. The differences were statistically significant (all P<0.05). Allo-HSCT could significantly improve the prognosis of patients in high-risk group. However,no corresponding benefit was observed in the low-risk group. Conclusion:Adult CN-AML with CEBPA-bZIP mutation has a complex co-mutation pattern. The nomogram model based on mutations of CFS3R,KMT2A and DNA methylation-related genes together with WBC count can further divide this subset of patients into a relatively low-risk group and a relatively high-risk group. For individuals in the high-risk group,allo-HSCT is proposed as post-remission therapy. The above data will benefit the prognosis estimation and treatment decision for adult CN-AML with CEBPA-bZIP mutation.

Objective The efficacy of Zang Bi Formula(ZBF)in cardiac complications of rheumatoid arthritis(RA)was observed through animal experiments.Ultra-high performance liquid chromatography tandem time-of-flight mass spectrometry(UHPLC-TOF-MS)and network pharmacology was used to analyze the active ingredients,targets,and pathways of ZBF for the treatment of cardiac hypertrophy,and molecular docking was applied to verify the binding ability of the ingredients to pathway-related proteins.Methods TNF transgenic(TNF-Tg)mice were used as RA and RA-complexed cardiac hypertrophy models,and the left ventricular hypertrophy of mice was observed by echocardiography after 8 weeks of continuous gavage with ZBF,and WGA staining,HE staining,and Masson staining were used to observe and analyze the pathological changes of cardiac tissues.The chemical composition of ZBF was identified by UHPLC-TOF-MS technique.The public database was then used to screen the active ingredients and component targets and disease targets,construct interaction networks,and analyze the bioconcentration data as well as the docking ability of the active ingredients and proteins.Results In animal experiments,ZBF reduced cardiac weight index and cardiac weight tibia length ratio in TNF-Tg mice(P＜0.05,P＜0.01),attenuated cardiac hypertrophy(P＜0.001)and cardiomyocyte hypertrophy(P＜0.01),and alleviated inflammatory infiltration and fibrosis in the heart(P＜0.0001).A total of 24 compounds were identified from ZBF by UHPLC-TOF-MS.A total of 105 active ingredients of ZBF were screened by network pharmacological analysis,and 187 potential targets of ZBF for cardiac hypertrophy were constructed,and the enriched pathways with significance included PI3K-AKT signaling pathway,TNF signaling pathway,and MAPK signaling pathway.Conclusion ZBF attenuated myocardial hypertrophy and cardiomyocyte hypertrophy in TNF-Tg mice and alleviated inflammatory infiltration and fibrosis in the heart,and ZBF may be a potential drug for the treatment of RA and its cardiac complications in the clinic.

Central nervous system (CNS) tumors have complex causes and poor prognosis. Tumor heterogeneity is a major cause of treatment failure, and in-depth understanding of the biodiversity of CNS tumors is critical. Single-cell sequencing technology provides an opportunity to reveal the complex ecosystem of CNS tumors. In this study, we review the significance of single-cell sequencing in exploring the heterogeneity, diagnosis, treatment, and prognosis of CNS tumors from three aspects: tumor stem cells, tumor microenvironment, and cerebrospinal fluid. Although most of the findings have not been clinically applicable, they lay the foundation for the development of new guidelines for CNS tumors that help improve tumor prognosis and prevent tumor recurrence.