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

AIM: To investigate the application of biological amniotic membrane soaked in pirfenidone(PFD)and to evaluate its anti-scarring effect and toxic side effects on glaucoma model of rabbit eyes.METHODS: The right eyes of 72 healthy New Zealand white rabbits were randomly divided into 0.5%PFD+ biological amniotic membrane group, biological amniotic membrane group, mitomycin C(MMC)group and blank control group after the glaucoma model was established by anterior chamber injection of compound carbomer solution, and 18 rabbits in each group underwent trabeculectomy, in which the 0.5% PFD+ biological amniotic membrane group was placed with 0.5% PFD solution-soaked biological amniotic membrane under the scleral flap, and the biological amniotic membrane group was placed with normal saline-soaked rehydrated biological amniotic membrane under the scleral flap. In the MMC group, a cotton pad soaked in MMC was placed under the scleral flap for 3 min and immediately rinsed with normal saline, while the blank control group received no implant after the scleral flap was made. The intraocular pressure(IOP), filtration blebs, toxic side effects and complications were evaluated, and the histopathological changes in the filtration area were observed by hematoxylin-eosin(HE), Masson staining and immunohistochemical staining.RESULTS: The mean IOP at 14, 21 and 28 d after trabeculectomy were 0.5%PFD+ biological amniotic membrane group<MMC group<biological amniotic membrane group<blank control group(all P<0.05). At 28 d after trabeculectomy, 0.5%PFD+ biological amniotic membrane group had the best effect of anti-inflammatory hyperplasia and inhibition of collagen formation, the highest survival rate of filtration blebs, and the inflammatory reaction was mild.CONCLUSION: Biological amniotic membrane soaked in pirfenidone has more obvious anti-scarring effect on glaucoma model, with less toxic side effects and good safety.

Background Exposure to diisononyl phthalate (DINP), an endocrine disruptor associated with metabolic diseases and widely used in plastic products, has been linked to the development of several adverse health outcomes in the liver, including non-alcoholic fatty liver disease (NAFLD). Objective To investigate the effects and the possible molecular mechanisms of DINP exposure on lipid metabolism in human hepatocellular carcinoma cells (HepG2 cells). Methods First, HepG2 cells were treated with DINP at three time spots (24, 48, and 72 h) and eleven doses (0, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 mmol·L⁻¹). Cell viability were detected using cell counting kit 8 (CCK8). Intracellular lipid deposition was determined by oil red O staining and lipid content detection, and triglyceride (TG) and cholesterol (TC) were further detected. Finally, the mRNA expression levels were detected by fluorescence quantitative PCR, including fatty acid synthesis related genes [acetyl-CoA carboxylase alpha (Accα), fatty acid synthase (Fasn), malonyl-CoA decarboxylase (Mlycd), and sterol regulatory element binding protein 1 (Srebp1)] and β-oxidation related genes [peroxisome proliferator activated receptor alpha (Pparα), AMP-activated protein kinase (Ampk), carnitine palmitoyltransferase 1A (Cpt-1a), transcription factor A, mitochondrial (Tfam), nuclear respiratory factor 1 (Nrf1), and peroxisome proliferator-activated receptor gamma and coactivator 1 alpha (Pgc1-α)]. Results Compared with the control group (0 mmol·L⁻¹), the no observed adverse effect levels (NOAEL) of HepG2 cell viability were 0.3, 0.1, and 0.1 mmol·L⁻¹ after 24, 48, and 72 h exposure to DINP, respectively, and the corresponding lowest observed adverse effect levels (LOAEL) were 1, 0.3, and 0.3 mmol·L⁻¹, respectively (P<0.05). After exposure to 30 mmol·L⁻¹ and 100 mmol·L⁻¹ DINP for 24 h, the intracellular lipid content, lipid deposition, TG, and TC levels were increased significantly compared with the control group (P<0.01). Compared with the control group, the mRNA expression levels of genes related to fatty acid synthesis, such as Mlycd, Srebp1, Fasn, and Accα, were down-regulated after the 100 mmol·L⁻¹ DINP exposure for 24 h, while the mRNA expression level of Mlycd was up-regulated in the 30 mmol·L⁻¹ group. The β-oxidation related genes such as Ampk, Pparα, and Tfam were up-regulated significantly after the 100 mmol·L⁻¹ DINP exposure, while Cpt-1a mRNA expression level was down-regulated (P<0.05). Conclusion Exposure to DINP at 30 mmol·L⁻¹ and 100 mmol·L⁻¹ can interfere with fatty acid synthesis and β-oxidation in lipid metabolism of HepG2 cells, resulting in lipid deposition.

Objective The aim of this study is to analyze the current situation and influencing factors of specialist nurses'work in 72 tertiary hospitals in Anhui Province which can provide suggestions for the training and use of specialist nurses.Methods Using stratified sampling,a survey of 2,400 specialist nurses in 72 tertiary hospitals across the province were recruited and investigated by a self-administered questionnaire on the current work status and competencies of specialist nurses,from December 2022 to January 2023.The one-way ANOVA and multiple linear regression methods to analyze the influencing factors.Results A total of 2,248 valid questionnaires were returned from specialist nurses,with a validity rate of 93.67%.Specialist nurses scored(19.07±5.11)for their current work status and(17.07±2.84)for their ability to work.The results of multiple linear regression analyses showed that the level and nature of the hospital,title,position,method of obtaining training qualifications,working time in the speciality after training,and the competence of the specialist nurses were the factors influencing the current status of the specialist nurses'work(P<0.05).Conclusion The current status of specialist nurses'work in tertiary hospitals in Anhui Province is relatively satisfactory,and it is influenced by the level and nature of the hospital,the way of training and selection,and factors of the specialist nurses themselves.It is recommended to pay attention to the subsequent use and training of specialist nurses to improve their ability to work and provide high-quality professional care to patients.

Objective To investigate the effects of long-term exposure to three new types of light emitting diode (LED) sources on the behavior, learning, and memory of rats. Methods A total of 160 specific pathogen-free SD rats were divided into eight groups as followed, trichromatic fluorescent lamps color temperature control group, violet-chip full-spectrum white LED group, blue-chip white LED group, and blue-chip full-spectrum white LED group based on the light sources types, with color temperature of 4 000 K and 6 500 K groups in each group using the 4×2 factorial design. There were 20 rats in each group, with half of the rats were males and half females. Rats were exposed to artificial lighting, and the illumination was set at 750 lx. The rats in each group were exposed to different lighting environments for 12 hours per day for 24 weeks. The open-field and step-down tests were conducted in rats after 24 weeks exposure, followed by sacrifice of rats and measurement of organ coefficients. Differences in body weight, organ coefficients, and neurobehavioral indexes of rats in different groups were compared. Results The spleen coefficient of female rats decreased in blue-chip white LED of 6 500 K color temperature group, and the liver coefficient of male rats decreased in the violet-chip full-spectrum white LED of 4 000 K color temperature, blue-chip full-spectrum white LED of 4 000 K color temperature, and blue-chip full-spectrum white LED of 6 500 K color temperature groups, compared with the same-sex rats in trichromatic fluorescent lamps with same-color temperature control group (all P<0.05). The result of different types of light sources compared in the open-field test showed that the index of total distance and movement speed of female rats in the blue-chip full-spectrum white LED group were lower than those in the other three groups, and the time cost to the central area was longer than that in the blue-chip white LED group and the violet-chip full-spectrum white LED group (all P<0.05). The total distance and movement speed of male rats in the blue-chip full-spectrum white LED group were longer or higher than those in the violet-chip full-spectrum white LED group (all P<0.05). Based on the comparison of color temperature, the time and total distance of male rats in 6 500 K color temperature group were lower than that in the 4 000 K color temperature group (both P<0.05). In the step-down test, both male and female rats in the blue-chip full-spectrum white LED group made more errors compared with other three groups with the same gender (all P<0.05). Conclusion Based on the experimental conditions of this study, the blue-chip full-spectrum white light LED affects behavior, learning and memory of the rats, and trichromatic fluorescent lamp has the lowest effect on neurobehavior. The color temperature also affects behavior of the rats, and high color temperature has higher risk.