OBJECTIVE: High-altitude hypoxia exposure often damages hippocampus-dependent learning and memory. Nogo-A is an important axonal growth inhibitory factor. However, its function in high-altitude hypoxia and its mechanism of action remain unclear. METHODS: In an in vivo study, a low-pressure oxygen chamber was used to simulate high-altitude hypoxia, and genetic or pharmacological intervention was used to block the Nogo-A/NgR1 signaling pathway. Contextual fear conditioning and Morris water maze behavioral tests were used to assess learning and memory in rats, and synaptic damage in the hippocampus and changes in oxidative stress levels were observed. In vitro, SH-SY5Y cells were used to assess oxidative stress and mitochondrial function with or without Nogo-A knockdown in Oxygen Glucose-Deprivation/Reperfusion (OGD/R) models. RESULTS: Exposure to acute high-altitude hypoxia for 3 or 7 days impaired learning and memory in rats, triggered oxidative stress in the hippocampal tissue, and reduced the dendritic spine density of hippocampal neurons. Blocking the Nogo-A/NgR1 pathway ameliorated oxidative stress, synaptic damage, and the learning and memory impairment induced by high-altitude exposure. CONCLUSION: Our results demonstrate the detrimental role of Nogo-A protein in mediating learning and memory impairment under high-altitude hypoxia and suggest the potential of the Nogo-A/NgR1 signaling pathway as a crucial therapeutic target for alleviating learning and memory dysfunction induced by high-altitude exposure. GRAPHICAL ABSTRACT available in www.besjournal.com.
Animals ; Oxidative Stress ; Hippocampus/metabolism* ; Rats ; Nogo Proteins/genetics* ; Male ; Rats, Sprague-Dawley ; Hypoxia/metabolism* ; Altitude ; Synapses ; Humans ; Altitude Sickness/metabolism*

Objective:To explore the mechanism of Amomi Fructus in ameliorating ethanol-induced gastric ulcer (GU) in mice using metabolomics, network pharmacology and molecular docking techniques.Methods:The mice were divided into the blank group, model group, aqueous extract of Amomi Fructus group, volatile oil of Amomi Fructus group, combined aqueous extract and volatile oil of Amomi Fructus group and omeprazole group according to the random number table method, with 10 mice in each group. The blank and model groups were gavaged with sodium carboxymethyl cellulose, the Amomi Fructusaqueous extract group was gavaged with 0.152 5 g/kg of Amomi Fructus aqueous extract, the Amomi Fructus volatile oil group was gavaged with 26 μl/kg of Amomi Fructus volatile oil, the Amomi Fructus aqueous extract and volatile oil combined group was gavaged with 0.152 5 g/kg+26 μl/kg of Amomi Fructus aqueous extract and volatile oil synergistic solution, and the omeprazole group was gavaged with 5.2 mg/kg of omeprazole, 1 time/day, which was administered continuously for 7 d. The gastric ulcer model was established by using ethanol 2 h after the last administration, and the pathological changes of gastric histology were observed by using HE staining; the main differential metabolites were detected by UPLC-Q-TOF-MS/MS non-targeted metabolomics technique, and the metabolic pathway enrichment analysis was carried out; the potential targets and key pathways of the anti-GU action of Amomi Fructus were predicted by network pharmacology; the "metabolite-response-enzyme-gene" network was established by combining the serum metabolomics and network pharmacology; and the key targets were verified by molecular docking technology.Results:HE staining showed that the gastric mucosa of mice in the model group was severely damaged, with cellular tissue damage and inflammatory cell infiltration, whereas the drug administration group showed some protective effects; the results of non-targeted metabolomics showed that 2 metabolites were up-regulated and 17 metabolites were down-regulated in sera of mice in the co-administration group of aqueous extract and volatile oil of Amomi Fructus compared with the control group, and the 19 metabolites were strongly correlated and well clustered, involving nicotinic acid and nicotinamide metabolism, citric acid cycle, glyoxylate and dicarboxylic acid metabolism, phenylalanine metabolism, alanine, aspartate and glutamate metabolism and other metabolic pathways; the results of network pharmacology showed that Amomi Fructus improved GU by affecting target proteins, such as STAT3, AKT1, SRC, and TLR4, which were closely linked to the signaling pathways of cancer pathway, human cytomegalovirus infection, and lipids and atherosclerosis; the joint analysis of network pharmacology and the combined analysis of network pharmacology and metabolomics identified the glycerophospholipid metabolic pathway as the main metabolic pathway in which Amomi Fructus may exert gastroprotective effects; the molecular docking results showed that the main active component of quercetin had a better binding ability to the key targets.Conclusion:Amomi Fructus exerts a protective effect on ethanol induced GU model by regulating the glycerophospholipid metabolism pathway, providing theoretical basis for further research on Amomi Fructus.

Objective To explore an experimental protocol for differentiating human-induced pluripotent stem cells(iPSCs)into highly pure midbrain dopaminergic(DA)neurons.Methods By optimizing a blend of small molecules and recombinant human growth factors,iPSCs were induced to differentiate into ventral midbrain floor plate DA progenitor cells and subsequently into mature substantia nigra pars compacta DA neurons.Throughout the differentiation process,Real-time PCR and immunofluorescent staining were utilized as a method for quality assessment.Results iPSCs firstly differentiate into dopaminergic precursor cells,and then gradually differentiate into DA neurons expressing tyrosine hydroxylase(TH).Conclusion The protocol successfully yields approximately high purity tyrosine hydroxylase-positive(TH+)DA neurons.This differentiation technique offers an effective cellular model for studying the physiological mechanisms and pathogenesis of Parkinson's disease,providing valuable insights for future research and potential therapeutic strategies.

Objective To investigate the clinical efficacy and safety of facilitated percutaneous coronary intervention(PCI)with half-dose recombinant staphylokinase(r-SAK)in patients with ST-segment elevation myocardial infarction(STEMI)who are expected to undergo PCI within 120 minutes.Methods From October 2021 to August 2022,a total of 200 STEMI patients in eight centers were included and randomly assigned in a 1﹕1 ratio to either r-SAK group or control group.Patients received loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive an intravenous bolus of either 5 mg r-SAK or normal saline prior to PCI.The outcomes were set as ST-segment resolution(STR)at 60-90 minutes after PCI,the proportion and transition of pathological Q waves on the 5th day after PCI,and the proportion of high-sensitivity cardiac troponin T(hs-cTnT)peaking within 12 hours of onset.The safety outcome was major bleeding events defined as Bleeding Academic Research Consortium(BARC)≥type 3 bleeding during hospitalization.Results Compared with the control group,the r-SAK group had a higher proportion of STR≥70%within 60-90 minutes after PCI(58.3%vs.40.3%,P=0.009);a lower proportion of pathological Q waves(59.1%vs.74.1%,P=0.040);a lower rate of Q wave progression(14.8%vs.43.2%,P＜0.001);a higher rate of Q wave disappearance(12.5%vs.3.7%,P=0.027);and a higher proportion of hs-cTnT peaking within 12 hours of symptom onset[31/40(77.5%)vs.17/33(51.5%),P=0.027].Regarding the safety outcome,no significant difference in BARC≥type 3 bleeding was found between the two groups during hospitalization(P＞0.05).Conclusions For STEMI patients who were expected to undergo primary PCI within 120 minutes of symptom onset,the facilitated PCI with half-dose r-SAK significantly increased the proportion of STR≥70%at 60-90 minutes after PCI,reduced the formation of pathological Q waves,and shortened the time to peak hs-cTnT,without increasing the risk of bleeding,which should be an alternative reperfusion strategy worthy of further study.

Objective To investigate the clinical efficacy and safety of facilitated percutaneous coronary intervention(PCI)with half-dose recombinant staphylokinase(r-SAK)in patients with ST-segment elevation myocardial infarction(STEMI)who are expected to undergo PCI within 120 minutes.Methods From October 2021 to August 2022,a total of 200 STEMI patients in eight centers were included and randomly assigned in a 1﹕1 ratio to either r-SAK group or control group.Patients received loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive an intravenous bolus of either 5 mg r-SAK or normal saline prior to PCI.The outcomes were set as ST-segment resolution(STR)at 60-90 minutes after PCI,the proportion and transition of pathological Q waves on the 5th day after PCI,and the proportion of high-sensitivity cardiac troponin T(hs-cTnT)peaking within 12 hours of onset.The safety outcome was major bleeding events defined as Bleeding Academic Research Consortium(BARC)≥type 3 bleeding during hospitalization.Results Compared with the control group,the r-SAK group had a higher proportion of STR≥70%within 60-90 minutes after PCI(58.3%vs.40.3%,P=0.009);a lower proportion of pathological Q waves(59.1%vs.74.1%,P=0.040);a lower rate of Q wave progression(14.8%vs.43.2%,P＜0.001);a higher rate of Q wave disappearance(12.5%vs.3.7%,P=0.027);and a higher proportion of hs-cTnT peaking within 12 hours of symptom onset[31/40(77.5%)vs.17/33(51.5%),P=0.027].Regarding the safety outcome,no significant difference in BARC≥type 3 bleeding was found between the two groups during hospitalization(P＞0.05).Conclusions For STEMI patients who were expected to undergo primary PCI within 120 minutes of symptom onset,the facilitated PCI with half-dose r-SAK significantly increased the proportion of STR≥70%at 60-90 minutes after PCI,reduced the formation of pathological Q waves,and shortened the time to peak hs-cTnT,without increasing the risk of bleeding,which should be an alternative reperfusion strategy worthy of further study.

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy.Prior research has illuminated reasons behind drug resistance,including increased drug efflux,alterations in drug targets,and abnormal activation of oncogenic pathways.However,there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment(TME).Recent studies on extracellular vesicles(EVs)have provided valuable insights.EVs are membrane-bound particles secreted by all cells,mediating cell-to-cell communication.They contain functional cargoes like DNA,RNA,lipids,proteins,and metabolites from mother cells,delivered to other cells.Notably,EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs.This review aims to summarize the mechanisms of EV-mediated anti-tumor drug resistance,covering therapeutic approaches like chemo-therapy,targeted therapy,immunotherapy and even radiotherapy.Detecting EV-based biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance.Additionally,targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance.We highlight the importance of conducting in-depth mechanistic research on EVs,their cargoes,and functional ap-proaches specifically focusing on EV subpopulations.These efforts will significantly advance the devel-opment of strategies to overcome drug resistance in anti-tumor therapy.

Objective To observe the value of contrast-enhanced mammography(CEM)for differentiating benign and malignant breast lesions with calcifications.Methods Data of 116 female patients with 132 breast imaging reporting and data system(BI-RADS)category 4 to 5 lesions were retrospectively analyzed.The lesions were divided into malignant group(n=86)and benign group(n=46)according to the pathologic results.The morphological manifestations of calcification and their distributions were classified into high or low risk,and the combined risk typing of calcifications was assessed according to these two.Finally,an overall risk typing of CEM was obtained through combining the combined risk type of calcifications and accompanied enhancement or not.Then receiver operating characteristic(ROC)curves were drawn,the area under the curves(AUC)were calculated,and the efficacy of the above indexes for differentiating benign and malignant breast lesions with calcifications were evaluated and compared.Results Significant differences of morphology,distribution and accompanied enhancement were found between groups(all P＜0.05).The AUC of morphology risk,distribution risk,the combined risk of calcification,accompanied enhancement and CEM overall risk for differentiating benign and malignant breast lesions with calcifications was 0.709,0.678,0.774,0.800 and 0.875,respectively,of CEM overall risk was higher than that of the others(all P＜0.05).Conclusion CEM overall risk type obtained through integrating morphology and distribution manifestations of calcifications and enhancement type could improve the efficiency of CEM for differentiating benign and malignant breast lesions with calcifications.

Objective To establish an acute exposure model of extreme plateau hypobaric hypoxia environment and explore transcriptomic changes related to learning and memory impairment in rats.Methods Healthy male SD rats aged 6-weeks,200-250 g,were selected and divided into control group and plateau group.The control group was treated with normal pressure and oxygen(19 rats),and the plateau group was placed in a hypobaric hypoxia chamber(19 rats)at a simulated altitude of 8000 meters and treated for 72 hours.Behavioral changes were detected with 16 animals from each group using contextual fear conditioning and Morris water maze(8 rats each).Three hippocampal tissues were extracted from each group for transcriptomic sequencing,and the molecular mechanism of learning and memory impairment induced by extreme plateau environment was analyzed by Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)and gene set enrichment analysis(GSEA)enrichment.Results The behavioral result showed that compared with the control group,the fear memory and spatial learning memory abilities of rats in plateau group were decreased.GO and KEGG analyses showed that the extreme altitude environment reshaped the hippocampal microenvironment and affected the intercellular signal transmission,while GSEA analysis showed that the extreme altitude environment up-regulated the gene set related to the plasma membrane and extracellular matrix.Conclusion The extreme plateau environment at an altitude of 8000 meters could affect the microenvironment of rat hippocampus,destroy intercellular connections and impair intercellular communication and then induce learning and memory impairment.

Objective: To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. Methods: This was a retrospective case study. Thirty-seven children with malignant infantile osteopetrosis admitted into Beijing Children's Hospital from January 2013 to September 2022 were enrolled in this study. According to the gene mutations, the patients were divided into the CLCN7 group and the TCIRG1 group. Clinical characteristics, laboratory tests, and prognosis were compared between two groups. Wilcoxon test or Fisher exact test were used in inter-group comparison. The survival rate was estimated with the Kaplan-Meier method and the Log-Rank test was used to compare the difference in survival between groups. Results: Among the 37 cases, there were 22 males and 15 females. The age of diagnosis was 0.5 (0.2, 1.0) year. There were 13 patients (35%) and 24 patients (65%) with mutations in CLCN7 and TCIRGI gene respectively. Patients in the CLCN7 group had an older age of diagnosis than those in the TCIRGI group (1.2 (0.4, 3.6) vs. 0.4 (0.2, 0.6) years, Z=-2.60, P=0.008). The levels of serum phosphorus (1.7 (1.3, 1.8) vs. 1.1 (0.8, 1.6) mmol/L, Z=-2.59, P=0.010), creatine kinase isoenzyme (CK-MB) (457 (143, 610) vs. 56 (37, 82) U/L, Z=-3.38, P=0.001) and the level of neutrophils (14.0 (9.9, 18.1) vs. 9.2 (6.7, 11.1) ×10⁹/L, Z=-2.07, P=0.039) at diagnosis were higher in the CLCN7 group than that in the TCIRG1 group. However, the level of D-dimer in the CLCN7 group was lower than that in the TCIRGI group (2.7 (1.0, 3.1) vs. 6.3 (2.5, 9.7) μg/L, Z=2.83, P=0.005). After hematopoietic stem cell transplantation, there was no significant difference in 5-year overall survival rate between the two groups (92.3%±7.4% vs. 83.3%±7.6%, χ²=0.56, P=0.456). Conclusions: TCIRGI gene mutations are more common in children with osteopetrosis. Children with TCIRGI gene mutations have younger age, lower levels of phosphorus, CK-MB, and neutrophils and higher level of D-dimer at the onset. After hematopoietic stem cell transplantation, patients with CLCN7 or TCIRGI gene mutations have similar prognosis.
Child ; Male ; Female ; Humans ; Osteopetrosis/therapy* ; Retrospective Studies ; Prognosis ; Genes, Recessive ; Phosphorus ; Chloride Channels/genetics* ; Vacuolar Proton-Translocating ATPases/genetics*

Memory loss induced by aging and hypoxia is very common, so exploring the mechanism of memory production, storage and retrieval is of great significance to daily life and clinical work. The storage and retrieval of memory is probably similar to the computer. We summarized the research progress of MeshCODE theory, the mechanical basis of memory. Memory loss in certain diseases (such as Alzheimer's disease) or pathological conditions (such as aging, lack of oxygen) may be associated with abnormal folding of talin, a mechanosensitive protein. It can dynamically regulate synaptic activity by changing the state of the domain, storing or updating information about small changes in mechanical forces in binary form, and initiating chemical processes such as ligand redistribution in neurons, so that memory is stored in the brain in a binary format, known as the MeshCODE theory.