Abstract Cells deploy adaptive programs to maintain homeostasis under stress, yet mechanisms counteracting damage triggered by transmembrane signaling remain poorly defined. Using a hyperaldosteronism model, we examined how autophagy regulates aldosterone-mediated mineralocorticoid receptor (MR) activation. In human umbilical vein endothelial cells (HUVECs), aldosterone induced autophagy, as evidenced by elevated Beclin-1, an increased LC3-II/LC3-I ratio, and reduced SQSTM1/p62. Aldosterone also promoted MR translocation from the cytosol to the nucleus. Co-immunoprecipitation and immunofluorescence revealed direct interaction and colocalization between MR and Beclin-1, as well as enhanced MR-lysosome association. Domain mapping showed that the Beclin-1 middle domain (161–241 AA) binds the MR C-terminal region (601–984 AA). Bioinformatic prediction and ChIP-qPCR confirmed that MR occupies the promoters of IL-1β , IL-6 , and TNF-α upon aldosterone stimulation. Beclin-1 overexpression attenuated MR nuclear translocation, promoter binding, and inflammatory cytokine expression, whereas Beclin-1 knockdown reversed these effects. In vivo, aldosterone-infused Beclin-1 transgenic ( Becn1-tg ) mice exhibited lower blood pressure, reduced aortic medial thickening, and attenuated cardiac hypertrophy relative to wild-type controls, with no difference in body weight. Our findings identify Beclin-1 as a critical negative regulator of aldosterone signaling through an autophagy-dependent negative feedback loop. By interacting with MR and directing it toward lysosomal sequestration, Beclin-1 limits MR nuclear translocation and transcriptional activity, thereby mitigating aldosterone-induced vascular inflammation and cardiovascular injury. Highlights Aldosterone activates autophagy and promotes MR–Beclin-1 interaction in HUVECs Beclin-1 binds the C-terminal MR domain and directs MR to lysosomal degradation Beclin-1 overexpression suppresses MR nuclear translocation and cytokine gene activation Beclin-1 transgenic mice are protected from aldosterone-induced cardiovascular injury

While the level of α-synuclein oligomers (α-SOs) in the CSF of patients with Parkinson’s disease (PD) is consistently increased, its pathogenic role in PD remains poorly understood. This study focuses on the role of CSF-derived α-SOs in PD pathology. We demonstrated that CSF-derived α-synuclein enters the brain via perivascular spaces, which was more abundant in the olfactory bulb (OB) than in the substantia nigra (SN). We also found that neuroinflammation was more pronounced in the OB than in the SN following α-SOs injection. α-SOs-treated mice exhibited an early and persistent loss of dopaminergic (DA) neurons in the OB, along with olfactory deficit. Conversely, DA neuron loss in the SN occurred later and was associated with motor dysfunction. Furthermore, reducing α-SOs dose alleviated OB pathology. These findings suggest that perivascular spread of CSF-derived α-SOs induces region-specific PD-like pathology, indicating that removing CSF-derived α-SOs could slow PD progression.

BACKGROUNDS:Chronic hypoxia-associated pulmonary hypertension (PH), especially COPD-related PH with right heart failure, is a recalcitrant clinical challenge as current therapies fail to effectively halt its progression. Olprinone (Olp), a phosphodiesterase III inhibitor with well-defined cardiovascular regulatory effects, has unclear roles and molecular mechanisms in hypoxia-induced PH. METHODS:This study combined clinical, preclinical and cellular approaches: a retrospective analysis of 24 COPD-related PH patients (13 with Olp plus standard therapy, 11 with standard therapy plus other inotropes); a chronic hypoxia-induced PH (CHPH) rat model (10% O₂ for 4 weeks) treated with intraperitoneal Olp (0.2/0.4 mg/kg/d) for 2 weeks; hypoxic human pulmonary artery smooth muscle cells (HPASMCs, 3% O₂) exposed to Olp (30-300 nM), with IDH1 function validated by overexpression. RESULTS:Clinically, Olp significantly reduced pulmonary artery systolic pressure (PASP) and serum NT-proBNP, and elevated the TAPSE/PASP ratio (a core right ventricular-pulmonary arterial coupling marker, all P < 0.05), with no significant changes in 6-minute walk distance or pulmonary function. In rats, Olp dose-dependently decreased mean PAP, RVSP and pulmonary artery medial thickening, and downregulated collagen I, α-SMA and PCNA (all P < 0.05 vs. hypoxia group). Olp suppressed hypoxic HPASMC proliferation, migration and invasion (P < 0.05), reduced IDH1 expression, and IDH1 overexpression completely reversed Olp's protective effects on HPASMCs. CONCLUSION:Our findings suggest olprinone improves key right ventricular-pulmonary arterial coupling and pulmonary vascular remodeling in hypoxia-associated PH models, likely via regulating IDH1-related pathways. Clinical observations remain preliminary; further studies with COPD-PH models and prospective clinical trials are needed to confirm its therapeutic value.

Background: Impaired insulin secretion by pancreatic beta cells drives chronic hyperglycemia, which characterizes type 2 diabetes mellitus. The mechanosensitive ion channel Piezo2 has been implicated in various physiological processes. However, its expression and functional role in pancreatic endocrine cells remain poorly understood. Methods: We investigated the expression, cellular localization, and potential functional significance of Piezo2 in the pancreatic islets of mice fed normal- and high-fat diets (HFD) using molecular, immunohistochemical, and immunofluorescence approaches. Results: Piezo2 mRNA and protein expression were detected in rat pancreatic tissue and the pancreatic beta cell line INS-1 via polymerase chain reaction and Western blotting analyses. Hematoxylin and eosin staining and histopathological analysis were performed to determine the localization of Piezo2, insulin, and glucagon in the islets of Langerhans from mouse pancreas. Immunofluorescence revealed that Piezo2 colocalized with insulin, glucagon, pancreatic polypeptide (PP, a pancreatic cell marker), and insulin/PP (suggesting Ppy-lineage beta cells). Piezo2 expression is significantly reduced in islets from HFD-fed mice and downregulated under high glucose conditions in INS-1 cells. Stretch stimulation, with or without D-GsMTx4 (a Piezo2-specific inhibitor), enhanced glucose-stimulated insulin secretion, whereas ruthenium red (a non-specific Piezo channel inhibitor) did not alter the response to high glucose. Conclusions: These findings demonstrate Piezo2 expression in pancreatic islets and suggest that it is enriched in beta cells and Ppy-lineage beta cells, minority in alpha cells and is responsive to metabolic stress. Although Piezo2 may contribute to beta-cell adaptation, its role in insulin secretion remains unclear.

BACKGROUND:The escalating prevalence of obesity has made it a critical public health concern. There is an urgent need to identify naturally derived compounds with anti-obesity potential. Britanin (BRI), a bioactive sesquiterpene lactone derived from Inula species, has shown promise in metabolic disorder management, but its anti-obesity mechanisms remain uncharacterized. OBJECTIVES:Combining animal experiments and network pharmacology analysis to explore the effect of BRI in high-fat diet-induced obesity. METHODS:C57BL/6J male mice were used for experiment. A high-fat diet (HFD)-induced obese mouse model was treated with BRI (5/15 mg/kg, i.p.) to validate lipid metabolism and weight loss. Network pharmacology identified potential targets via SwissTargetPrediction, GeneCards and OMIM databases, with molecular docking (CB-DOCK) and PPI network analysis (STRING/Cytoscape). Relevant validations were conducted based on the screened targets. Additionally, a biosafety assessment was performed. RESULTS:In-vivo, 15 mg/kg BRI reduced body weight by 18%, decreased serum TG (-45%, p<0.001), TC (-37%, p<0.001) and LDL-C (-32%, p<0.01) and reversed adipocyte hypertrophy. Thirty-nine intersection targets were identified, with MAPK1, EGFR, PTGS2, MAP2K1 and MAPK8 as top hubs (degree centrality >15). BRI exhibited strong binding affinity (-7.7 to -10.3 kcal/mol) to these targets. Mechanistically, BRI exerts its anti-obesity effects by regulating key targets within the MAPK signaling pathway, particularly MAPK1 and inhibited the PPARγ, thereby blocking adipogenesis and promoting the transition of adipose tissue. CONCLUSION:BRI may alleviate obesity by regulating the Mitogen-Activated Protein Kinase signaling pathway, providing a rationale for natural compound-based obesity therapy.

A key characteristic of hypoxic pulmonary hypertension (HPH) is pulmonary vascular remodeling, involving abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Recent studies indicate that mesenchymal stem cell-derived exosomes (MSC-exo) exhibit therapeutic effects on HPH. MSC-exosomes were isolated from the conditioned medium of bone mesenchymal stem cells using ultracentrifugation, confirmed via Western blotting (WB), transmission electron microscopy (TEM), and nanoparticle tracking analyses (NTA). Platelet-derived growth factor BB (PDGFBB) induced pathological behavior in PASMCs, replicating the conditions observed in HPH. HPH rats were subjected to a low oxygen environment (10 ± 1% oxygen) for 8 h daily over 28 days. Parameters such as right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and pulmonary vascular remodeling were evaluated. MSC-exosomes suppressed PDGFBB-induced proliferation and migration of PASMCs. Additionally, MSC-exosomes protected rats from hypoxia-induced increases in RVSP, right ventricular hypertrophy, and pulmonary vascular remodeling. The expression of epidermal growth factor receptor (EGFR) and Erb-B2 receptor tyrosine kinase 2 (ErbB2) was investigated in both HPH lung tissues and PDGFBB-induced PASMCs. Results indicated significant upregulation of EGFR/ErbB2 expression in HPH and PDGFBB-induced PASMCs, which was suppressed by MSC-exosomes. The study demonstrates that MSC-exosomes inhibit the development of HPH by suppressing excessive proliferation and migration of PASMCs through the inhibition of EGFR/ErbB2 heterodimerization.

BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a serious chronic lung disease characterized by progressive dyspnea and deterioration of lung function. According to existing observations, platelet activation and fibroblast-myofibroblast differentiation plays an important role in the development of IPF. This study aimed to investigate the role of podoplanin (PDPN) in this differentiation process during IPF progression. Specifically, the article explores PDPN expression in human IPF and bleomycin (BLM)-induced pulmonary fibrosis in mice, along with the effects and mechanisms of the PDPN monoclonal antibody SZ168 on pulmonary fibrosis both in vitro and in vivo. METHODS:Data analysis of human IPF datasets to identify PDPN as a differentially expressed gene. Following this, in vivo and in vitro experiments were conducted to investigate the role and underlying mechanisms of PDPN in the progression of IPF. Additionally, we measured PDPN levels in the serum of IPF patients to validate its differential expression. RESULTS:Our findings show that PDPN is highly expressed in IPF patients. Additionally, PDPN expression is elevated in TGF-β1-induced fibroblasts and in the lungs of bleomycin-induced mouse models. We particularly found that PDPN was expressed in WI-38 human pulmonary fibroblasts. Knockdown of PDPN in fibroblasts suppresses TGF-β-induced differentiation into myofibroblasts. Furthermore, the PDPN monoclonal antibody SZ168 inhibits platelet-induced fibroblast differentiation. Mechanistic analysis reveals that PDPN promotes bleomycin-induced pulmonary fibrosis via the activation of the RhoA/ROCK signaling pathway. CONCLUSIONS:PDPN is significantly upregulated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and closely associated with the differentiation of fibroblasts into myofibroblasts. The monoclonal antibody SZ168 effectively inhibits platelet activation, thereby inhibiting the differentiation of fibroblasts induced by PDPN and mitigating the progression of pulmonary fibrosis.

Proopiomelanocortin (POMC) is a critical precursor protein in the pituitary gland that regulates adrenal steroid hormone secretion by producing the adrenocorticotropic hormone (ACTH). Corticotropin-releasing hormone (CRH) modulates ACTH release via calcium influx through the voltage-operated Ca²⁺ channels and activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). In this study, we aimed to investigate the role of the calcium/calmodulin-dependent protein kinase kinase/ calcium/calmodulin-dependent protein kinase IV (CaMKK/CaMKIV) signaling cascade in CRH-induced POMC expression using ACTH-producing AtT20 cells, a cell line isolated from the pituitary gland of a mouse with tumor. Protein expression levels of CaMKK and CaMKIV were determined via western blotting. POMC transcription was analyzed via real-time polymerase chain reaction and reporter gene assays, and ACTH secretion was measured via enzyme-linked immunosorbent assay. In addition, effects of constitutively active CaMKK (CaMKK-CA) and CaMKIV (CaMKIV-CA) and their dominant-negative mutants on POMC promoter activity were assessed. CRH-induced CaMKIV phosphorylation was examined via western blotting. Both CaMKK and CaMKIV were expressed in the rat pituitary tissues; three random rats were used. Moreover, 10 nM CRH significantly increased POMC transcription and ACTH secretion in AtT20 cells. Inhibition of CaMKK and protein kinase A by STO-609 and H89, respectively, suppressed CRH-induced POMC transcription. Furthermore, CaMKK-CA and CaMKIV-CA independently activated the POMC promoter. CRH rapidly induced CaMKIV phosphorylation and nuclear localization, but these effects were blocked by STO-609. Overall, these findings suggest that the CaMKK/CaMKIV signaling pathway plays a crucial role in CRH-mediated POMC transcription and ACTH secretion in AtT20 cells.

Systolic dysfunction has been observed following isolated moderate–severe traumatic brain injury (Ims-TBI). However, early risk factors for the development of systolic dysfunction after Ims-TBI and their impact on the prognosis of patients with Ims-TBI have not been thoroughly investigated. A prospective observational study among patients aged 16 to 65 years without cardiac comorbidities who sustained Ims-TBI (Glasgow Coma Scale [GCS] score ≤12) was conducted. Systolic dysfunction was defined as left ventricular ejection fraction <50% or apparent regional wall motion abnormality assessed by transthoracic echocardiography within 24 hours after admission. The primary endpoint was the incidence of systolic dysfunction after Ims-TBI. The secondary endpoint was survival on discharge. Clinical data and outcomes were assessed within 24 hours after admission or during hospitalization. About 23 of 123 patients (18.7%) developed systolic dysfunction after Ims-TBI. Higher admission heart rate (odds ratios [ORs]: 1.05, 95% confidence interval [CI]: 1.02–1.08; P = .002), lower admission GCS score (OR: 0.77, 95% CI: 0.61–0.96; P = .022), and higher admission serum high-sensitivity cardiac troponin T (Hs-cTnT) (OR: 1.14, 95% CI: 1.06–1.22; P < .001) were independently associated with systolic dysfunction among patients with Ims-TBI. A combination of heart rate, GCS score, and serum Hs-cTnT level on admission improved the predictive performance for systolic dysfunction (area under curve = 0.85). Duration of mechanical ventilation, intensive care unit length of stay, and in-hospital mortality of patients with systolic dysfunction was higher than that of patients with normal systolic function (P < .05). Lower GCS (OR: 0.66, 95% CI: 0.45–0.82; P = .001), lower admission oxygen saturation (OR: 0.82, 95% CI: 0.69–0.98; P = .025), and the development of systolic dysfunction (OR: 4.85, 95% CI: 1.36–17.22; P = .015) were independent risk factors for in-hospital mortality in patients with Ims-TBI. Heart rate, GCS, and serum Hs-cTnT level on admission were independent early risk factors for systolic dysfunction in patients with Ims-TBI. The combination of these 3 parameters can better predict the occurrence of systolic dysfunction.

Previous research has demonstrated that Dexmedetomidine (DEX), an α2 adrenergic agonist commonly used for its sedative and analgesic properties, can attenuate lipopolysaccharide (LPS)-induced acute kidney injury (AKI). This study explores the possibility that DEX’s protective effects in LPS-induced AKI are mediated through the inhibition of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, and the activation of the antioxidant response through the Keap1/Nrf2/HO-1 signaling pathway. We induced AKI in 42 mice using LPS and divided them into six groups: saline control, LPS, LPS + DEX, LPS + Ferrostatin-1 (LPS + Fer-1; a ferroptosis inhibitor), LPS + DEX with α2-receptor antagonist Altipamizole (LPS + DEX + ATI), and LPS + DEX with Nrf2 inhibitor ML385 (LPS + DEX + ML385). After 24 h, we analyzed blood and kidney tissues. LPS exposure resulted in AKI, with increased serum creatinine, BUN, and cystatin C, and tubular damage, which DEX and Fer-1 ameliorated. However, Altipamizole and ML385 negated these improvements. The LPS group exhibited elevated oxidative stress markers and mitochondrial damage, reduced by DEX and Fer-1, but not when α2-adrenergic or Nrf2 pathways were blocked. Nrf2 and HO-1 expression declined in the LPS group, rebounded with LPS + DEX and LPS + Fer-1, and fell again with inhibitors; inversely, Keap1 expression varied. Our results demonstrate that DEX may protect against LPS-induced AKI, at least partially by regulating ferroptosis and the α2-adrenergic receptor/Keap1/Nrf2/HO-1 pathway, suggesting a potential therapeutic role for DEX in AKI management by modulating cell death and antioxidant defenses.

Recently, attention has been drawn to the adverse outcomes of N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPDQ) on human health, but its cardiac toxicity has been relatively understudied. This work aims to investigate the effects of 6PPDQ on differentiated H9c2 cardiomyocytes. Our findings demonstrated that exposure to 6PPDQ altered cellular morphology and disrupted the expression of cardiac-specific markers. Significantly, 6PPDQ exposure led to cardiomyocyte senescence, characterized by elevated β-Galactosidase activity, upregulation of cell cycle inhibitor, induction of DNA double-strand breaks, and remodeling of Lamin B1. Furthermore, 6PPDQ hindered autophagy flux by promoting the formation of autophagosomes while inhibiting the degradation of autolysosomes. Remarkably, restoration of autophagic flux using rapamycin counteracted 6PPDQ-induced cardiomyocyte senescence. Additionally, our study revealed that 6PPDQ significantly increased the ROS production. However, ROS scavenger effectively reduced the blockage of autophagic flux and cardiomyocyte senescence caused by 6PPDQ. Furthermore, we discovered that 6PPDQ activated the Aryl hydrocarbon receptor (AhR) signaling pathway. AhR antagonist was found to reverse the blockage of autophagy and alleviate cardiac senescence, while also reducing ROS levels in 6PPDQ-treated group. In conclusion, our research unveils that exposure to 6PPDQ induces ROS overproduction through AhR activation, leading to disruption of autophagy flux and ultimately contributing to cardiomyocyte senescence.

Background and Aim The present study aimed to investigate whether the mitochondrial KATP channel contributes to angiotensin II (Ang II)-induced vascular dysfunction, the development of hypertension, and atherosclerosis. Methods and Results ApoE (-/-) mice fed a high-fat diet were chronically infused with Ang II for eight weeks and concomitantly treated with losartan (ARB), apocynin, or 5-hydroxy decanoate (5-HD), or 3-methyladenine (3-MA). Systolic blood pressure was measured, and pathological changes of aortic or liver tissue were observed. Nitric oxide (NO), superoxide dismutase 2 (SOD2) levels and vasorelaxation rate were measured, and protein and mRNA expressions were examined by western blot and RT-PCR. Ang II-induced development of hypertension was suppressed not only by ARB, and apocynin but also by 5-HD or 3-MA. Ang II infusion decreased aortic NO production and relaxation, as well as SOD2 activity in liver, which were improved by all treatments. In addition, Ang II-induced activation of autophagy was suppressed by 5-HD in aortic tissue, furthermore, Ang II increases the atherosclerotic index in plasma and exacerbates the development of atherosclerosis by increases of fat deposition in the aorta and liver. Lipid metabolism-related mRNA expressions (LXR-α, LDLR, SRBI, Acca, and FASN) were changed by Ang II. Similarly, not only ARB, and apocynin, but also 5-HD and 3-MA suppressed Ang II-induced these changes. Conclusions Our present findings evidence that mitochondrial KATP channel-mediated autophagy contributes to Ang II-induced vascular dysfunction, development of hypertension, and atherosclerosis.

Hypoxic pulmonary hypertension (HPH) is a serious and life-threatening chronic cardiopulmonary disease characterized by progressive elevation of pulmonary artery pressure and pulmonary vascular remodeling. Mesenchymal stem cell- derived exosomes (MSC-Exos) can relieve HPH by reversing pulmonary vascular remodeling. The HPH model was established in healthy male Sprague-Dawley (SD) rats aged 6 to 8 weeks. The rats were placed in a room with oxygen concentration of (10 ± 1) % for 8 hours a day over 28 days, were then injected intravenously with MSC-Exos (100 ug protein/kg) or equal-volume phosphate buffer saline (PBS) once a day over 1 week. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and pulmonary vascular remodeling were observed after anesthesia. In addition, platelet-derived growth factor BB (PDGF-BB) was used to stimulate rat pulmonary artery smooth muscle cells (PASMCs) to construct HPH pathological cell models. The results showed that MSC-Exos could not only reduce the elevation of RVSP, right ventricular hypertrophy and the degree of pulmonary vascular remodeling in HPH rats, but also reduce the proliferation, migration and apoptosis resistance of PASMCs. Finally, GSE53408 and GSE113439 datasets were analyzed and showed that the expression of Hsp90aa1 and pERK/ERK were significantly increased in HPH, also could be inhibited by MSC-Exos. Meanwhile, inhibition of Hsp90aa1 also reduced PASMCs migration and pERK/ERK protein level. In conclusion, MSC-Exos alleviated HPH by suppressing PASMCs proliferation, migration and apoptosis resistance through inhibiting the Hsp90aa1/ERK/pERK pathway.

Objective: Thrombospondin-1 (TSP-1) plays an important role in platelet activation and aggregation and aggravates thrombosis. Chronic stress can cause a variety of diseases, including coagulation disorders, increased thrombosis, atherosclerosis, and a series of cardiovascular and cerebrovascular diseases. However, it is still unknown how chronic stress regulates the expression of TSP-1 after glucocorticoid receptor activation. Approach and Results: rats chronic unpredictable mild stress model was applied and the changes of TSP-1 and microRNAs in plasma were examined. Effects of glucocorticoid receptor activation on human umbilical vein endothelial cells and platelets were observed. Glucocorticoid receptor (GR) activation upregulated the expression of TSP-1 and downregulated the expression of microRNA-1-3p accompanied with increase of phosphorylation of p38 mitogen-activated protein kinase (MAPK) and argonaute-2 (AGO-2). Blockade of p38 MAPK phosphorylation resulted in decrease of phosphorylation level of AGO-2, increase of microRNA-1-3p expression, and decrease of TSP-1 expression. Transfection of AGO-2 Y393F point mutant plasmid, increased microRNA-1-3p expression and decreased TSP-1 expression, transfection of microRNA-1-3p mimic also decreased TSP-1 expression, while transfection of microRNA-1-3p inhibitor increased TSP-1 expression. Finally, GR activation led to an increase in the phosphorylation level of p38 MAPK in platelets and an increase in the level of TSP-1 in the supernatant. Conclusions: our study demonstrates that GR activation in HUVEC stimulates the phosphorylation of p38 MAPK, which in turn promotes the phosphorylation of AGO-2 and inhibits the maturation of microRNA-1-3p, leading to elevated expression of TSP-1, GR activation in platelets leads to the release of TSP-1. ![Graphical Abstract][1] Graphical Abstract HSS: Hydrocortisone sodium succinate ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes

新医科背景下虚拟教研室的建设是落实国家"双一流"专业建设目标、提升高校教学水平和人才培养质量的重要举措.苏州大学医学机能学团队积极响应国家需要与时代呼唤,与贵州医科大学和右江民族医学院联合申报跨校医学机能学虚拟教研室建设点,成为首批江苏省虚拟教研室建设培育点.教研室结合新医科人才培养要求,对教学理念、课程体系、教学内容和教学方法进行重构,为新医科背景下医学基层教学组织的构建与运行提供了有益参考.

Objective: Hypoxic pulmonary hypertension (HPH) is a progressive and life-threatening disease characterized by perivascular inflammation, pulmonary vascular remodeling, and occlusion. Mesenchymal stromal cell-derived exosomes (MSC-exo) have emerged as potential therapeutic agents due to their role in cell communication and the transportation of bioactive molecules. In this study, we aimed to investigate the therapeutic effects of MSC-exo against HPH and elucidate the underlying molecular mechanism. Methods: Exosomes were isolated from conditioned media of human bone mesenchymal stromal cells using ultracentrifugation and characterized through western blotting, transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). An HPH animal model was established in male SD rats, and MSC-exo or phosphate-buffered saline (PBS) were administered via the tail vein for three weeks. Subsequently, right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and pulmonary vascular remodeling were evaluated. Lung tissues from HPH rats and normal rats underwent high-throughput sequencing and transcriptomic analysis. Gene Ontology (GO) analysis was employed to identify upregulated differentially expressed genes. Additionally, rat pulmonary artery smooth muscle cells (PASMC) exposed to platelet-derived growth factor-BB (PDGF-BB) were used to simulate HPH-related pathological behavior. In vitro cellular models were established to examine the molecular mechanism of MSC-exo in HPH. Results: MSC-exo administration protected rats from hypoxia-induced increases in RVSP, RVHI, and pulmonary vascular remodeling. Additionally, MSC-exo alleviated PDGF-BB-induced proliferation and migration of PASMC. Transcriptomic analysis revealed 267 upregulated genes in lung tissues of HPH rats compared to control rats. Gene Ontology analysis indicated significant differences in pathways associated with Yes Associated Protein 1 (YAP1), a key regulator of cell proliferation and organ size. RT-qPCR and western blot analysis confirmed significantly increased expression of YAP1 in HPH lung tissues and PASMC, which was inhibited by MSC-exo treatment. Furthermore, analysis of datasets demonstrated that Secreted Phosphoprotein 1 (SPP1), also known as Osteopontin (OPN), is a downstream binding protein of YAP1 and can be upregulated by PDGF-BB. MSC-exo treatment reduced the expression of both YAP1 and SPP1. Lentivirus-mediated knockdown of YAP1 inhibited PDGF-BB-induced PASMC proliferation, migration, and SPP1 protein levels. Conclusion: Our findings demonstrate that MSC-exo exert a therapeutic effect against hypoxia-induced pulmonary hypertension by modulating the YAP1/SPP1 signaling pathway. The inhibition of YAP1 and downstream SPP1 expression by MSC-exo may contribute to the attenuation of pulmonary vascular remodeling and PASMC proliferation and migration. These results suggest that MSC-exo could serve as a potential therapeutic strategy for the treatment of HPH. Further investigations are warranted to explore the clinical applicability of MSC-exo-based therapies in HPH patients.

Background: Dexmedetomidine (DEX) reportedly protects against ischemia-reperfusion (I/R) injury and associated damage to the kidneys, but the underlying mechanisms have yet to be established. Methods: Unilateral nephrectomy was performed in Wistar rats, and the remaining kidney was clamped for 1 h prior to reperfusion to establish an experimental model system. These animals were then randomized into Sham, DEX + Sham, DEX + I/R, ATI (Altepamizole, α2-adrenergic receptor inhibitor) + DEX + I/R, and 3-MA (3-methyladenine, autophagy inhibitor) + DEX + I/R groups. Serum renal function biomarkers, acute kidney injury (AKI) histopathological scores, serum inflammatory factors, redox biomarkers, markers of autophagic flux, and autophagosome numbers were assessed. Levels of proteins related to the autophagic pathway, including mTOR and AMPK, were also analyzed. Results: Serum creatinine and urea nitrogen levels in the I/R group were significantly elevated over those in sham control rats, as were AKI scores, serum inflammatory cytokine concentrations (IL-6, IL-1β, and TNF-α), and serum levels of the oxidative stress biomarker malondialdehyde (MDA). All of these parameters were significantly reduced in the DEX + I/R group relative to I/R model rats. I/R group rats also exhibited significant decreases in renal levels of autophagic flux-related biomarkers and autophagosome numbers relative to sham controls, while DEX administration partially restored normal autophagic flux in these rats. Acute I/R also suppress the expression of AMPK in the kidney while increasing mTOR expression, and DEX reversed these effects. The beneficial impact of DEX on I/R-associated AKI was ablated by ATI or 3-MA administration. Conclusions: These analyses provide strong evidence for the ability of DEX to protect against I/R-associated AKI via the α2-AR/AMPK/mTOR pathway-mediated enhancement of autophagic activity.

生理学是西医院校医学生的一门专业基础课,生理学实验是生理学教学的重要组成部分.在当下培养复合型医学人才的导向下,文章认为有必要在生理学实验教学中适当引入中医药实验和实操,这不仅有利于医学生从中西医两个不同角度来探索生命活动规律,也有利于在专业课学习的同时进行思政教育,培养大学生的民族文化自信.在生理学实验课上,教师通过人体实操和动物实验的方式,让学生见证中医药的真实疗效,认识到实践在探索生命活动规律过程中的重要性以及中医在方法论上的独特之处,文章也对可能遇到的问题进行了分析.

The glymphatic system contributes to the clearance of amyloid-β from the brain and is disrupted in Alzheimer's disease. However, whether the system is involved in the removal of α-synuclein (α-syn) and whether it is suppressed in Parkinson's disease (PD) remain largely unknown. In mice receiving the intranigral injection of recombinant human α-syn, we found that the glymphatic suppression via aquaporin-4 (AQP4) gene deletion or acetazolamide treatment reduced the clearance of injected α-syn from the brain. In mice overexpressing the human A53T-α-syn, we revealed that AQP4 deficiency accelerated the accumulation of α-syn, facilitated the loss of dopaminergic neurons, and accelerated PD-like symptoms. We also found that the overexpression of A53T-α-syn reduced the expression/polarization of AQP4 and suppressed the glymphatic activity of mice. The study demonstrates a close interaction between the AQP4-mediated glymphatic system and parenchymal α-syn, indicating that restoring the glymphatic activity is a potential therapeutic target to delay PD progression.