ObjectiveTo investigate the therapeutic effect of Shaoyao Gancaotang （SYGCT） on high-fat diet （HFD）-aggravated colitis induced by dextran sulfate sodium （DSS） in mice and decipher the potential mechanism. MethodsForty male C57BL/6J mice were fed an HFD for 14 days， followed by gavage of 2%DSS for 7 days for the modeling of HFD-aggravated colitis. The mice were randomly allocated into control， model （HFD-aggravated colitis）， low-dose （5.2 g·kg^-1） SYGCT， high-dose （10.4 g·kg^-1） SYGCT， and 5-aminosalicylic acid （5-ASA， positive control， 50 mg·kg^-1） groups. Body mass changes and disease activity index （DAI） scores were recorded. The colon length was measured. Pathological changes in the colon tissue were observed through hematoxylin-eosin （HE） staining. Transcriptomic analysis was performed to identify differentially expressed genes. Western blot was employed to quantify the protein levels of Occludin， Claudin3， solute carrier family 7 member 11 （SLC7A11）， glutathione peroxidase 4 （GPX4）， and ferritin heavy chain 1 （FTH1）. ResultsCompared with the control group， the model group exhibited diarrhea， bloody stools， increased DAI scores （P<0.01）， colon shortening （P<0.01）， severe colonic pathological damage， and reduced expression of tight junction proteins Occludin and Claudin3 （P<0.05， P<0.01）. Transcriptomic analysis revealed that the differentially expressed genes between the high-dose SYGCT group and the model group were significantly enriched in the ferroptosis signaling pathway. Compared with the model group， SYGCT treatment alleviated diarrhea and bloody stools， reduced DAI scores （P<0.01）， increased the colon length （P<0.01）， mitigated colonic pathological damage， and upregulated the expression of Occludin and Claudin3 （P<0.01）， as well as proteins （SLC7A11， GPX4， and FTH1） associated with the inhibition of ferroptosis （P<0.05）. ConclusionSYGCT significantly ameliorates HFD-aggravated DSS-induced colitis by suppressing ferroptosis via activation of the SLC7A11/GPX4 pathway.

BACKGROUND:Although researchers have noted that fibroblast growth factor receptor 1 shows great potential in rheumatoid arthritis bone destruction,there is a lack of reviews related to the potential mechanisms of fibroblast growth factor receptor 1 in rheumatoid arthritis bone destruction. OBJECTIVE:To comprehensively analyze the mechanism of fibroblast growth factor receptor 1 in bone destruction in rheumatoid arthritis by reviewing the relevant literature at both home and abroad. METHODS:We searched the CNKI database using the Chinese search terms"fibroblast growth factor receptor 1,rheumatoid arthritis,bone destruction,bone cells,osteoblasts,osteoclasts,chondrocytes,macrophages,synovial fibroblasts,T cells,vascular endothelial cells."PubMed database was searched using the English search terms"fibroblast growth factor receptor 1,rheumatoid arthritis,bone destruction,osteocytes,osteoblasts,osteoclasts,chondrocytes,macrophages,synovial fibroblasts,T cells,endothelial cells."The search period focused on April 1992 to January 2024.After screening the literature by reading titles,abstracts,and full texts,a total of 82 articles were finally included for review according to inclusion and exclusion criteria. RESULTS AND CONCLUSION:Fibroblast growth factor receptor 1 was found to be widely expressed in bone tissue-associated cells,including osteoblasts,osteoclasts,and osteoclasts.Fibroblast growth factor receptor 1 affects bone remodeling and homeostasis by regulating the function of these cells,as well as promoting the onset and progression of bone destruction in rheumatoid arthritis.Fibroblast growth factor receptor 1 is involved in the inflammatory response of synovial fibroblasts and macrophages and regulates angiogenesis of endothelial cells in synovial tissues.Fibroblast growth factor receptor 1 promotes bone destruction in several ways.Fibroblast growth factor receptor 1 may be a potential causative agent of bone destruction in rheumatoid arthritis and provides a reference for further research on its therapeutic targets.

Autoimmune hepatitis （AIH） is a chronic inflammatory liver disease. The pathogenesis of AIH remains unclear， but it is mainly autoimmune injury caused by the breakdown of autoimmune tolerance due to the abnormal activation of the immune system， while the specific molecular mechanism remains unknown. Recent studies have shown that abnormal amino acid metabolism plays an important role in the development and progression of AIH. This article reviews the research advances in amino acid metabolic reprogramming in AIH， in order to provide a theoretical basis for amino acid metabolism as a new target for the clinical diagnosis and treatment of AIH.

BACKGROUND:Preliminary research by our group suggests that targeting fibroblast growth factor receptor 1(FGFR1)may be an effective strategy for treating RA. OBJECTIVE:To investigate the effects of an FGFR1 inhibitor(PD173074)on bone destruction in rats with collagen-induced arthritis. METHODS:Twenty-five female Sprague-Dawley rats were randomly divided into five groups:normal control group,model group,methotrexate group,low-dose PD173074 group,and high-dose PD173074 group.Except for the normal control group,rat models of type Ⅱ collagen-induced arthritis were made in each group.After successful modeling,rats were injected intraperitoneally with sterile PBS in the normal and model groups,1.04 mg/kg methotrexate in the methotrexate group,and 5 and 20 mg/kg in the low-dose group and high-dose PD173074 groups,once a week.After 4 weeks of drug administration,clinical symptoms and joint swelling in rats were observed.Micro-CT was used for three-dimensional reconstruction and analysis of the ankle joints.Pathological changes in the ankle joints were observed.Periarticular angiogenesis and the expression of receptor activator of nuclear factor-Κb ligand were detected.The expression levels of p-FGFR1,vascular endothelial growth factor A,and tartrate-resistant acid phosphatase in the synovial membrane were measured.Pathological changes in the liver,spleen,and kidney were observed and liver,spleen,and kidney indices were calculated. RESULTS AND CONCLUSION:PD173074 could alleviate clinical symptoms and joint swelling,delay bone loss,improve bone structure,reduce synovial invasion and cartilage bone erosion,reduce the number of periarticular osteoclasts,inhibit angiogenesis in synovial tissues,reduce the expression of receptor activator of nuclear factor-Κb ligand,and inhibit the expression of FGFR1 phosphorylated protein,tartrate-resistant acid phosphatase and vascular endothelial growth factor A.Pathologic observation of the liver,spleen and kidney in rats showed no obvious toxic side effects after PD173074 treatment.To conclude,the FGFR1 inhibitor can delay the progression of joint inflammation and bone destruction and inhibit angiogenesis in the rat model of type Ⅱ collagen-induced arthritis.The therapeutic effect of PD173074 has been preliminarily validated in the type Ⅱ collagen-induced arthritis model and may act by inhibiting FGFR1 phosphorylation,which provides a direction for the search of new therapeutic targets for rheumatoid arthritis.

All four patients were female, with an average age of 28.8 days and an average weight of 3.64 kg. Only case 4 was born prematurely at 34 W+5 and was treated conservatively until 71 days to complete operation. All the others completed primary corrective surgery in the neonatal period, and all survived after operation. Two different surgical techniques were used to repair the aortic-pulmonary window and the aortic origin of the right pulmonary artery, including 1 case using the aortic internal baffle technique and another 3 cases underwent replantation of the right pulmonary artery (1 case was reconstructed in situ, and the other 2 cases were reconstructed by moving the right pulmonary artery in the anterior of aorta). Case 2 who received aortic internal baffle technique underwent two reoperation because of right pulmonary artery stenosis. While, right pulmonary artery of cases 3 and 4 developed well after being reconstructed the right pulmonary artery anterior translocation. After the diagnosis of Berry syndrome through cardiac color ultrasound and CT angiography, a primary surgical radical treatment should be performed as soon as possible at an experienced pediatric cardiac center. Although the surgery is high-risk and complex, it is safe and effective.

OBJECTIVE: To explore the impact of age on the genetic variant spectrum and prognosis of patients with previously untreated Diffuse large B-cell lymphoma (DLBCL). METHODS: A retrospective analysis was conducted on the clinical data and follow-up information of 254 previously untreated DLBCL patients from 14 hospitals in the Jiangsu Cooperative Lymphoma Group (JCLG) enrolled from July 2018 and July 2023. Following extraction of DNA from tumor tissue samples, next-generation sequencing (NGS) technique was employed to analyze the genetic variant spectrum of the DLBCL patients, with an evaluation of the relationship between age and genetic variants as well as prognosis. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Nantong University (Ethics No.: 2023-K048-01). RESULTS: The median age of the 254 DLBCL patients was 62 years old, with 55% of patients aged 60 years or above. Clinical evaluation showed that younger (< 60 years) patients had higher complete response (CR) (70% vs. 59%), and objective response rate (ORR) (88% vs. 79%) than older patients, though the difference between the two groups was not statistically. Survival analysis indicated that both the five-year overall survival (OS) (82.7% vs. 71.7%, P = 0.006) and progression-free survival (PFS) (70.6% vs. 50.2%, P < 0.05) rates were significantly higher in younger patients. NGS showed that 99.6% of the patients harbored genetic variants, with PIM1, KMT2D, TP53, MYD88, and CD79B being the most common genes. Age significantly affected the variant frequency of certain genes, with MYC variants serving an adverse prognostic factor for OS in younger patients (P = 0.002), while TP53 (P = 0.024) and BCL2 (P = 0.002) variants significantly impacted OS in older patients. Prognostic analysis identified age ≥ 60 years (HR = 3.439, 95%CI: 1.318~9.874), presence of B symptoms (HR = 2.871, 95%CI = 1.133~7.307), and elevated lactate dehydrogenase (HR = 3.528, 95%CI = 1.231~10.66) as independent adverse prognostic factors. CONCLUSION Age, genetic variants, and clinical factors may significantly affect the prognosis of the DLBCL patients. Younger patients have better survival compared to older patients. Variants of the MYC, BCL2, and TP53 genes are closely associated with poor prognosis.
Humans ; Lymphoma, Large B-Cell, Diffuse/diagnosis* ; Middle Aged ; Female ; Male ; Retrospective Studies ; Aged ; Prognosis ; Adult ; Aged, 80 and over ; High-Throughput Nucleotide Sequencing ; Young Adult ; Adolescent ; Genetic Variation

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

Peptide-based radiopharmaceuticals targeting integrin α5β1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target α5β1 demonstrate inadequate in vivo performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an α5β1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [⁶⁴Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [⁶⁴Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [⁶⁴Cu]QM-2303 from the bloodstream. Administration of a single dose of [¹⁷⁷Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for α5β1-overexpressing tumors.

BACKGROUND: Pancreatic cancer is a lethal malignancy prone to gemcitabine resistance. The single-strand selective monofunctional uracil DNA glycosylase (SMUG1), which is responsible for initiating base excision repair, has been reported to predict the outcomes of different cancer types. However, the function of SMUG1 in pancreatic cancer is still unclear. METHODS: Gene and protein expression of SMUG1 as well as survival outcomes were assessed by bioinformatic analysis and verified in a cohort from Fudan University Shanghai Cancer Center. Subsequently, the effect of SMUG1 on proliferation, cell cycle, and migration abilities of SMUG1 cells were detected in vitro . DNA damage repair, apoptosis, and gemcitabine resistance were also tested. RNA sequencing was performed to determine the differentially expressed genes and signaling pathways, followed by quantitative real-time polymerase chain reaction and Western blotting verification. The cancer-promoting effect of forkhead box Q1 (FOXQ1) and SMUG1 on the ubiquitylation of myelocytomatosis oncogene (c-Myc) was also evaluated. Finally, a xenograft model was established to verify the results. RESULTS: SMUG1 was highly expressed in pancreatic tumor tissues and cells, which also predicted a poor prognosis. Downregulation of SMUG1 inhibited the proliferation, G1 to S transition, migration, and DNA damage repair ability against gemcitabine in pancreatic cancer cells. SMUG1 exerted its function by binding with FOXQ1 to activate the Protein Kinase B (AKT)/p21 and p27 pathway. Moreover, SMUG1 also stabilized the c-Myc protein via AKT signaling in pancreatic cancer cells. CONCLUSIONS SMUG1 promotes proliferation, migration, gemcitabine resistance, and c-Myc protein stability in pancreatic cancer via protein kinase B signaling through binding with FOXQ1. Furthermore, SMUG1 may be a new potential prognostic and gemcitabine resistance predictor in pancreatic ductal adenocarcinoma.
Humans ; Pancreatic Neoplasms/pathology* ; Forkhead Transcription Factors/genetics* ; Signal Transduction/genetics* ; Animals ; Cell Line, Tumor ; Proto-Oncogene Proteins c-akt/metabolism* ; Cell Proliferation/physiology* ; Mice ; Uracil-DNA Glycosidase/genetics* ; Female ; Male ; Gemcitabine ; Mice, Nude ; Apoptosis/physiology* ; Deoxycytidine/analogs & derivatives* ; Cell Movement/genetics*

Objective To evaluate value of combined detection of cerebrospinal fluid synaptosom-al-associated protein 25(SNAP-25)and long non-coding RNA nuclear-enriched transcript 1(NEAT1)in assessing cognitive impairment severity and disease progression in patients with Alzhei-mer's disease.Methods A total of 650 patients with Alzheimer's disease were selected as research subjects and divided into normal group(n=162),mild cognitive impairment group(n=380)and dementia group(n=108)according to their cognitive function.The correlations of the levels of SNAP-25 and NEAT1 in cerebrospinal fluid with the scores of Mini-Mental State Examination(MMSE)and Clinical Dementia Rating Scale(CDR)were analyzed.According to whether the patients in the mild cognitive impairment group progressed to dementia(followed up for 6 months),they were divided into disease progression group(progressed to dementia)and stable disease group(did not progress to dementia).The levels of SNAP-25 and NEAT1 in cerebrospinal fluid of patients in each group were compared.The receiver operating characteristic(ROC)curve was used to analyze the diagnostic value of cerebrospinal fluid SNAP-25 combined with NEAT1 for dementia and its predictive efficacy for the progression of mild cognitive impairment to dementia.Results The levels of SNAP-25 and NEAT1 mRNA in cerebrospinal fluid in the mild cognitive impairment group and the dementia group were significantly higher than those in the normal group;the levels of cerebrospinal fluid SNAP-25 and NEAT1 mRNA in the dementia group were significantly higher than those in the mild cognitive impairment group(P＜0.05).The levels of cerebrospinal fluid SNAP-25 and NEAT1 mRNA in pa-tients of the mild cognitive impairment group and the dementia group were negatively correlated with the MMSE score(P＜0.05),and positively correlated with the CDR score(P＜0.05).In the mild cognitive impairment group,133 patients' conditions progressed from mild cognitive impairment to dementia.The levels of cerebrospinal fluid SNAP-25 and NEAT1 mRNA in the disease progres-sion group were significantly higher than those in the stable disease group(P＜0.05).ROC curve analysis showed that the sensitivity of cerebrospinal fluid SNAP-25 combined with NEAT1 in diagno-sing dementia was 89.63％,the specificity was 54.08％,and the area under the curve(AUC)was 0.884.The sensitivity of cerebrospinal fluid SNAP-25 combined with NEAT1 in predicting the pro-gression of mild cognitive impairment to dementia was 83.41％,the specificity was 56.70％,and the AUC was 0.867.Conclusion The levels of SNAP-25 and NEAT1 in cerebrospinal fluid in-crease significantly with the aggravation of cognitive impairment in patients with Alzheimer's dis-ease.The combined detection of SNAP-25 and NEAT1 has relatively high diagnostic efficacy for de-mentia and predictive value for the progression from mild cognitive impairment to dementia.