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.

The prefrontal cortex (PFC) plays a pivotal role in orchestrating higher-order emotional and cognitive processes, a function that depends on the precise modulation of synaptic activity. Although pharmacological studies have demonstrated that dopamine signaling through dopamine D1 receptor (DRD1) in the PFC is essential for these functions, the cell-type-specific and molecular mechanisms underlying the neuromodulatory effects remain elusive. Using cell-type-specific knockout mice and patch-clamp recordings, we investigated the regulatory role of DRD1 on neurons and astrocytes in synaptic transmission and plasticity. Furthermore, we explored the mechanisms by which DRD1 on astrocytes regulate synaptic transmission and plasticity at the cellular level, as well as emotional and cognitive functions at the behavioral level, through two-photon imaging, microdialysis, high-performance liquid chromatography, transcriptome sequencing, and behavioral testing. We found that conditional knockout of the Drd1 in astrocytes (CKO^AST) increased glutamatergic synaptic transmission and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC), whereas Drd1 deletion in pyramidal neurons did not affect synaptic transmission. The elevated level of d-serine in the mPFC of CKO^AST mice increased glutamatergic transmission and LTP through NMDA receptors. In addition, CKO^AST mice exhibited abnormal emotional and cognitive function. Notably, these behavioral changes in CKO^AST mice could be reversed through the administration of d-serine degrease to the mPFC. These results highlight the critical role of the astrocytic DRD1 in modulating mPFC synaptic transmission and plasticity, as well as higher brain functions through d-serine, and may shed light on the treatment of mental disorders.

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.

Tooth pulpitis is a prevalent oral disorder. Understanding the underlying mechanisms of pulpitis and developing effective treatment strategies hold great significance. Ferroptosis has recently emerged as a new form of cell death, but the role of ferroptosis in pulpitis remains largely unknown. In our study, single-cell RNA sequencing (scRNA-seq) was used to identify cellular heterogeneity between 3 pulpitis tissue and 3 healthy pulp tissue, and explored ferroptosis occurrence in pulpitis tissue and inflamed dental pulp cells (DPCs). In scRNA-seq, 40 231 cells (Pulpitis: 17 814; Healthy pulp: 22 417) were captured, and visualized into 12 distinct cell clusters. Differentially expressed ferroptosis-related genes (DE-FRGs) were almost presented in each cluster in pulpitis vs healthy pulp. ROS and Fe²⁺ levels significantly rose, and immunohistochemistry showed low expression of GPX4 and high expression of PTGS2 in pulpitis. In LPS-stimulated DPCs, thymosin α1 increased the expression of GPX4 and FTL, and decreased expression of TNF-α, IL-1β, IL-6, and Fe²⁺ levels. In rat pulpitis models, both prothymosin α (PTMA, precursor of thymosin α1) gelatin sponge placed at the hole of pulp (LPS-P(gs)) and PTMA injection in pulp (LPS-P(i)) significantly reduced infiltration of inflammatory cells and expression of PTGS2, and increased the expression of GPX4. In RNA sequencing, the expression of DE-FRGs were reversed when thymosin α1 were added in LPS-stimulated DPCs. Collectively, single-cell atlas reveals cellular heterogeneity between pulpitis and healthy pulp, and ferroptosis occurrence in pulpitis. Thymosin α1 may reduce ferroptosis in DPCs to alleviate pulpitis and thus potentially has the ability to treat pulpitis.
Ferroptosis/drug effects* ; Dental Pulp/drug effects* ; Animals ; Pulpitis/pathology* ; Rats ; Thymalfasin/pharmacology* ; Humans ; Male ; Thymosin/pharmacology* ; Disease Models, Animal ; Rats, Sprague-Dawley

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 screen potential comorbid genes shared between inflammatory bowel disease(IBD)and colorectal cancer(CRC),and to explore the relationship between the key gene a disintegrin and metalloprotease 8(ADAM8)and the pathogenesis of IBD and CRC,as well as the underlying mechanisms.Methods:Transcriptomic data and corresponding clinical information for IBD and CRC were downloaded from the GEO database and TCGA database.Differential expression analysis,prognostic gene screening,and intersection analysis were performed to identify shared genes.Multiple datasets were used to analyze and validate the expression patterns of ADAM8 in IBD and CRC and its correlation with clinicopathological features.Survival analysis was conducted to evaluate the prognostic value of ADAM8 in CRC.Functional and pathway enrichment analyses were conducted to explore the potential mechanisms by which ADAM8 influences CRC progression.The correlation between ADAM8 and tumor microenvironment components was further assessed using tumor microenvironmental algorithms.The database data was validated by detecting the expression in Chinese CRC tissues using immunohistochemistry(IHC).Results:ADAM8 was identified as a potential shared comorbidity gene in IBD and CRC.ADAM8 was significantly upregulated in both IBD and CRC tissues(all P<0.01),and its high expression was associated with disease progression(P<0.01).CRC patients with high ADAM8 expression had shorter overall survival(OS)(P<0.05 or P<0.01).ADAM8 was also significantly highly expressed in Chinese CRC tissues(P<0.01).Pathway analysis revealed that ADAM8 expression was closely linked to immune cell migration,cytokine production,and immune receptor interactions.Additionally,ADAM8 expression positively correlated with immune cell infiltration,including neutrophils and macrophages(P<0.01 or P<0.001).Conclusion:ADAM8 is highly expressed in IBD and CRC tissues and is closely associated with patient prognosis,disease progression,and immune cell infiltration.It holds promise as a common therapeutic target for both diseases.

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.

The application of pesticides(mostly insecticides and fungicides)during the tea-planting process will undoubtedly increase the dietary risk associated with drinking tea.Thus,it is necessary to ascertain whether pesticide residues in tea products exceed the maximum residue limits.However,the complex matrices present in tea samples comprise a major challenge in the analytical detection of pesticide residues.In this study,nine types of lateral flow immunochromatographic strips(LFICSs)were developed to detect the pesticides of interest(fenpropathrin,chlorpyrifos,imidacloprid,thiamethoxam,acet-amiprid,carbendazim,chlorothalonil,pyraclostrobin,and iprodione).To reduce the interference of tea substrates on the assay sensitivity,the pretreatment conditions for tea samples,including the extraction solvent,extraction time,and purification agent,were optimized for the simultaneous detection of these pesticides.The entire testing procedure(including pretreatment and detection)could be completed within 30 min.The detected results of authentic tea samples were confirmed by ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS),which suggest that the LFICS coupled with sample rapid pretreatment can be used for on-site rapid screening of the target pesticide in tea products prior to their market release.