BACKGROUND AND PURPOSE:Aminoacylase-1 (ACY1) pathway has emerged as a strategy for reducing myocardial fibrosis in heart failure. We have identified astragaloside II (AS-II) as a potent activator of ACY1 and are investigating its underlying mechanisms in cardiac hypertrophy. EXPERIMENTAL APPROACH:Molecular docking and surface plasmon resonance (SPR) assays were used to screen for ACY1 activators derived from QiShenYiQi (QSYQ) pills. Cardiac hypertrophy was induced by transverse aortic constriction. Echocardiography, histopathology and serum biochemical indicators were detected. Transcriptomics and ACY1 siRNA were performed to explore the downstream mechanisms. Neonatal rat ventricular myocytes were treated with angiotensin II to establish a model of cardiomyocyte hypertrophy. The expression levels of hypertrophic markers and mitochondrial function were assessed. Using cardiac ACY1 overexpression and inhibition was used to investigate the role of angiotensin II in regulating ACY1-mediated pathways. KEY RESULTS:Through virtual screening followed by experimental validation, AS-II was identified as a potent activator of ACY1, demonstrating high binding affinity to human ACY1. In vivo studies showed that AS-II significantly improved cardiac function and attenuated pressure overload-induced cardiac hypertrophy. AS-II enhanced mitochondrial respiration and inhibited hypertrophy in angiotensin II-injured cardiomyocytes. AS-II inhibited β-catenin nuclear translocation and phosphorylation leading to the suppression of transcription factor 4-mediated transcriptional activation of the hypertrophy-associated gene UCHL1. ACY1 inhibition abolished the cardioprotective effects of AS-II, confirming its actions are dependent on ACY1. CONCLUSION AND IMPLICATIONS:AS-II as a novel activator of ACY1 that effectively attenuates cardiac hypertrophy. These findings provide new perspectives for the prevention and treatment of heart failure.

Hepatic encephalopathy (HE) is a severe clinical condition with limited therapeutic options. Silybin, a principal bioactive constituent of milk thistle, is a natural compound known for its protective effects against various liver diseases and neurodegenerative disorders. Silibinin meglumine (SM), the meglumine salt of silybin, is widely used in the management of hepatic disorders. However, the therapeutic potential and mechanistic basis of SM in HE remain incompletely elucidated. In this study, SM reduced serum ammonia levels and improved hepatic function markers, including alanine transaminase, aspartate transaminase, and total bilirubin (TBil), in thioacetamide (TAA)-induced HE mice. SM also attenuated inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) in both plasma and brain tissue, reduced the oxidative stress marker malondialdehyde, and increased glutathione levels. Furthermore, molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, and microscale thermophoresis (MST) assay collectively indicated that uncoupling protein 2 (UCP2) may serve as a direct molecular target of SM in mitigating HE. Notably, SM downregulated UCP2 expression in liver tissue and alleviated oxidative stress and mitochondrial dysfunction through modulation of the UCP2/PINK1/Drp1/mitofusin-2 (MFN2)/LC3B pathway. Additionally, co-administration of a UCP2 inhibitor partially attenuated the antioxidant effects of SM; however, no statistically significant reduction was observed in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In summary, this study demonstrates that SM-mediated targeting of UCP2 enhances hepatic mitochondrial function and suppresses excessive mitophagy, thereby ameliorating TBil in TAA-induced HE. These findings suggest that SM may represent a promising therapeutic strategy for TAA-induced HE.

The pathogenesis of acute lung injury (ALI) and the severe form of ALI, acute respiratory distress syndrome (ARDS), is incompletely understood. We aimed to determine the mechanism of action for non-muscle myosin heavy-chain IIA (NMMHC IIA) and the NMMHC IIA targeting compound in the context of lipopolysaccharide (LPS)-induced pulmonary endothelial barrier dysfunction associated with ALI. Endothelial-specific monoallelic knockout of NMMHC IIA alleviated ALI and reversed alterations in sphingosine-1-phosphate (S1P), a serum metabolite. Inhibition of NMMHC IIA upregulated SPHK1, a key S1P-synthesizing enzyme, and the SPHK1 transcriptional regulator, KLF2. NMMHC IIA directly interacted with FOXO1 in LPS-treated endothelial cells to promote FOXO1 nuclear translocation. Knockdown of MYH9 or FOXO1 restored barrier integrity by activating the KLF2/SPHK1 pathway. Endothelial NMMHC IIA knockdown promoted FOXO1 dephosphorylation and KLF2/SPHK1 activation in vivo, which increased serum S1P levels; NMMHC IIA overexpression exerted opposite effects. Furthermore, DT-13, a steroidal sapogenin derived from Liriope muscari, was confirmed to bind to NMMHC IIA via the cellular thermal shift assay (CETSA) and microscale thermophoresis (MST) assay. DT-13 attenuated LPS-induced endothelial barrier disruption by targeting NMMHC IIA and mediating the FOXO1/KLF2/SPHK1 axis. The findings herein elucidate a new mechanism underlying ALI pathogenesis and suggest promising therapeutic strategies.

Aging-related neurological disorders, including stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, and various neuroinflammatory conditions, affect over three billion individuals worldwide and constitute leading causes of morbidity, disability, and socioeconomic burdens. Aging contributes not only to the increased incidence of these disorders but also to their progression through interconnected mechanisms, including endothelial dysfunction, oxidative stress, chronic inflammation, mitochondrial dysfunction, cellular senescence, metabolic imbalance, and gut microbiota dysbiosis. These processes collectively impair neuronal survival, synaptic plasticity, and cognitive and motor functions. Traditional Chinese medicine (TCM), with its characteristic multi-component and multi-target therapeutic strategies, has emerged as a promising approach to counteract age-associated neurological decline. Accumulating preclinical studies suggest that TCM interventions may exert neuroprotective, anti-inflammatory, and antioxidant effects, modulate autophagy, restore metabolic homeostasis, and potentially delay cellular senescence. However, high-quality clinical evidence on safety and efficacy remains limited. This review summarizes current insights into the molecular interplay between aging and neurological disorders and highlights the therapeutic potential of TCM in targeting hallmarks of aging, providing perspectives for integrative prevention and treatment strategies for neurodegenerative and neurovascular diseases.

Yiqi Huoxue (YQHX) formula is an empirical prescription for the treatment of qi deficiency and blood stasis syndrome in traditional Chinese medicine (TCM). Qi deficiency and blood stasis is one of the typical TCM syndromes in heart failure. However, little is known about the mechanism of the YQHX formula in treating heart failure patients with qi deficiency and blood stasis syndrome. This study aimed to systematically investigate the therapeutic mechanisms of YQHX formula in heart failure with comorbid insomnia. HPLC-Q-TOF-MS/MS analysis identified twenty-one bioactive components in the YQHX formula, including caffeic acid, hydroxysafflor yellow A, and salvianolic acid B. Research results in vivo revealed that treatment with YQHX formula significantly improved cardiac function and alleviated myocardial injury in the mice model of TAC-induced HF. Meanwhile, YQHX formula effectively suppressed pressure overload-induced cardiac hypertrophy and significantly ameliorated insomnia and anxiety-like behaviors through modulation of neurotransmitter systems. Mechanistically, YQHX formula upregulated RORα expression, thereby facilitating mitophagy and restoring mitochondrial dynamics homeostasis. Consistent with these in vivo findings, in vitro experiments demonstrated that YQHX formula markedly inhibited Ang II-induced cardiomyocyte hypertrophy, enhanced mitochondrial membrane potential (ΔΨm), reduced reactive oxygen species (ROS) production and preserved mitochondrial structural integrity. Our findings identify the promotion of the RORα pathway as the underlying mechanism through which the YQHX formula alleviates heart failure and comorbid insomnia, offering new insights into the prevention and treatment of cardiovascular diseases accompanied by sleep disturbances.

Pathological cardiac hypertrophy induced by pressure overload is a critical precursor to heart failure, necessitating the identification of novel pathogenesis-specific therapeutic targets. Here, we identify aminoacylase-1 (ACY1), a central enzyme in amino acid metabolism, as a critical cardioprotective molecule. ACY1 expression was significantly downregulated in cardiomyocytes from both a mice transverse aortic constriction (TAC) model and patients with hypertrophic cardiomyopathy. Conversely, cardiac specific overexpression of ACY1 in mice substantially alleviated TAC-induced cardiac hypertrophy, dysfunction, and fibrotic remodeling, whereas its inhibition aggravated these pathological features. In vitro, ACY1 overexpression in neonatal rat cardiomyocytes (NRCMs) significantly suppressed angiotensin II (Ang II)-induced hypertrophy, while its inhibition promoted cardiomyocytes hypertrophy. Mechanistically, integrated transcriptomic and molecular analyses revealed that ACY1 binds directly to β-catenin, thereby inhibiting its phosphorylation at Ser675 and subsequent nuclear translocation. ChIP-qPCR assays confirmed that this cytosolic sequestration of β-catenin prevents TCF4-mediated transcription of the pro-hypertrophic ubiquitin carboxyl-terminal hydrolase L1 (UCHL1). Furthermore, KEGG pathway analysis revealed that ACY1 overexpression influenced genes enriched in oxidative phosphorylation. Functional metabolic assays confirmed that ACY1 preserved mitochondrial integrity under stress, rescuing impairments in oxygen consumption rate, extracellular acidification rate, and mitochondrial membrane potential induced by pressure overload. Importantly, the anti-hypertrophic effects of ACY1 were significantly blunted by pharmacological inhibition of the β-catenin/TCF4 pathway. Our findings establish the ACY1/β-catenin/TCF4/UCHL1 pathway as a fundamental mechanism in disease progression, thereby proposing the enhancement of ACY1 function as a rational and innovative strategy to treat pressure-overload heart failure.

BACKGROUND AND PURPOSE:Targeting the retinoid-related orphan receptor α (RORα) signalling pathway represents a promising therapeutic strategy for cardiovascular diseases comorbid with insomnia. Here, we identify 6‴-feruloylspinosin (6-FS) as a potent RORα activator and investigate its therapeutic efficacy and underlying mechanisms in HF accompanied by insomnia. EXPERIMENTAL APPROACH:Transverse aortic constriction (TAC) was conducted to induce heart failure comorbid with insomnia. Echocardiography, histopathology and serum biochemical indicators were examined. Transcriptomics analysis, molecular docking, surface plasmon resonance binding assays, cellular thermal shift and microscale thermophoresis assays were performed. Subsequently, the mechanisms underlying 6-FS-mediated protection were elucidated through Western blot (WB), immunofluorescence (IF) and immunohistochemistry (IHC). KEY RESULTS:6‴-Feruloylspinosin (6-FS) effectively improved cardiac function and mitigated myocardial injury in the mice model of TAC-induced HF. 6-FS attenuated pressure overload-induced cardiac hypertrophy and significantly improved insomnia and anxiety-like behaviours through modulation of neurotransmitter systems. 6-FS ameliorated insomnia through restoration of tight junction integrity and suppression of neuroinflammation. Mass spectrometry analysis confirmed the presence of 6-FS in both cardiac and cerebral tissues, and transcriptomic analysis demonstrated a marked up-regulation of RORα following 6-FS administration. Mechanistically, 6-FS exhibited the strongest binding affinity for RORα and simultaneously enhanced RORα-mediated regulation of the JAK2/STAT3 signalling pathway. Importantly, RORα inhibition completely abrogated the protective effects of 6-FS against TAC-induced cardiac hypertrophy and insomnia. CONCLUSIONS AND IMPLICATIONS:Our findings highlight 6-FS as a novel RORα activator with dual cardioprotective and sleep-enhancing benefits, offering new insights into the prevention and treatment of cardiovascular diseases with comorbid sleep disturbances.

Silibinin (Sil) is a major bioactive component of silymarin, extracted from the fruit and seeds of Silybum marianum. Silibinin meglumine (SM) is a water-soluble derivative of silibinin that has shown significant potential in liver fibrosis. However, the potential effects and underlying mechanisms of SM on acute liver failure (ALF) are still not fully understood. This study aims to find the likely mechanism. An ALF mouse model and a cell model were established with GalN/LPS. SM was administered to mice via the tail vein or to a hepatocyte line (alpha mouse liver 12, AML12). The results showed that SM particularly lowered the mortality and improved liver pathological lesions in ALF mice. Meanwhile, SM improved the levels of GSH, SOD, TNF-α, IL-6, IL-1β, and IL-10 in the liver tissues and serum. Additionally, SM enhanced cell viability and reduced oxidative stress in vitro. In the AKT/GSK3β/Nrf2/GPX4 pathway, the subpathway of AKT/GSK3β was inhibited, and the subpathway of Nrf2/GPX4 was activated by SM both in vivo and in vitro. In addition, ferrostatin-1, a ferroptosis inhibitor, and the silencing of AKT using siRNA weakened the protective effect of SM, indicating that this process is mediated in an AKT-dependent manner. All the results suggested that SM inhibits inflammation and oxidative stress by modulating the AKT/GSK3β/Nrf2/GPX4 pathway.

Disruption of the blood-brain barrier (BBB) is a key event in the onset of ischemic stroke (IS), primarily driven by endothelial cytoskeletal rearrangement. The interaction between non-muscle myosin heavy chain IIA (NMMHC IIA) and actin, along with the ROCK/MLC pathway, is central to this cytoskeletal reorganization. While our previous studies have shown that the Caspase-3/ROCK1/MLC/NMMHC IIA-actin positive feedback loop mediates H2O2-induced neuronal apoptosis, its role in cerebral ischemia-reperfusion (I/R) injury and BBB disruption remains unclear. In vivo, we used endothelial-specific NMMHC IIA conditional knockdown mice, NMMHC IIA-inducible endothelial conditional knock-in mice and C57BL/6J to establish a middle cerebral artery occlusion/reperfusion model. In vitro, we employed brain microvascular endothelial cells in an oxygen-glucose deprivation/reoxygenation model. The effects of the NMMHC IIA inhibitor blebbistatin, the ROCK1 inhibitor Y-27632, and the actin depolymerizer cytochalasin D were assessed for their impact on I/R-induced activation of the ROCK/MLC/NMMHC IIA-actin pathway, tight junction proteins (TJs) degradation, and brain damage. Inhibition of NMMHC IIA expression and stress fiber depolymerization significantly reduced NMMHC IIA-actin interactions, suppressed the ROCK/MLC pathway, decreased TJs degradation, and alleviated cerebral I/R injury. Conversely, overexpression of NMMHC IIA further exacerbated cerebral I/R injury and BBB disruption and amplified activation of the ROCK1/MLC pathway. Y-27632 inhibited the ROCK/MLC/NMMHC IIA-actin pathway, mitigating I/R-induced BBB disruption. This study reveals that the ROCK1/MLC/NMMHC IIA-actin pathway is implicated in I/R-induced BBB disruption and operates as a positive feedback loop. These findings offer a promising therapeutic strategy for the treatment of IS and BBB damage.

BACKGROUND:Ischemic stroke (IS), the predominant clinical stroke subtype, is increasingly linked to dysregulation of the gut-brain axis (GBA)-a bidirectional neuroendocrine-immune interface connecting intestinal homeostasis with cerebrovascular pathophysiology. Xinqingning Tablet (XQNT) demonstrates neuroprotective potential in IS complicated by gut dysbiosis (GD), yet its mechanisms of GBA modulation remain unclear. METHODS:A dual-hit IS-GD mouse model was established via fecal slurry transplantation and permanent middle cerebral artery occlusion (pMCAO) surgery. Gut function was evaluated by constipation indices and histopathological changes, while the neuroprotective efficacy of XQNT (0.36, 0.48, and 0.61 g kg⁻¹) was assessed via TTC staining, neurological deficit scores, cerebral water content, and Evans blue (EB) extravasation assays. Additionally, Western blot was employed to quantify blood-brain barrier (BBB) and inflammation-associated proteins. microRNA sequencing was used to screen the differentially expressed miRNAs. miR-126 expression levels were measured by RT-qPCR, while concentrations of LPS, IL-6 and IL-10 were determined by ELISA. Finally, mechanistic validation employed intravenous miR-126 agonism/antagonism coupled with phenotypic rescue experiments. RESULTS:XQNT conferred robust survival benefits, while concurrently ameliorating intestinal dysfunction and neurovascular injury. Mechanistically, XQNT elevated miR-126 expression, suppressing NF-κB-driven neuroinflammation. Additionally, miR-126 agonism phenocopied XQNT efficacy, whereas miR-126 inhibition abrogated therapeutic benefits. CONCLUSIONS:This study provides early evidence that XQNT functions as a dual-target GBA modulator that alleviates IS with GD via regulation of the miR-126/NF-κB axis. By simultaneously promoting barrier restoration and inflammatory resolution, XQNT offers a promising therapeutic approach that links regulation of the gastrointestinal system with cerebrovascular protection.

Sepsis is a condition characterized by a systemic inflammatory response due to infection, resulting in numerous organ dysfunction. Salvianolic acid A (SAA) is a phenolic acid substance extracted from the plant Salvia miltiorrhiza Bunge, possessing antioxidant and anti-platelet aggregation properties. Although aberrant stimulator of interferon genes (STING) signaling is associated with sepsis, it is uncertain if SAA can influence this pathway to avert sepsis-induced organ injury. This study examined the antiseptic efficacy and biological mechanisms of SAA. The pharmacodynamics and mechanism of action of SAA in countering STING-induced inflammation during sepsis were investigated utilizing a cecal ligation and puncture (CLP) sepsis animal model. In vitro, RAW264.7 and THP-1 cells were preincubated with SAA for one hour before exposure to lipopolysaccharide (LPS). The molecular mechanism of SAA in the treatment of sepsis was examined by biochemical assays, pathological sections, enzyme-linked immunosorbent assay (ELISA), and western blot analysis. The association between SAA and its targets was examined via cellular thermal shift assay (CETSA), molecular docking, and molecular dynamics simulation analysis. The SAA intervention enhanced the survival rate of mice (18.75 % in the model group versus 55 % in the high-dose group) and dramatically reduced neutrophil infiltration in lung tissue as well as histological changes. It enhanced hepatorenal function and reduced inflammatory cytokines. Furthermore, the in vivo findings demonstrated that SAA could suppress the activation of the STING and TBK1/IRF3 signaling pathway, corroborating the in vitro results. SAA directly interacts with STING and regulates the TBK1/IRF3 signaling pathway to mitigate organ damage and inflammation caused by sepsis. It may serve as a viable therapeutic agent and prospective STING inhibitor.

Qin Gui Huo Luo oral liquid (QGHL) is a modern formulation derived from the Traditional Chinese Medicine (TCM) Daqinjiao Decoction. QGHL has been widely adopted in China's clinical settings as a therapeutic agent for microcirculatory dysfunction. However, the mechanistic interplay of QGHL in animal models for ischemic stroke (IS) treatment remains unexplored. This study aimed to investigate the impact of QGHL on blood-brain barrier (BBB) disruption induced by cerebral ischemia-reperfusion (I/R) injury. HPLC analysis was employed to identify the major chemical constituents of QGHL while maintaining stringent quality standards. Male C57BL/6J mice were subjected to 1-h right middle cerebral artery occlusion, followed by 24-h reperfusion to induce I/R injury. Subsequently, QGHL was administered intragastrically at 3 different doses (7.8, 15.6, and 31.2 g kg-1). QGHL treatment significantly attenuated cerebral I/R injury, as evidenced by reduced infarct volume, improved neurological scores, attenuated cerebral edema, and restored cerebral blood flow. Moreover, QGHL preserved BBB integrity by upregulating zonula occludens-1 (ZO-1) and occludin while suppressing matrix metalloproteinase (MMP)-2/9 expression. Network pharmacology revealed that phosphatidylinositol 3-kinase (PI3K)/AKT/FOXO3A axis served as a major signaling pathway mediating QGHL's therapeutic effects against IS, which was further confirmed by Western blot analysis. QGHL exerts neuroprotection against cerebral I/R injury in mice via modulation of the PI3K/AKT/FOXO3A signaling pathway, suggesting its potential as a novel therapeutic strategy for IS.

Astragali Radix (AR) and Notoginseng Radix et Rhizoma (NR) are frequently employed in cardiovascular disease treatment. However, the efficacy of the AR-NR medicine pair (AN) in improving cardiac remodeling and its underlying mechanism remains unclear. This study aimed to evaluate AN's cardioprotective effect and potential mechanism on cardiac remodeling using transverse aortic constriction (TAC) in mice and angiotensin II (Ang II)-induced neonatal rat cardiomyocytes (NRCMs) and fibroblasts in vitro. High-performance liquid chromatography-quadrupole-time of flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS) characterized 23 main components of AN. AN significantly improved cardiac function in the TAC-induced mice. Furthermore, AN considerably reduced the serum levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin T (CTn-T), and interleukin-6 (IL-6) and mitigated inflammatory cell infiltration. Post-AN treatment, TAC-induced heart size approached normal. AN decreased cardiomyocyte cross-sectional area and attenuated the upregulation of cardiac hypertrophy marker genes (ANP, BNP, and MYH7) in vivo and in vitro. Concurrently, AN alleviated collagen deposition in TAC-induced mice. AN also reduced the expression of fibrosis-related indicators (COL1A1 and COL3A1) and inhibited the activation of the transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog 3 (Smad3) pathway. Thus, AN improved TAC-induced cardiac remodeling. Moreover, AN downregulated p-dynamin-related protein (Drp1) (Ser616) expression and upregulated mitogen 2 (MFN-2) and optic atrophy 1 (OPA1) expression in vivo and in vitro, thereby restoring mitochondrial fusion and fission balance. In conclusion, AN improves cardiac remodeling by regulating mitochondrial dynamic balance, providing experimental data for the rational application of Chinese medicine prescriptions with AN as the main component in clinical practice.

BACKGROUND AND PURPOSE:The sirtuin 3 (SIRT3) signalling pathway is an essential target for various cardiovascular diseases (CVDs), although effective interventions in myocardial ischaemia-induced mitochondrial dysfunction remain to be elucidated. Here, we discovered a potent SIRT3 activator and explored its efficacy and mechanism against mitochondrial dysfunction. EXPERIMENTAL APPROACH:Molecular docking screened for SIRT3 activators among the 10 more common rare ginsenosides. In vivo, left coronary artery ligation induced myocardial ischaemia injury, followed by echocardiography, histopathology and serum biochemical indicators, in C57BL/6J mice. Expression levels of mitophagy and mitochondrial dynamics-associated proteins were examined by western blot (WB), immunofluorescence (IF) and immunohistochemistry (IHC). In vitro, oxygen-glucose deprivation-induced hypoxic injury in neonatal rat ventricular myocytes, and cell viability and mitochondrial function were investigated. SIRT3 small interference RNA (siRNA) was transfected into cardiomyocytes to validate mitochondrial dynamics and mitophagy mechanism regulated by ginsenoside Rh1. KEY RESULTS:Rh1 exhibited the strongest binding affinity as an effective activator of SIRT3. Rh1 improved cardiac function and mitigated myocardial ischaemia injury in vivo. Rh1 ameliorated oxidative stress, improved mitochondrial network morphology and mitochondrial respiration function in hypoxia-injured cardiomyocytes. Rh1 bound to SIRT3 and simultaneously up-regulated Foxo3a, facilitating its nuclear translocation and reducing acetylation of Foxo3a. Rh1 markedly promoted mitochondrial fusion, inhibited mitochondrial fission and accelerated mitophagy. SIRT3 siRNA abrogated the regulation of Rh1 on oxidative stress, mitochondrial dynamics and mitophagy. CONCLUSION AND IMPLICATIONS:Rh1 is a novel SIRT3 activator and protects against myocardial ischaemia-induced mitochondrial dysfunction, providing new clues to prevent and treat ischaemic injury-associated CVD.

Chronic heart failure (CHF) arises from structural and functional changes in the myocardial tissue attributable to various etiologies. Crocetin and its derivative trans‐sodium crocetinate (TSC) have exhibited cardioprotective attributes; however, their poor aqueous solubility and bioavailability impede clinical development. This study aimed to construct a cyclodextrin metal–organic frameworks (CDMOFs)‐based oral delivery system to enhance the pharmacokinetic profile and therapeutic efficacy of TSC for CHF treatment. TSC was loaded into the synthesized γ‐CDMOFs via vacuum adsorption. The CDMOFs@TSC formulation was characterized and evaluated in vitro. Pharmacokinetic and pharmacodynamic analyses were performed in beagle dogs and CHF rats induced by coronary artery ligation, respectively. Both TSC and CDMOFs@TSC elicited no discernible toxicity or pathological changes in major organs of rats, providing preliminary evidence for their biosafety. Pharmacokinetic study in beagle dogs demonstrated that CDMOFs@TSC capsules markedly increase the relative oral bioavailability by 198% versus free TSC capsules. In rats afflicted with CHF, the administration of CDMOFs@TSC yielded notable enhancements in cardiac function. Additionally, it precipitated a reduction in biomarkers linked to myocardial injury, manifested anti‐inflammatory and antifibrotic effects, and induced alterations in myocardial energy metabolism. This is the first report of CDMOFs‐based oral delivery to improve the TSC bioavailability and efficacy. The utilization of CDMOFs@TSC resulted in superior therapeutic outcomes in comparison to standalone TSC by optimizing pharmacokinetics and precise targeted delivery. These results highlight the clinical potential of CDMOF as porous carriers to enable oral delivery of natural products for CHF therapy.

Gardenia is both a food and medicine plant. It is widely used for cardiovascular protection, and its main bioactive ingredient is crocetin. This study aims to observe the therapeutic effects of crocetin on chronic heart failure in rats induced by various etiologies. It further compares the efficacy differences between preventative and treatment administration, varying dosages, and treatment durations, to provide improved guidance for medication in heart failure rats and determine which categories of chronic heart failure rats might benefit most from crocetin. Chronic heart failure models induced by abdominal aorta constriction, renal hypertension, and coronary artery ligation were constructed. By examining cardiac function, blood biochemistry, and histopathology, the study assessed the preventive and therapeutic effects of crocetin on load-induced and myocardial ischemia-induced heart failure. The results showed that in all three models, both treatment and preventative administration of crocetin significantly improved chronic heart failure in rats, especially in preventative administration. The results indicate crocetin may be beneficial for improving symptoms and functional capacity in rats with heart failure. Furthermore, long-term administration was more effective than short-term administration across all three rat models, with therapeutic onset observed over 6 weeks.

BackgroundLimb remote ischemic postconditioning (LRIP) and paeoniflorin (PF) both can ameliorate cerebral ischemia reperfusion (I/R) injury. At present, whether LRIP combined with PF can achieve better therapeutic effect is unknown.PurposeThis study explored the alleviating effect and mechanism of LRIP in combination with PF on cerebral I/R injury in rats.MethodsMiddle cerebral artery occlusion (MCAO) surgery was performed on rats except Sham group. Then PF (2.5mg/kg, 5mg/kg, 10mg/kg) was administrated by intraperitoneal injection 10min before the start of reperfusion. LRIP was operated on the left femoral artery at 0h of reperfusion. Behavioral testing was used to assess neurological impairment, while TTC staining was used to examine infarct volume. Protein expression of MyD88, TRAF6, p38-MAPK and phosphorylation of p47phox in neutrophils from rat peripheral blood were tested by Western blot. Rat bone marrow neutrophils were extracted and incubated for 24h with serum from rats after LRIP combined with PF. p38 MAPK inhibitor group was administrated SB203580 while the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor group was administrated Apocynin. Neutrophils were stimulated by fMLP (10μM). Reactive oxygen species (ROS) production and protein expression of MyD88, TRAF6, p38 MAPK, and p47phox (ser 304 and ser 345) were detected.ResultsLRIP combined with PF (5mg/kg) reduced cerebral infarct volume, ameliorated neurological deficit score (NDS), decreased fMLP-stimulated ROS release and downregulated the protein expression of MyD88, TRAF6, p38-MAPK and phosphorylation of p47phox (ser 304 and ser 345) in neutrophils.ConclusionThe protective effect of LRIP combined with PF on cerebral I/R injury was better than either alone. Taken together, we provided solid evidence to demonstrate that the combination of LRIP and PF had potential to alleviate cerebral I/R injury, which was regulated by MyD88-TRAF6-p38 MAPK pathway and neutrophil NADPH oxidase pathway.

Background: Hippophae Rhamnoides L. (also known as Seabuckthorn SLE), a unique and valuable plant, has recently received worldwide attention. Due to its nutritional and medicinal properties, it has now been domesticated in several regions of the world from the Atlantic coast of Europe to Central Asia, Siberia, northwestern China, and northwestern Mongolia.16 The plant has been extensively used in Indian, Chinese, Tibetan, and Mongolian folk remedies for gastric ulcers, cough, circulatory disorders, skin diseases, asthma, cardiovascular diseases, lung disorders, and liver damage. Materials and methods: Then, the mice model of ALI was induced by PM via intra-tracheally instilled with 50 mg/ kg body weight of Standard Reference Material1648a (SRM1648a), and SLE (12.5, 25, 50 mg/kg) were administered orally 1 h prior to PM. The efficacy and molecular mechanisms in the presence or absence of SLE were elucidated. Results: Eleven main ingredients were detected in SLE and the contents of homoorientin and berberine were quantified. Additionally, the results demonstrated that SLE profoundly inhibited weight loss in mice and ameliorated lung pathological injury induced by PM. Furthermore, we also found that SLE. significantly decreased the lung wet-to-dry weight (W/D) ratios, reduced total protein in bronchoalveolar lavage fluid (BALF), and effectively attenuated PM-induced increased leukocyte and macrophages in BALF. Meanwhile, SLE. could pronouncedly inhibit myeloperoxidase (MPO) activity in lung tissues, decreased the PM-induced inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β), reduced nitric oxide (NO) and increased superoxide dismutase (SOD) in BALF. Conclusion: These findings indicated that SLE attenuated PM-induced ALI by suppressing the release of inflammatory cytokines.

Introduction There is an urgent need for cerebroprotective interventions to improve the suboptimal outcomes with intracerebral hemorrhage (ICH). Despite the important role of nonmuscle myosin heavy chain IIA (NMMHC IIA) in the blood–brain barrier (BBB), its function in ICH remains unclear. Objectives The objective of this study is to explore how NMMHC IIA functions in ICH and to evaluate the effectiveness of targeting NMMHC IIA as a treatment for ICH. Methods We firstly examined the protein expression of NMMHC IIA in clinical patients and animal models with ICH. The function of NNMMHC IIA was then corroborated by using overexpress or knockdown NMMHC IIA specifically in ECs mice and pBMECs. In addition, we explored protein interacts with NMMHC IIA and signaling pathways after ICH by LC-MS/MS and transcriptomics analysis with an emphasis on the function of PAR1 and the CREB3/ARF4 signaling pathway, and validated them in three kind of animal models. To support the clinical translation of our results, we targeted NMMHC IIA to bicalutamide selected from a library of marketed drugs and examined to validate its ameliorative effect on ICH. Results We observed an upregulation of endothelial NMMHC IIA in the brain following the onset of ICH in both patients and mice, while inhibited NMMHC ⅡA improved ICH induced by thrombin, warfarin or tissue plasminogen activator (tPA) after ischemic stroke. Mechanistically, the head domain of NMMHC IIA interacted with protease-activated receptor 1 (PAR1) at the 380–430 aa region and subsequently dissociated and activated the CREB3/ARF4 signaling pathway. We found that bicalutamide and blebbistatin could bind to NMMHC IIA and effectively protect mice from thrombin-mediated ICH. Conclusion The findings indicated that NMMHC IIA dissociated from PAR1 and activated CREB3/ARF4 pathway, which aggravated BBB damage induced by thrombin. This suggested that NMMHC IIA was a novel potential therapeutic target for BBB-related diseases.

大黄素作为一种羟基蒽醌类活性成分,在大黄、虎杖及何首乌等中药中含量丰富.现代药理研究表明,大黄素具有广泛药理活性,包括抗肿瘤、抗炎和免疫调节、抗菌和抗病毒、心肌保护、神经保护、肾脏保护、骨保护、抗纤维化等作用,药用价值高,具有广阔的应用前景.本文旨在总结近5年来发表于国内外期刊有关大黄素的药理活性和作用机制研究进展,重点介绍并总结大黄素在发挥药理作用过程中涉及的潜在靶点及重要分子信号通路,为大黄素的进一步开发和临床应用提供参考依据与线索.