BACKGROUND:Exosomes,as a type of extracellular vesicle,have become a key medium for cell-to-cell communication due to their nanoscale size and enrichment of various bioactive substances.The study of exosome secretion regulation not only has important scientific value,but also has broad application prospects in clinical practice,and is of great significance for promoting medical progress and improving human health.OBJECTIVE:To review the biological characteristics,biological functions,biogenesis process and biochemical regulation mechanism of exosomes,and to explore the application prospects of exosomes in disease diagnosis,treatment and vaccine development,so as to provide theoretical basis and reference for basic research and clinical transformation of exosomes.METHODS:The first author searched PubMed and CNKI databases in October 2024 for relevant literature published from January 2010 to October 2024.Key words were"exosomes,biological functions,biogenesis,secretion or release,regulatory mechanisms,application prospects"in Chinese and English.Finally,92 articles were included for analysis.RESULTS AND CONCLUSION:The secretion level of exosomes can be regulated through physical or biochemical means.Exosomes show broad application prospects in the fields of disease diagnosis,treatment,and vaccine development,and may play a key role in the treatment of cardiovascular and cerebrovascular diseases as well as cancer.This review provides valuable information for the clinical translation and application research of exosomes,helping to promote future progress in exosome research and application.

BACKGROUND:Exosomes,as a type of extracellular vesicle,have become a key medium for cell-to-cell communication due to their nanoscale size and enrichment of various bioactive substances.The study of exosome secretion regulation not only has important scientific value,but also has broad application prospects in clinical practice,and is of great significance for promoting medical progress and improving human health.OBJECTIVE:To review the biological characteristics,biological functions,biogenesis process and biochemical regulation mechanism of exosomes,and to explore the application prospects of exosomes in disease diagnosis,treatment and vaccine development,so as to provide theoretical basis and reference for basic research and clinical transformation of exosomes.METHODS:The first author searched PubMed and CNKI databases in October 2024 for relevant literature published from January 2010 to October 2024.Key words were"exosomes,biological functions,biogenesis,secretion or release,regulatory mechanisms,application prospects"in Chinese and English.Finally,92 articles were included for analysis.RESULTS AND CONCLUSION:The secretion level of exosomes can be regulated through physical or biochemical means.Exosomes show broad application prospects in the fields of disease diagnosis,treatment,and vaccine development,and may play a key role in the treatment of cardiovascular and cerebrovascular diseases as well as cancer.This review provides valuable information for the clinical translation and application research of exosomes,helping to promote future progress in exosome research and application.

OBJECTIVE: To explore the clinical characteristics and genetic etiology of STISS syndrome (an autosomal dominant disorder characterized by ubiquitin-proteasome system dysfunction) in a child. METHODS: A child with STISS syndrome diagnosed at the Affiliated Women and Children's Hospital of Ningbo University in September 2024 due to "abnormal development of external genitalia" was selected as the study subject. Clinical data were retrospectively collected. Peripheral blood samples were obtained from the child and his family members. Following genomic DNA extraction, whole-exome sequencing (WES) and Sanger sequencing validation were carried out. Pathogenicity of the candidate variants was assessed based on the guidelines from American College of Medical Genetics and Genomics (ACMG). The study was approved by the Ethics Committee of the hospital (Ethics No.: EC2023-094). RESULTS: The proband, a 16-year-old boy, presented with micropenis, testicular hypoplasia, delayed sexual development, insulin resistance, diabetes mellitus, and obesity. WES revealed that he has harbored a c.934del; p.Met312TrpfsTer3 frameshifting variant of the PSMD12 gene, which was unreported previously. Sanger sequencing confirmed that the variant to be de novo in origin. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PM2_supporting+PM6_supporting). The variant was predicted to result in a premature termination codon. Bioinformatics analysis suggested that the amino acid at position 312 is highly conserved, and the variant may therefore affect the protein structure. CONCLUSION Patients with STISS syndrome exhibit clinical features including psychomotor retardation, intellectual disability, distinctive facial features, and urogenital abnormalities. The c.934del (p.Met312TrpfsTer3) frameshift variant of the PSMD12 gene probably underlay the pathogenesis in the proband. Above finding has enriched the mutational spectrum of the PSMD12 gene.
Adolescent ; Humans ; Male ; Exome Sequencing ; Mutation ; Proteasome Endopeptidase Complex/genetics* ; Syndrome

Objective:To investigate the present situation and influencing factors of hearing loss among noise exposed workers in a gas production plant, and to provide basis and guidance for enterprises to prevent hearing loss.Methods:In November 2023, a cross-sectional survey was conducted among personnel exposed to noise in a gas production plant. A total of 380 questionnaires were collected, among which 319 were valid resulting in an effective recovery rate of 83.9%. Ultimately, 292 were included in the study. The questionnaire covered demographic characteristics, work conditions, behavioral and lifestyle habits, hearing loss, and medical history. The noise exposure levels of the research subjects were determined based on the occupational disease hazard factor detection reports provided by the gas production plant for 2022 and 2023. Whether hearing loss occurred was determined based on the pure tone audiometry results from the occupational health examination. Chi-square tests were used to analyze the influence of demographic characteristics, work conditions, and behavioral and lifestyle habits on hearing loss. A multivariate logistic regression model was used to analyze the relationship between hearing loss and related influencing factors.Results:Among the noise-exposed workers in the gas production plant, the incidence of high-frequency hearing loss was 14.4% (42/292) . The rate of hearing loss among men was higher than that among women ( P=0.010) , and the rate of hearing loss among those with a history of smoking was higher than that among those who had never smoked ( P=0.015) . Conclusion:Gas production enterprises should prioritize targeted interventions for workers with prolonged employment histories and smoking habits. Training programs should be implemented to cultivate proper ear protection practices, enhance knowledge of hearing conservation, and promote healthier lifestyle behaviors among employees.

Objective To investigate effect of cassava RS3 resistant starch(Ce-RS3)on serum homocysteine(Hcy)level in patients with atherosclerotic cerebral infarction(ACI)during the recovery period.Methods A total of 55 patients with ACI at the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine from October 2023 to October 2024 were selected as subjects.They were devieded into observation group(n=28)and control group(n=27)using a random number table.The control group received atorvastatin calcium,phospholipids,and aspirin,while the observation group received atorvastatin calcium,phospholipids,aspirin,and Ce-RS3.After 12 weeks of treatment,homocysteine(Hcy)levels,carotid plaque diameter,National Institutes of Health stroke scale(NIHSS)scores,Barthel index(BI)scores,and traditional Chinese medicine(TCM)syndrome scores were compared between two groups.Results After treatment,the serum Hcy levels decreased and carotid plaque size reduced in both groups,with the NIHSS scores and TCM syndrome scores also decreased,and observation group was lower than control group(P＜0.05).After treatment,the BI score increased,with observation group higher than control group(P＜0.05).Conclusion The use of Ce-RS3 in the recovery phase of patients with ACI can effectively improve neurological function and enhance treatment efficacy.

Objective:To investigate the clinical, pathological, and molecular biological characteristics of gastric hepatoid adenocarcinoma (HAS) in order to provide reference for clinical treatment.Methods:Thirty-two patients diagnosed with hepatoid adenocarcinoma after radical gastrectomy for gastric cancer at Shanxi Cancer Hospital were included from January 2019 to December 2021. Immunohistochemistry, in situ hybridization, and next-generation sequencing (NGS) methods were used to analyze immune markers and molecular characteristics in the pathological tissues from 32 patients with HAS. Cox regression analysis and Kaplan-Meier method were used to analyze the prognostic factors of overall survival and disease-free survival.Results:Among the 32 patients with HAS, 26 were male, 6 were female; aged 28-77 years, with an median age 62.0 (53.8, 67.2) years. Fifteen cases of HAS were located in the cardia, 10 cases in the antrum, and 7 cases in the body of the stomach. The maximum diameter of the mass was 3-10 cm, and mainly ulcerative in gross. The immunohistochemistry and in situ hybridization results showed that the positive rates of AFP, SALLA4, and Glypican-3 were 68.8% (22/32), 68.8% (22/32), 78.1% (25/32), respectively; Seven patients had microsatellite status of dMMR. Two cases of HER2 gene amplification and 2 cases of EB virus positivity. The NGS results showed that HAS was often accompanied by multiple gene mutations, with 23 cases having ≥ 2 gene mutations and 6 cases having ≥10 gene mutations. The TP53 gene had the highest mutation frequency; 4 cases had genetic structural variations; 28 cases had copy number variation. In addition, there were 7 cases of MSI-H and 9 cases of TMB-H. Follow-up results showed that 12 cases died, 9 cases developed metastasis, and the shortest survival time was 5 months.Conclusions:Gastric HAS is a type of tumor with high invasiveness and poor prognosis. The combined detection of AFP, SALLA4 and Glypican-3 can improve the diagnostic rate of tumors. dMMR/MSI-H and TMB-H patients in HAS are significantly higher than those in ordinary gastric cancer, and the high frequency mutation genes in HAS are often accompanied by multiple potential therapeutic targets. Immunotherapy combined with chemotherapy and targeted therapy are expected to become the treatment direction of HAS.

BACKGROUND:Mammary stem cells are vital for the development and homeostasis of mammary gland tissue.The occurrence of breast cancer has a close relationship with the mammary stem cells.Recent studies have shown that Hopx,as an important transcriptional regulator of morphogenesis and cell differentiation,has been confirmed to be expressed in a variety of adult stem cells such as nerves,intestines,hair follicles and lungs.However,its role in mammary stem cells has not been reported so far.OBJECTIVE:To investigate whether Hopx expression marks mammary stem cells.METHODS:(1) Female Hopx-LacZ transgenic mice aged 8 weeks were selected to detect the background expression of Hopx in breast tissue by β-galactosidase staining.(2) Female wild-type mice at 4,6,and 8 weeks of age and 14.5 days of gestation were selected for whole-tissue magenta staining and K14 and K8 immunofluorescence staining,respectively.(3) Female Hopx-CreERT2;Rosa26LacZ transgenic mice aged 8 weeks and 17.5 days of gestation were selected and stained with breast β-galactosidase.(4) The 4-week-old female Hopx-CreERT2;Rosa26LacZ transgenic mice were selected.The Cre/loxp system was activated by intraperitoneal injection of tamoxifen (once every other day,three times),and breast β-galactosidase staining was performed 4 weeks after injection.The 8-week-old female Hopx-CreERT2;Rosa26LacZ transgenic mice were selected.The Cre/loxp system was activated by intraperitoneal injection of tamoxifen (once every other day,three times),and breast β-galactosidase staining was performed 4 and 10 weeks after the last injection.(5) Female Hopx-CreERT2;Rosa26LacZ transgenic mice aged 8 weeks were selected.The Cre/loxp system was activated by intraperitoneal injection of tamoxifen (once every other day,three times).Hopx-CreERT2;Rosa26LacZ transgenic mice were pregnant 2 weeks after injection.The mammary tissue of mice at 17.5 days of the first pregnancy and 17.5 days of the third pregnancy was stained with β-galactosidase.RESULTS AND CONCLUSION:(1) The results of β-galactosidase staining showed that the mammary ducts of Hopx-LacZ transgenic mice at 8 weeks of age did contain Hopx-positive cells and were located in the basal epithelia,with a small number.(2) Whole-mount staining of mammary glands and immunofluorescence staining results exhibited that the mammary glands of mice had different characteristics with corresponding developmental stages such as puberty,maturity,and pregnancy,and underwent a series of complex epithelial remodeling processes.(3) The results of β-galactosylase staining showed that Hopx-labeled positive cells in the mammary duct of Hopx-CreERT2;Rosa26LacZ transgenic mice at 17.5 days of gestation increased compared with female Hopx-CreERT2;Rosa26LacZ transgenic mice at 8 weeks of age.(4) The results of β-galactosylase staining showed that the Hopx-labeled positive cells in the mammary glands of 4-and 8-week-old female Hopx-CreERT2;Rosa26LacZ transgenic mice after tamoxifen injection were located in the basal epithelium with a small number.(5) The results of β-galactosidase staining showed that Hopx-labeled positive cells in the mammary glands of mice at 17.5 days of the first and third gestation were located in the basal epithelia around the alveoli,and the number of Hopx-labeled positive cells at 17.5 days of the third gestation was more.(6) In conclusion,Hopx reporter-marked basal epithelial cells belong to dormant mammary stem cells,which are responsible for the growth of the mammary glands during pregnancy and contribute to acinar formation.

Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

BACKGROUND:Mammary stem cells are vital for the development and homeostasis of mammary gland tissue.The occurrence of breast cancer has a close relationship with the mammary stem cells.Recent studies have shown that Hopx,as an important transcriptional regulator of morphogenesis and cell differentiation,has been confirmed to be expressed in a variety of adult stem cells such as nerves,intestines,hair follicles and lungs.However,its role in mammary stem cells has not been reported so far.OBJECTIVE:To investigate whether Hopx expression marks mammary stem cells.METHODS:(1) Female Hopx-LacZ transgenic mice aged 8 weeks were selected to detect the background expression of Hopx in breast tissue by β-galactosidase staining.(2) Female wild-type mice at 4,6,and 8 weeks of age and 14.5 days of gestation were selected for whole-tissue magenta staining and K14 and K8 immunofluorescence staining,respectively.(3) Female Hopx-CreERT2;Rosa26LacZ transgenic mice aged 8 weeks and 17.5 days of gestation were selected and stained with breast β-galactosidase.(4) The 4-week-old female Hopx-CreERT2;Rosa26LacZ transgenic mice were selected.The Cre/loxp system was activated by intraperitoneal injection of tamoxifen (once every other day,three times),and breast β-galactosidase staining was performed 4 weeks after injection.The 8-week-old female Hopx-CreERT2;Rosa26LacZ transgenic mice were selected.The Cre/loxp system was activated by intraperitoneal injection of tamoxifen (once every other day,three times),and breast β-galactosidase staining was performed 4 and 10 weeks after the last injection.(5) Female Hopx-CreERT2;Rosa26LacZ transgenic mice aged 8 weeks were selected.The Cre/loxp system was activated by intraperitoneal injection of tamoxifen (once every other day,three times).Hopx-CreERT2;Rosa26LacZ transgenic mice were pregnant 2 weeks after injection.The mammary tissue of mice at 17.5 days of the first pregnancy and 17.5 days of the third pregnancy was stained with β-galactosidase.RESULTS AND CONCLUSION:(1) The results of β-galactosidase staining showed that the mammary ducts of Hopx-LacZ transgenic mice at 8 weeks of age did contain Hopx-positive cells and were located in the basal epithelia,with a small number.(2) Whole-mount staining of mammary glands and immunofluorescence staining results exhibited that the mammary glands of mice had different characteristics with corresponding developmental stages such as puberty,maturity,and pregnancy,and underwent a series of complex epithelial remodeling processes.(3) The results of β-galactosylase staining showed that Hopx-labeled positive cells in the mammary duct of Hopx-CreERT2;Rosa26LacZ transgenic mice at 17.5 days of gestation increased compared with female Hopx-CreERT2;Rosa26LacZ transgenic mice at 8 weeks of age.(4) The results of β-galactosylase staining showed that the Hopx-labeled positive cells in the mammary glands of 4-and 8-week-old female Hopx-CreERT2;Rosa26LacZ transgenic mice after tamoxifen injection were located in the basal epithelium with a small number.(5) The results of β-galactosidase staining showed that Hopx-labeled positive cells in the mammary glands of mice at 17.5 days of the first and third gestation were located in the basal epithelia around the alveoli,and the number of Hopx-labeled positive cells at 17.5 days of the third gestation was more.(6) In conclusion,Hopx reporter-marked basal epithelial cells belong to dormant mammary stem cells,which are responsible for the growth of the mammary glands during pregnancy and contribute to acinar formation.