S-nitrosylation of AMPKγ impairs coronary collateral circulation and disrupts VSMC reprogramming.

Collateral circulation is essential for blood resupply to the ischemic heart, which is dictated by the contractile phenotypic restoration of vascular smooth muscle cells (VSMC). Here we investigate whether S-nitrosylation of AMP-activated protein kinase (AMPK), a key regulator of the VSMC phenotype, impairs collateral circulation. In rats with collateral growth and development, nitroglycerin decreases coronary collateral blood flow (CCBF), inhibits vascular contractile phenotypic restoration, and increases myocardial infarct size, accompanied by reduced AMPK activity in the collateral zone. Nitric oxide (NO) S-nitrosylates human recombinant AMPKγ1 at cysteine 131 and decreases AMP sensitivity of AMPK. In VSMCs, exogenous expression of S-nitrosylation-resistant AMPKγ1 or deficient NO synthase (iNOS) prevents the disruption of VSMC reprogramming. Finally, hyperhomocysteinemia or hyperglycemia increases AMPKγ1 S-nitrosylation, prevents vascular contractile phenotypic restoration, reduces CCBF, and increases the infarct size of the heart in Apoe-/- mice, all of which is rescued in Apoe-/-/iNOSsm-/- mice or Apoe-/- mice with enforced expression of the AMPKγ1-C130A mutant following RI/MI. We conclude that nitrosative stress disrupts coronary collateral circulation during hyperhomocysteinemia or hyperglycemia through AMPK S-nitrosylation.

Vitamin B6 inhibits macrophage activation to prevent lipopolysaccharide-induced acute pneumonia in mice.

Macrophage activation participates in the pathogenesis of pulmonary inflammation. As a coenzyme, vitamin B6 (VitB6) is mainly involved in the metabolism of amino acids, nucleic acids, glycogen and lipids. We have previously reported that activation of AMP-activated protein kinase (AMPK) produces anti-inflammatory effects both in vitro and in vivo. Whether VitB6 via AMPK activation prevents pulmonary inflammation remains unknown. The model of acute pneumonia was induced by injecting mice with lipopolysaccharide (LPS). The inflammation was determined by measuring the levels of interleukin-1 beta (IL-1ß), IL-6 and tumour necrosis factor alpha (TNF-α) using real time PCR, ELISA and immunohistochemistry. Exposure of cultured primary macrophages to VitB6 increased AMP-activated protein kinase (AMPK) Thr172 phosphorylation in a time/dose-dependent manner, which was inhibited by compound C. VitB6 downregulated the inflammatory gene expressions including IL-1ß, IL-6 and TNF-α in macrophages challenged with LPS. These effects of VitB6 were mirrored by AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). However, VitB6 was unable to inhibit LPS-induced macrophage activation if AMPK was in deficient through siRNA-mediated approaches. Further, the anti-inflammatory effects produced by VitB6 or AICAR in LPS-treated macrophages were abolished in DOK3 gene knockout (DOK3-/- ) macrophages, but were enhanced in macrophages if DOK3 was overexpressed. In vivo studies indicated that administration of VitB6 remarkably inhibited LPS-induced both systemic inflammation and acute pneumonia in wild-type mice, but not in DOK3-/- mice. VitB6 prevents LPS-induced acute pulmonary inflammation in mice via the inhibition of macrophage activation.

Floralozone Ameliorated Atherosclerosis in Experimental Atherosclerotic Rats Involved with Sphingosine 1-Phosphate 1 Enhancement.

Atherosclerosis (AS) is a chronical pathological process of the arterial narrows due to the AS plaque formation. The aim of this study was to explore the therapeutic effect and the underlying mechanism of Floralozone on experimental atherosclerotic model rats. Experimental atherosclerotic model rats were induced by the right carotid artery balloon injury and intraperitoneal injection of vitamin D3 in rats after 4 weeks high-fat diet. The results exhibited that Floralozone could ameliorate vascular injury and vasorelaxation of descending aortas and increase the superoxide dismutase activity and the expression of sphingosine 1-phosphate (S1P) 1 and reduce the intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, interleukin (IL)-1, IL-6 level, and the malondialdehyde activity in experimental atherosclerotic rats. However, Fingolimod, an S1P1 inhibitor, could reverse these Floralozone effects in experimental atherosclerotic rats. Our results indicated that Floralozone could inhibit the atherosclerotic plaque formation and improves arterial stenosis and reduces endothelial dysfunction in experimental atherosclerotic rats, which might be involved with S1P1 enhancement.

Angiotensin II type 1 receptor blockers prevent aortic arterial stiffness in elderly patients with hypertension.

Backgrounds and aims: Increased arterial stiffness may increase cardiovascular morbidity and mortality. Angiotensin II type 1 receptor blockers (ARBs) are potentially useful in controlling the central blood pressure and arterial stiffness in mild to moderate essential hypertension, while the effects of ARBs in aged patients with essential hypertension are not entirely investigated. Methods: The carotid-femoral arterial pulse wave velocity (PWV) was measured in aged patients with essential hypertension. Results: In a cross-sectional study, PWV value was significantly higher in these old patients with essential hypertension, compared to patients without essential hypertension. In correlation analysis, PWV was associated positively with age, hypertension duration, and carotid atherosclerosis. However, there was no relationship between PWV and gender in aged patients with essential hypertension. In a perspective study, 6-12 months administration of ARBs (losartan, 50 mg/day; telmisartan, 40 mg/day; valsartan 80 mg/day; irbesartan, 150 mg/day) remarkably reduced PWV in aged patients with essential hypertension. Regression analyses of multiple factors indicated that the effects of ARBs on arterial stiffness were not associated with the reduction of blood pressure. Conclusion: ARB treatment is a negative risk factor of arterial stiffness in aged patients with essential hypertension.

Vitamin B6 prevents isocarbophos-induced vascular dementia in rats through N-methyl-D-aspartate receptor signaling.

BACKGROUND: We have previously reported that the long-term exposure of organophosphorus induces vascular dementia (VD) in rats. As a coenzyme, vitamin B6 is mainly involved in the regulation of metabolisms. Whether vitamin B6 improves VD remains unknown. METHODS: The model of VD was induced by feeding rats with isocarbophos (0.5 mg/kg per two day, 12 weeks). The blood flow of the posterior cerebral artery (PCA) in rat was assessed by transcranial Doppler (TCD). The learning and memory were evaluated by the Morris Water Maze (MWM) test. RESULTS: Administration of vitamin B6 increased the blood flow in the right and left posterior cerebral arteries and improved the functions of learning and memory in isocarbophos-treated rats. Vitamin B6 increased the protein levels of N-methyl-D-aspartate receptor (NMDAR) 2B, postsynaptic densities (PSDs) protein 95, and calmodulin-dependent protein kinase II (CaMK-II) in the hippocampus, which were decreased by isocarbophos in rats. Morphological analysis by light microscope and electronic microscope indicated disruptions of the hippocampus caused by isocarbophos were normalized by vitamin B6. Importantly, the antagonist of NMDAR signaling by eliprodil abolished these beneficial effects produced by vitamin B6 on PCA blood flow, learning, memory, and hippocampus structure in rats, as well as the protein expression of NMDAR 2B, PSDs protein 95, and CaMK-II in the hippocampus. CONCLUSION: Vitamin B6 activates NMDAR signaling to prevent isocarbophos-induced VD in rats.

Inhibition of Aberrant MicroRNA-133a Expression in Endothelial Cells by Statin Prevents Endothelial Dysfunction by Targeting GTP Cyclohydrolase 1 in Vivo.

BACKGROUND: GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation. METHODS: Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization. RESULTS: We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin. CONCLUSIONS: Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases.

Berberine promotes ischemia-induced angiogenesis in mice heart via upregulation of microRNA-29b.

BACKGROUND: Berberine has several preventive effects on cardiovascular diseases. Increased expression of miR-29b has been reported to attenuate cardiac remodeling after myocardial infarction (MI). We hypothesized that berberine via an miR-29b-dependent mechanism promotes angiogenesis and improves heart functions in mice after MI. METHODS: The MI model was established in mice by ligation of left anterior descending coronary artery. The expression of miR-29b was examined by RT-qPCR. Angiogenesis was assessed by immunohistochemistry. RESULTS: Berberine increased miR-29b expression and promoted cell proliferations and migrations in cultured endothelial cells, which were abolished by miR-29b antagomir or AMP-activated protein kinase inhibitor compound C. In mice following MI, administration of berberine significantly increased miR-29b expressional level, promoted angiogenesis, reduced infarct size, and improved heart functions after 14 postoperative days. Importantly, these in vivo effects of berberine were ablated by antagonism of miR-29b. CONCLUSION: Berberine via upregulation of miR-29b promotes ischemia-induced angiogenesis and improves heart functions.

Chronic administration of isocarbophos induces vascular cognitive impairment in rats.

Vascular dementia, being the most severe form of vascular cognitive impairment (VCI), is caused by cerebrovascular disease. Whether organophosphorus causes VCI remains unknown. Isocarbophos (0.5 mg/kg per 2 days) was intragastrically administrated to rats for 16 weeks. The structure and function of cerebral arteries were assayed. The learning and memory were evaluated by serial tests of step-down, step-through and morris water maze. Long-term administration of isocarbophos reduced the hippocampal acetylcholinesterase (AChE) activity and acetylcholine (ACh) content but did not alter the plasma AChE activity, and significantly damaged the functions of learning and memory. Moreover, isocarbophos remarkably induced endothelial dysfunction in the middle cerebral artery and the expressions of ICAM-1 and VCAM-1 in the posterior cerebral artery. Morphological analysis by light microscopy and electron microscopy indicated disruptions of the hippocampus and vascular wall in the cerebral arteries from isocarbophos-treated rats. Treatment of isocarbophos injured primary neuronal and astroglial cells isolated from rats. Correlation analysis demonstrated that there was a high correlation between vascular function of cerebral artery and hippocampal AChE activity or ACh content in rats. In conclusion, chronic administration of isocarbophos induces impairments of memory and learning, which is possibly related to cerebral vascular dysfunction.

The antihypertensive effect of Alizarin is achieved by activating VEGFR2/eNOS pathway, attenuating oxidative stress-induced mitochondrial damage and premature senescence.

The primary and initial manifestations of hypertension encompass arterial hypoelasticity and histiocyte senescence. Oxidative stress plays a pivotal role in the progression of senescence. Elevated intracellular oxidative stress levels will directly induce cell damage, disrupt normal physiological signal transduction, which can cause mitochondrial dysfunction to accelerate the process of senescence. Alizarin, an anthraquinone active ingredient isolated from Rubia cordifolia L., has a variety of pharmacological effects, including antioxidant, anti-inflammatory and anti-platelet. Nevertheless, its potential in lowering blood pressure (BP) and mitigating hypertension-induced vascular senescence remains uncertain. In this study, we used spontaneously hypertensive rats (SHR) and human umbilical vein endothelial cells (HUVECs) to establish a model of vascular senescence in hypertension. Our aim was to elucidate the mechanisms underpinning the vascular protective effects of Alizarin. By assessing systolic blood pressure (SBP) and diastolic blood pressure (DBP), H&E staining, SA-ß-Gal staining, vascular function, oxidative stress levels, calcium ion concentration and mitochondrial membrane potential, we found that Alizarin not only restored SBP and increased endothelium-dependent relaxation (EDR) in SHR, but also inhibited oxidative stress-induced mitochondrial damage and significantly delayed the vascular senescence effect in hypertension, and the mechanism may be related to the activation of VEGFR2/eNOS signaling pathway.

Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

Protective effect of alizarin on vascular endothelial dysfunction via inhibiting the type 2 diabetes-induced synthesis of THBS1 and activating the AMPK signaling pathway.

BACKGROUND: In this study, we investigated the protective effects of alizarin (AZ) on endothelial dysfunction (ED). AZ has inhibition of the type 2 diabetes mellitus (T2DM)-induced synthesis of thrombospondin 1 (THBS1). Adenosine 5'-monophosphate- activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. PURPOSE: The aim of this study was to investigate the ameliorative effect of AZ on vascular injury caused by T2DM and to reveal the potential mechanism of AZ in high glucose (HG)-stimulated human umbilical vein endothelial cells (HUVECs) and diabetic model rats. STUDY DESIGN: HUVECs, rats and AMPK-/- transgenic mice were used to investigate the mitigating effects of AZ on vascular endothelial dysfunction caused by T2DM and its in vitro and in vivo molecular mechanisms. METHODS: In type 2 diabetes mellitus rats and HUVECs, the inhibitory effect of alizarin on THBS1 synthesis was verified by immunohistochemistry (IHC), immunofluorescence (IF) and Western blot (WB) so that increase endothelial nitric oxide synthase (eNOS) content in vitro and in vivo. In addition, we verified protein interactions with immunoprecipitation (IP). To probe the mechanism, we also performed AMPKα2 transfection. AMPK's pivotal role in AZ-mediated prevention against T2DM-induced vascular endothelial dysfunction was tested using AMPKα2-/- mice. RESULTS: We first demonstrated that THBS1 and AMPK are targets of AZ. In T2DM, THBS1 was robustly induced by high glucose and inhibited by AZ. Furthermore, AZ activates the AMPK signaling pathway, and recoupled eNOS in stressed endothelial cells which plays a protective role in vascular endothelial dysfunction. CONCLUSIONS: The main finding of this study is that AZ can play a role in different pathways of vascular injury due to T2DM. Mechanistically, alizarin inhibits the increase in THBS1 protein synthesis after high glucose induction and activates AMPKα2, which increases NO release from eNOS, which is essential in the prevention of vascular endothelial dysfunction caused by T2DM.

Perillaldehyde improves diabetic cardiomyopathy by upregulating miR-133a-3p to regulate GSK-3ß.

Diabetic cardiomyopathy (DCM) is part of the most important causes of death from cardiovascular disease. Perillaldehyde (PAE), a major component of the herb perilla, has been shown to ameliorate doxorubicin-induced cardiotoxicity, but it is unclear whether PAE exerts beneficial effects on DCM. Exploring the potential molecular mechanisms of PAE for the treatment of DCM through network pharmacology and molecular docking. The SD rat type 1 diabetes model was established by a single intraperitoneal injection of streptozotocin (60 mg/kg), the cardiac function indexes of each group were detected by echocardiography; the morphological changes, apoptosis, protein expression of P-GSK-3ß (S9), collagen I (Col-Ⅰ), collagen III (Col-Ⅲ) and alpha-smooth muscle actin (α-SMA), and miR-133a-3p expression levels were detected. An DCM model of H9c2 cells was established in vitro and transfected with Mimic and Inhibitor of miR-133a-3p. The results showed that PAE ameliorated cardiac dysfunction, reduced fasting glucose and cardiac weight index, and improved myocardial injury and apoptosis in DCM rats. It reduced high glucose-induced apoptosis, promoted migration and improved mitochondrial division injury in H9c2 cells. PAE decreased P-GSK-3ß (S9), Col-Ⅰ, Col-Ⅲ and α-SMA protein expression and upregulated miR-133a-3p expression levels. After miR-133a-3p Inhibitor treatment, the expression of P-GSK-3ß (S9) and α-SMA expression were significantly increased; after miR-133a-3p Mimic treatment, the expression of P-GSK-3ß (S9) and α-SMA decreased significantly in H9c2 cells. It suggests that the mechanism of action of PAE to improve DCM may be related to the upregulation of miR-133a-3p and inhibition of P-GSK-3ß expression.

Amorphous selenium inhibits oxidative stress injury of neurons in vascular dementia rats by activating NMDAR pathway.

Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze, Transcranial Doppler TCD, hematoxylin-eosin (HE) staining, Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR pathway.

Cardioprotective role of A-cycloglycosylated derivative of Rubiadin in diabetic cardiomyopathy in rats.

Diabetic cardiomyopathy (DCM) is a kind of idiopathic heart disease, which is one of the main complications of diabetes and seriously threatens the life of diabetic patients. Rubiadin, an anthraquinone compound extracted from the stems and roots of rubiaceae, has been widely discussed for its anti-diabetes, anti-oxidation and other pharmacological effects. However, Rubiadin can cause drug-induced liver injury. Therefore, A-cycloglycosylated derivative of Rubiadin (ACDR) was obtained by modifying its structure. The purpose of this study was to investigate the effect of ACDR on DCM cardiac injury and its mechanism. The DCM animal model was established by streptozotocin, and the success of DCM was verified by blood glucose level, echocardiographic evidence of impaired myocardial functions along with enhanced myocardial fibrosis. We performed liver function tests, morphological staining of the heart and tests for oxidative stress to evaluate cardiac functional and structural changes. Finally, the expression of Na+/H+ exchanger (NHE1) protein was analyzed by immunohistochemistry and western bolt, and the expression of hairy/enhancer-of-split related with YRPW motif 1 (Hey1) and P-p38 protein was detected by immunofluorescence chemistry and western blotting. The results showed that ACDR can improve cardiac dysfunction, reduce myocardial injury, reduce oxidative stress, and protect the liver in DCM rats. Interestingly, all variations were countered by LiCl. Our study suggests that, along with controlling hyperglycemia, ACDR may improve DCM by reducing NHE1 expression, further inhibiting P-p38 activity and increasing Hey1 expression to reduce oxidative stress.

Epigallocatechin-3-gallate alleviates type 2 diabetes mellitus via ß-cell function improvement and insulin resistance reduction.

Objectives: Epigallocatechin-3-gallate (EGCG) has a good therapeutic effect on type 2 diabetes mellitus (T2DM). This work was designed to explore EGCG's effectiveness in insulin resistance (IR) and pancreas islet ß-cell function in a rat model of T2DM. Materials and Methods: Eight-week-old male Sprague Dawley rats were randomly divided into 6 groups, including the Control (normal diet), Diabetes (high-sucrose high-fat [HSHF] diet combined with tail vein injection of streptozotocin [STZ] for T2DM induction) and Treatment Diabetic rats which were treated with metformin [500 mg/kg/d] or EGCG [25, 50 or 100 mg/kg/d] intragastric administration for 10 weeks. With the exception of control animals, the other groups were fed the HSHF diet. EGCG's effects on IR and insulin secretion were assessed by measuring body weights, and fasting blood glucose (FBG), postprandial blood glucose (PBG) and insulin levels. The morphological and molecular changes of pancreas islet ß-cells were examined by hematoxylin-eosin (H&E) staining, transmission electron microscopy (TEM) and immunofluorescence. Results: Rats fed the HSHF diet combined with STZ treatment had increased body weights and blood glucose amounts, accompanied by IR and impaired ß-cell function, induced T2DM, and EGCG dose-dependently restored the above indicators. Additionally, EGCG upregulated the pancreatic transcription factors pancreatic duodenal homeobox protein-1 (PDX-1) and musculoaponeurotic fibrosarcoma oncogene homolog A (MafA). Conclusion: These results suggest that EGCG reduces blood glucose amounts, and improve IR and islet ß-cell disorder in T2DM.

Floralozone improves cognitive impairment in vascular dementia rats via regulation of TRPM2 and NMDAR signaling pathway.

Vascular dementia (VD) is the second largest type of dementia after Alzheimer's disease. At present, the pathogenesis is complex and there is no effective treatment. Floralozone has been shown to reduce atherosclerosis in rats caused by a high-fat diet. However, whether it plays a role in VD remains elusive. In the present study, the protective activities and relevant mechanisms of Floralozone were evaluated in rats with cognitive impairment, which were induced by bilateral occlusion of the common carotid arteries (BCCAO) in rats. Cognitive function, pathological changes and oxidative stress condition in the brains of VD rats were assessed using Neurobehavioral tests, Morris water maze tests, hematoxylin-eosin staining, Neu N staining, TUNEL staining, Golgi staining, Western blot assay and antioxidant assays (MDA, SOD, GSH), respectively. The results indicated that VD model was established successfully and BCCAO caused a decline in spatial learning and memory and hippocampal histopathological abnormalities of rats. Floralozone (50, 100, 150 mg/kg) dose-dependently alleviated the pathological changes, decreased oxidative stress injury, which eventually reduced cognitive impairment in BCCAO rats. The same results were shown in further experiments with neurobehavioral tests. At the molecular biological level, Floralozone decreased the protein level of transient receptor potential melastatin-related 2 (TRPM2) in VD and normal rats, and increased the protein level of NR2B in hippocampus of N-methyl-D-aspartate receptor (NMDAR). Notably, Floralozone could markedly improved learning and memory function of BCCAO rats in Morris water maze (MWM) and improved neuronal cell loss, synaptic structural plasticity. In conclusion, Floralozone has therapeutic potential for VD, increased synaptic structural plasticity and alleviating neuronal cell apoptosis, which may be related to the TRPM2/NMDAR pathway.

Amorphous selenium nanodots alleviate non-alcoholic fatty liver disease via activating VEGF receptor 1 to further inhibit phosphorylation of JNK/p38 MAPK pathways.

In clinic, there is still no unified standard for the treatment of non-alcoholic fatty liver disease (NAFLD), and the development of effective novel drugs to alleviate NAFLD remains a challenge. This study aimed to explore the effect and mechanism of amorphous selenium nanodots (A SeNDs) in alleviating NAFLD. Model rats with NAFLD were induced by the high-fat diet (HFD). Histomorphology was used to observe liver tissue, automatic biochemical analyzer was used to analyze liver function indicators, and ELISA kit was used to detect the effect of A SeNDs on oxidative stress and inflammatory factors in NAFLD rats. The results exhibited that A SeNDs could reduce hepatocyte steatosis, liver index, blood lipid level, and transaminase level in NAFLD rats. Furthermore, A SeNDs could relieve the oxidative stress and inflammatory reaction and maintain liver tissue structure in NAFLD rats. Mechanistically, A SeNDs (0.3 mg/kg/day) inhibit the phosphorylation of JNK/p38 MAPK pathways after activating vascular endothelial growth factor receptor 1 (VEGFR1) in the liver of rats with NAFLD to allay oxidative stress and inflammatory response and improves hepatic structure and liver function. Therefore, it should be an important method to mitigate NAFLD by supplementing A SeNDs to normalize hepatic structure and liver function.

PAE ameliorates doxorubicin-induced cardiotoxicity via suppressing NHE1 phosphorylation and stimulating PI3K/AKT phosphorylation.

Doxorubicin (DOX), a broad-spectrum anti-tumor drug, has severe cardiotoxic side effects that limit its clinical application. Perillaldehyde (PAE) is the main component of volatile oil extracted from the stems and leaves of Herbaceous plant-perilla, which demonstrates antioxidant, anti-inflammatory, hypolipidemic, and other health functions. The present study aimed to explore the protective effect of perillaldehyde on DOX-induced cardiotoxicity in rats and to confirm its possible mechanism. The results showed that PAE could significantly improve cardiac function, alleviate myocardial fibrosis, and attenuate oxidative stress and inflammatory responses in DOX-induced cardiotoxicity in rats. Mechanistically, PAE could DOX-induced cardiotoxicity, which is related to its regulation of the PI3K/Akt signaling pathway and inhibition of NHE1 phosphorylation. Therefore, the finding demonstrates that perillaldehyde may be a promising cardioprotective agent for the prevention and treatment of cardiotoxicity caused by DOX.

Nitrosative stress induced by homocysteine thiolactone drives vascular cognitive impairments via GTP cyclohydrolase 1 S-nitrosylation in vivo.

BACKGROUND: s: Hyperhomocysteinemia (HHcy) is one of risk factors for vascular cognitive impairment (VCI). GTP cyclohydrolase 1 (GCH1) deficiency is critical to oxidative stress in vascular dysfunction. The aim of this study was designed to examine whether HHcy induces VCI through GCH1 S-nitrosylation, a redox-related post-translational modification of cysteine. METHODS: The VCI model was induced by feeding mice homocysteine thiolactone (HTL) for 16 consecutive weeks. The cognitive functions were evaluated by step-down avoidance test, passive avoidance step-through task test, and Morris water maze (MWM) test. Protein S-nitrosylation was assayed using a biotin-switch method. RESULTS: In cell-free system, nitric oxide (NO) donor induced GCH1 protein S-nitrosylation and decreased GCH1 activity. In endothelial cells, HTL increased GCH1 S-nitrosylation, reduced tetrahydrobiopterin, and induced oxidative stress, which were attenuated by N-acetyl-cysteine, L-N6-1-Iminoethyl-lysine, mutant of GCH1 cysteine 141 to alanine (MT-GCH1) or gene deletion of inducible NO synthase (iNOS). Further, HTL incubation or iNOS overexpression promoted endothelial cellular senescence, but abolished by exogenous expression of MT-GCH1 or pharmacological approaches including N-acetyl-cysteine, L-sepiapterin, and tempol. In wildtype mice, long-term administration of HTL induced GCH1 S-nitrosylation and vascular stiffness, decreased cerebral blood flow, and damaged the cognitive functions. However, these abnormalities induced by HTL administration were rescued by enforced expression of MT-GCH1 or gene knockout of iNOS. In human subjects, GCH1 S-nitrosylation was increased and cognitive functions were impaired in patients with HHcy. CONCLUSION: The iNOS-mediated nitrosative stress induced by HTL drives GCH1 S-nitrosylation to induce cerebral vascular stiffness and cognitive impairments.

Citronellal alleviate macro- and micro-vascular damage in high fat diet / streptozotocin - Induced diabetic rats via a S1P/S1P1 dependent signaling pathway.

Citronellal (CT) is an acyclic monoterpene aldehyde isolated from lemon citronella, which could ameliorate vascular endothelial dysfunction in atherosclerosis in our previous study, however, whether CT can alleviate vascular endothelial dysfunction related with type 2 diabetes (T2DM) is still unknown. So, we investigated the role of CT in vascular dysfunction related to T2DM and the mechanism involved. T2DM rat model was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) (60 mg/kg) to rats fed with high-fat diet (HFD) (4 weeks). After treated with CT (150 mg/kg/d), both the thoracic aorta injury and micro-vascular pathological injury in T2DM rats ex vivo were alleviated, and the oxidative stress in T2DM rats treated with CT were attenuated, manifested as increased content of endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD), and decreased content of malondialdehyde (MDA). Furthermore, CT (15 µg/L) increased the migration capacity of human umbilical vein endothelial cells (HUVECs) under high glucose circumstance (30 mM), and increased the endothelial-dependent relaxation in thoracic aorta isolated from T2DM rats in vitro. Finally, all of these effects of CT were blocked by fingolimod (FTY720), a sphingosine-1-phosphate receptor agonist, and the expression of sphingosine-1-phosphate receptor 1 (S1P1) was increased by CT. In conclusion, CT improved vascular function through S1P/S1P1 signaling pathway.