Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

Ischemic stroke (IS), a leading cause of morbidity and mortality worldwide, primarily results from blood clot formation in cerebral vessels, leading to vessel occlusion, reduced cerebral blood flow, and subsequent tissue ischemia. While thrombolytic therapies and mechanical thrombectomy remain cornerstone treatments for restoring blood flow, their clinical efficacy is significantly limited by the narrow therapeutic window, which underscores the critical need for novel, safe, and effective therapeutic strategies. In this review, we present an intensive analysis of four pathophysiological stages of IS progression and their intervention targets, and evaluate both established and emerging therapeutic strategies with the molecular mechanisms underpinning these methods, aiming to enhance the understanding of IS intervention. Additionally, we discuss current challenges in IS therapy, emphasizing the importance of timely, stage-specific approaches to optimize therapeutic outcomes. Finally, we highlight some promising research directions and innovations to advance IS field.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy predominantly managed via chemotherapy. Our clinical sample analysis revealed a significant correlation between elevated CD24 expression in TNBC tumor cells and patient survival rates. We developed a novel antibody-drug conjugate (ADC), named HN03, consisting of an antibody with engineered cysteines for site-specific conjugation with a low toxic nitric oxide (NO) precursor as its payload through a novel Pt(IV)-mediated bioorthogonal self-cleavable linker. HN03 specifically targets tumor cells expressing high levels of CD24, concurrently generating cisplatin and releasing NO upon activation. HN03 also exhibited potent in vitro and in vivo antitumor activity. It significantly reduced tumor growth at various doses, prevented tumor metastasis, with markedly lower toxicity than traditional chemotherapy agents. We found that a key mechanism of its action involved inducing apoptosis and endoplasmic reticulum stress, substantially decreasing the number of M2-type macrophages. Overall, HN03 stands out as a promising therapeutic option for TNBC, offering a targeted treatment with reduced side effects and the potential for improved outcomes. Furthermore, using Pt(IV) in the linker and an NO precursor as the payload enhances the versatility of the Antibody-NO donor Conjugate (ANC), offering new avenues for the design of the next generation of ADCs.

BACKGROUND:Stem cell transplantation has a promising therapeutic prospect in the treatment of myocardial infarction,but the efficacy of stem cell transplantation is limited by the low homing efficiency of transplanted cells to the heart and the low retention rate and survival rate in the heart.Exercise therapy is an important integral component of cardiac rehabilitation for patients with myocardial infarction.However,the role of exercise in stem cell therapy for myocardial infarction has not yet been clarified.OBJECTIVE:To investigate the effect of exercise(including acute exercise and chronic exercise)on bone marrow mesenchymal stem cell transplantation in rats with myocardial infarction.METHODS:Eighty female SD rats were randomly divided into sham operation group,model group,transplantation group or combination group with random number table method(n=20).Myocardial infarction model of rats in model group,transplantation group,or combination group was made by coronary artery ligation.24 hours after the model was made,the combination group underwent aerobic exercise for 8 weeks(chronic exercise,30 min/d,5 days per week),and within 5 minutes after the first exercise(acute exercise).SD rat bone marrow mesenchymal stem cells labeled with green fluorescent protein were injected into the tail vein of the transplantation group and the combination group.A part of animals from each group were taken 24 hours after the first exercise.The survival rate of stem cells transplanted into rat myocardium,sex-determining region of Y,protein expression of homing factors,oxidative stress,and inflammatory response parameters were measured.After 72 hours of the last exercise,the remaining rats were taken to detect cardiac structure and function,myocardial histological changes,and the number of Ki67+cells.RESULTS AND CONCLUSION:(1)After acute exercise:Compared with sham operation group,myocardial reactive oxygen species level,malondialdehyde content,tumor necrosis factor-α,and interleukin-1β protein expression increased(P<0.05),and superoxide dismutase activity decreased(P<0.05)in model group.Compared with model group,reactive oxygen species,malondialdehyde content,tumor necrosis factor-α,and interleukin-1β protein expression reduced(P<0.05),superoxidation dismutase activity,stromal cell-derived factor 1α,and CXC chemokine receptor 4 protein expression increased(P<0.05)in transplantation and combination groups.Compared with the transplantation group,reactive oxygen species,malondialdehyde content,tumor necrosis factor-α,and interleukin-1β protein expression decreased(P<0.05),stem cell survival rate,sex-determining region of Y mRNA expression,superoxide dismutase activity,stromal cell-derived factor 1α,and CXC chemokine receptor 4 protein expression increased(P<0.05)in combination group.(2)After chronic exercise:Compared with sham operation group,cardiomyocyte cross-sectional area and collagen content increased(P<0.05),left ventricular ejection fraction and left ventricular short-axis shortening rate decreased(P<0.05)in model group.Compared with model group,cardiomyocyte cross-sectional area and collagen content decreased(P<0.05),Ki67+cells increased(P<0.05)in transplantation group.Compared with transplantation group,collagen content decreased(P<0.05),cardiomyocyte cross-sectional area,left ventricular ejection fraction,left ventricular short-axis shortening rate,and Ki67+cells increased(P<0.05)in the combination group.(3)Acute exercise improves the survival rate of exogenous stem cells by promoting stem cell homing and improving myocardial microenvironment,while chronic exercise can stimulate cardiomyocyte proliferation,inhibit cardiac remodeling,and enhance cardiac function after stem cell transplantation.Therefore,exercise can help to optimize the efficacy of stem cell transplantation after myocardial infarction in rats.

Objective To investigate the predictive value of serum human epididymis protein 4(HE4)levels in primary Sj?gren's syndrome(pSS)patients for renal injury.Methods A retrospective analysis of 77 pSS patients admitted to the Second People's Hospital of Yichang from September 2021 to August 2023 was performed,including 43 cases of renal injury group 34 instances of non-renal injury group,and 54 healthy physical examination subjects(HCs)as control group.Fasting peripheral venous blood(4ml)was collected to detect the serum levels of HE4,Cys-C,TNF-α,CR,C3,C4,immunoglobulin,Anti-SSA,Anti-SSB and other indicators,and analyzed the value of HE4 in the early diagnosis of kidney injury in pSS patients.Results Compared with HCs,the pSS patients had increased levels of HE4(120.02±103.86 pmol/L vs 57.5±16.52 pmol/L),Cys-C(1.30±0.81mg/L vs 0.87±014 mg/L),and the differences were statistically significant(t=4.382,3.860,all P<0.05).The serum levels of HE4,CR and TNF-α in the renal damage group were higher than those in the non-renal damage group,and the differences were statistically significant(t/χ2=2.552～4.371,all P<0.05).Pearson correlation analysis showed that,the levels of serum HE4,Cys-C,CR and TNF-α were all positively correlated with renal damage in pSS(r=0.287～0.546,all P<0.05).Logistic regression analysis showed that elevated serum HE4 level might be an independent risk factor for inducing renal damage in pSS(Wald χ2=11.932,P<0.05).Receiver operating characteristic(ROC)curve analysis showed that the best cut-offvalue of serum HE4 for the diagnosis of pSS renal damage was 70.46pmol/L,the maximum Youden index was 0.625,AUC(95%CI)=0.876(0.799～0.954).Conclusion The serum HE4 level in patients with pSS is positively correlated with renal injury and has predictive value for the occurrence of renal injury.

BACKGROUND:Bone relies on the close connection between blood vessels and bone cells to maintain its integrity.Bones are in a physiologically hypoxic environment.Therefore,the study of angiogenesis and osteogenesis in hypoxic environment is closer to the microenvironment in vivo. OBJECTIVE:To explore the influence of Wenshen Tongluo Zhitong(WSTLZT)formula on H-type bone microvascular endothelial cell/bone marrow mesenchymal stem cell co-culture system in hypoxia environment and its related mechanism. METHODS:Enzyme digestion method and flow sorting technique were used to isolate and identify H-type bone microvascular endothelial cells.Mouse bone marrow mesenchymal stem cells were isolated and obtained by bone marrow adhesion method.H-type bone microvascular endothelial cell/bone marrow mesenchymal stem cell hypoxic co-culture system was established using Transwell chamber and anoxic culture workstation.WSTLZT formula powder was used to intervene in each group at a mass concentration of 50 and 100 μg/mL.The angiogenic function of H-type bone microvascular endothelial cells in the co-culture system was evaluated by scratch migration test and tube formation test.The osteogenic differentiation ability of bone marrow mesenchymal stem cells in the co-cultured system was evaluated by alkaline phosphatase staining and alizarin red staining.The protein and mRNA expression changes of PDGF/PI3K/AKT signal axis related molecules in H-type bone microvascular endothelial cells in the co-cultured system were detected by Western Blotting and q-PCR,respectively. RESULTS AND CONCLUSION:(1)Compared with the normal oxygen group,the scratch mobility and new blood vessel length of H-type bone microvascular endothelial cells were significantly higher(P<0.05);the osteogenic differentiation capacity of bone marrow mesenchymal stem cells was higher(P<0.05);the expression of PDGF/PI3K/AKT axis-related molecular protein and mRNA increased(P<0.05)in the hypoxia group.(2)Compared with the hypoxia group,scratch mobility and new blood vessel length were significantly increased in the H-type bone microvascular endothelial cells(P<0.05);bone marrow mesenchymal stem cells had stronger osteogenic function(P<0.05);the expression of PDGF/PI3K/AKT axis-related molecular proteins and mRNA further increased(P<0.05)after treatment with different dose concentrations of WSTLZT formula.These findings conclude that H-type angiogenesis and osteogenesis under hypoxia may be related to the PDGF/PI3K/AKT signaling axis,and WSTLZT formula may promote H-type vasculo-dependent bone formation by activating the PDGF/PI3K/AKT signaling axis,thereby preventing and treating osteoporosis.

In recent years, the prevalence of obstructive coronary artery disease has continued to rise. Despite the widespread application of strategies such as intensive pharmacotherapy, coronary artery bypass grafting, or percutaneous coronary intervention, a subset of patients still experience recurrent angina symptoms, which severely impacts their quality of life. For such cases of refractory angina (RA), researchers domestically and internationally have explored therapeutic approaches such as spinal cord stimulation, transmyocardial laser revascularization, and sympathectomy. However, existing studies are largely limited to small-scale clinical trials, and their clinical translation still faces challenges due to insufficient validation of safety and efficacy. Injectable hydrogels, as functional materials with hydrophilic three-dimensional network structures, demonstrate unique advantages in the treatment of RA. They can not only provide mechanical support but also serve as controlled-release carriers for drugs and proteins, and synergize with gene therapy and stem cell therapy to promotemyocardial tissue repair. This article systematically reviews the application prospects of injectable hydrogels in the treatment of RA, aiming to provide insights for future therapeutic strategies.

ObjectiveTo investigate the prevalence of cardiovascular diseases and their influencing factors in community-based schizophrenia patients in Shanghai, and to provide a scientific basis for the early identification and prevention of cardiovascular disease in this population. MethodsBased on the Shanghai community cohort with severe mental disorders in 2022, a total of 3 954 community-based schizophrenia patients were identified and included in this study through a stratified cluster sampling method. Basic information and relevant clinical data (including metabolic index data) were collected through questionnaire survey, physical examination and laboratory testing. Univariate analyses were performed using the chi-square tests, and multivariate logistic regression analyses were employed to identify influencing factors of comorbid cardiovascular diseases. ResultsA total of 3 954 community-based schizophrenia patients were included, of which a total of 1 237 (31.28%) patients had comorbid cardiovascular diseases. Multivariate logistic regression analyses showed that age 60 years old or above (OR=5.524, 95%CI: 3.716‒8.214), smoking behavior (OR=1.328, 95%CI: 1.042‒1.692), overweight (OR=1.900, 95%CI: 1.046‒3.451) or obesity (OR=2.678, 95%CI: 1.439‒4.985), elevated blood pressure (OR=1.546, 95%CI: 1.294‒1.846), abnormal fasting blood glucose (OR=1.552, 95%CI: 1.322‒1.823) and high-density lipoprotein cholesterol abnormalities (OR=1.283, 95%CI: 1.025‒1.606) were positively associated with the risk of comorbid cardiovascular diseases in patients with schizophrenia, while educational attainment of college/bachelor’s degree or above (OR=0.640, 95%CI: 0.450‒0.910) and being unmarried (OR=0.552, 95%CI: 0.457‒0.667) were negatively associated with the risk of cardiovascular diseases comorbidity. ConclusionAdvanced age, unhealthy behaviors and lifestyles, as well as abnormalities in blood pressure, blood glucose, and blood lipids, could all increase the risk of comorbid cardiovascular diseases in community schizophrenia patients. It is suggested to strengthen the monitoring and management of these risk factors in this population in the future, so as to achieve early detection, early diagnosis and early intervention of cardiovascular diseases.

Objectives:To investigate the factors affecting the formation of coronary collateral circulation(CCC)in patients with chronic total occlusion(CTO)lesion of coronary artery.Methods:A total of 305 consecutive patients who were hospitalized in the department of cardiology of the First Hospital of Lanzhou University from December 2022 to December 2023 and CTO lesions were confirmed by coronary angiography in at least one major coronary artery were included.The clinical data were collected,and the patients were divided into poor CCC group(Rentrop grade 0-1,n=109)and good CCC group(Rentrop grade 2-3,n=196)according to Rentrop criteria.Univariate logistic regression and multivariate logistic regression analysis were used to investigate the risk factors of poor CCC formation in CTO lesion patients.Results:There were 109 patients with poor CCC formation and 196 patients with good CCC formation in this cohort.The levels of white blood cell count,neutrophil count,platelet count,platelet to lymphocyte ratio,neutrophil to lymphocyte ratio,systemic immunoinflammatory index(SII),lipoprotein a and fibringen(Fib)were significantly higher,lymphocyte count and mean platelet volume were significantly lower in patients with poor CCC formation than in patients with good CCC formation(all P<0.05).Multivariate logistic regression analysis showed that higher SII(OR=1.004,95%CI:1.003-1.006,P<0.001),Fib(OR=1.546,95%CI:1.038-2.301,P=0.032)levels were independent predictors of poor CCC formation in CTO lesion patients.Conclusions:Higher levels of SII and Fib are independently correlated with poor CCC formation,which may be used as clinical predictor of poor CCC formation in CTO lesion patients.