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1.
Artigo em Inglês | MEDLINE | ID: mdl-31483567

RESUMO

Biomaterials provide novel platforms to deliver stem cell and growth factor therapies for central nervous system (CNS) repair. The majority of these approaches have focused on the promotion of neural progenitor cells and neurogenesis. However, it is now increasingly recognized that glial responses are critical for recovery in the entire neurovascular unit. In this study, we investigated the cellular effects of epidermal growth factor (EGF) containing hydrogels on primary astrocyte cultures. Both EGF alone and EGF-hydrogel equally promoted astrocyte proliferation, but EGF-hydrogels further enhanced astrocyte activation, as evidenced by a significantly elevated Glial fibrillary acidic protein (GFAP) gene expression. Thereafter, conditioned media from astrocytes activated by EGF-hydrogel protected neurons against injury and promoted synaptic plasticity after oxygen-glucose deprivation. Taken together, these findings suggest that EGF-hydrogels can shift astrocytes into neuro-supportive phenotypes. Consistent with this idea, quantitative-polymerase chain reaction (qPCR) demonstrated that EGF-hydrogels shifted astrocytes in part by downregulating potentially negative A1-like genes (Fbln5 and Rt1-S3) and upregulating potentially beneficial A2-like genes (Clcf1, Tgm1, and Ptgs2). Further studies are warranted to explore the idea of using biomaterials to modify astrocyte behavior and thus indirectly augment neuroprotection and neuroplasticity in the context of stem cell and growth factor therapies for the CNS. Stem Cells Translational Medicine 2019.

2.
Brain Res ; 1722: 146353, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31356784

RESUMO

Angiotensin-II (Ang-II) is a key factor in hypertension, diabetes and aging, which are all primary risk factors for CNS disease. Furthermore, Ang-II may play under-appreciated roles in neurogenesis, angiogenesis and CNS remodeling. Therefore, any contemplated attempts for neurorestorative therapies in the CNS should consider the context of Ang-II signaling. Here, we investigate how Ang-II may regulate cerebral endothelial permeability, a key functional feature of the neurovascular unit. Exposure of human brain endothelial cell cultures to Ang-II increased its permeability to BSA-Alexa488 tracer. Immunocytochemistry and pulse-chase experiments suggested that both para-cellular as well as trans-cellular pathways were involved. Candesartan but not PD123319 blocked Ang-II permeability effects, suggesting that Ang-II effects may be mediated via type 1 receptor. Immunocytochemistry and western blots showed that Ang-II disrupted the membrane distributions of ZO-1 and VE-Cad, decreased total levels of JAM-A and Mfsd2a, and increased Cav1. These effects of Ang-II were accompanied by dephosphorylation of PPARalpha. Finally, Ang-II-induced increases in endothelial permeability were ameliorated by PPARalpha agonists. Taken together, these studies suggest that Ang-II may disrupt both para- and trans-cellular permeability in cerebral endothelium, and PPARalpha-related pathways may offer potential therapeutic targets for ameliorating these effects in cell-based regenerative medicine.

3.
Pharmacol Res ; 146: 104318, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31228552

RESUMO

Si-Miao-Yong-An decoction (SMYAD), a Chinese herbal formula, has been used in treating ischemic cardiovascular diseases. However, the cardioprotective mechanism of SMYAD treating heart failure (HF) remains unclear. Herein we investigated the effect of SMYAD on isoprenaline (ISO)-induced HF in C57BL/6 mice. Cardiac function and pathological changes in myocardial tissue were evaluated as well as A-type natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression. The underlying mechanism of SMYAD was deciphered using UHPLC MS/MS coupled with bioinformatics and was verified. SMYAD treatment significantly ameliorated cardiac function, reduced collagen deposition and cardiomyocyte apoptosis, reversed cardiac hypertrophy and down-regulated the expression levels of ANP and BNP mRNA compared with those in HF mice. Decipherment analyses based on 138 ingredients prompted that anti-oxidation was the key mechanism of SMYAD treating HF. In vitro and in vivo, SMYAD showed antioxidant activity, significantly up-regulated superoxide dismutase (SOD)-1 and SOD-2 mRNA expression levels and reduced NADP/NADPH ratio. Moreover, the increased expression levels of NADPH oxidase 2 (NOX2), p47phox and Rac family small GTPase 1 (Rac1) were obviously ameliorated after SMYAD treatment. Together, this study reveals that SMYAD can apparently improve heart function of ISO-induced HF mice by inhibiting the myocardial oxidative stress through restoring the equilibrium of SOD and NOX2.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31177049

RESUMO

Diosmin (diosmetin-7-O-rutinoside) and its aglycone diosmetin, natural bioflavonoids distributing in a variety of citrus fruits and Chinese herbal medicines, possessed positive effects against hepatic, renal, lung, gastric, cerebral and cardiac injury. However, the in vivo metabolic profiles of diosmin and diosmetin in urine, plasma and feces still remain ambiguous. In this study, metabolites of diosmin and diosmetin were identified using an UHPLC-LTQ-Orbitrap MSn strategy coupled with multiple metabolite templates, extracted ion chromatograms (EICs) and diagnostic product ions (DPIs). As a result, 46 diosmetin metabolites and 64 diosmin metabolites were respectively identified in rat biological samples. Methylation, demethylation, hydroxylation, glycosylation, glucuronidation, diglucuronidation and sulfation were common metabolic pathways of diosmetin and diosmin, while demethoxylation, decarbonylation, dihydroxylation and dehydroxylation were particular metabolic pathways of diosmin comparing with that of diosmetin. Diosmetin was not detected in all the biological samples, suggesting that it was quickly transformed into other metabolites in vivo. Diosmin and diosmetin-7-O-glucoside identified in urine and feces as well as their subsequent metabolites accounted for a substantial part of all the diosmin metabolic products. Metabolic profiles of diosmetin and diosmin indicated that they were primarily excreted through the urine route possibly originating from the dominant role of their phase II metabolism in vivo. Our results have provided a better understanding of the similarities and differences in pharmacodynamics and pharmacokinetics of diosmetin and diosmin in the future.

5.
Viral Immunol ; 32(4): 170-178, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31063043

RESUMO

Hand, foot, and mouth disease (HFMD) is a common infection for children younger than the age of five. HFMD is mainly induced by coxsackievirus A16 and enterovirus 71 (EV71). EV71-associated HFMD often has serious neurological disease complications. The purpose of this study was to reveal the mechanisms of action of EV71 on neurons. SH-SY5Y cells transfected or untransfected with EV71 were sequenced. After data preprocessing, differentially expressed genes (DEGs) were screened using the limma package in R, and clustering analysis was then performed using the ComplexHeatmap package in R. The DAVID tool was used for EDG enrichment analysis. Protein-protein interactions (PPIs) were predicted using the STRING database and PPI networks were then constructed using Cytoscape software. After pathways involved in the key PPI network nodes were enriched, pathway deviation scores were calculated. Clustering analysis was also conducted for these pathways. There were 978 DEGs in the transfected samples. Upregulated TNF was enriched in NF-kappa B signaling pathway. Among the top 20 nodes in the PPI network, CDK1, STAT3, CCND1, TNF, and MYC had the highest degrees. A total of 28 pathways were enriched for the top 20 nodes, including Epstein-Barr virus infection (p = 3.78E-06), proteoglycans in cancer (p = 4.96E-06), and melanoma (p = 1.99E-05). In addition, clustering analysis showed that these pathways could clearly differentiate the two groups of samples. EV71 may affect neurons by mediating CDK1, STAT3, CCND1, TNF, and MYC, indicating that these genes are promising targets for preventing the neuronal complications of HFMD.

6.
J Neuroinflammation ; 16(1): 103, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101061

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic dysfunction characterized by progressive insulin resistance and hyperglycaemia. Increased blood-brain barrier (BBB) permeability is a critical neurovascular complication of T2DM that adversely affects the central nervous system homeostasis and function. Histone deacetylase 3 (HDAC3) has been reported to be elevated in T2DM animals and may promote neuroinflammation; however, its involvement in the BBB permeability of T2DM has not been investigated. In this study, we tested our hypothesis that HDAC3 expression and activity are increased in the T2DM mouse brain. Inhibition of HDAC3 may ameliorate T2DM-induced BBB permeability through Nrf2 activation. METHODS: T2DM (db/db, leptin receptor-deficient), genetic non-hyperglycemic control (db/+), and wild-type male mice at the age of 16 weeks were used in this study. HDAC3 expression and activity, Nrf2 activation, and BBB permeability and junction protein expression were examined. The effects of HDAC3 activity on BBB permeability were tested using highly selective HDAC3 inhibitor RGFP966. In primary cultured human brain microvascular endothelial cells (HBMEC), hyperglycemia (25 mM glucose) plus interleukin 1 beta (20 ng/ml) (HG-IL1ß) served as T2DM insult in vitro. The effects of HDAC3 on transendothelial permeability were investigated by FITC-Dextran leakage and trans-endothelial electrical resistance, and the underlying molecular mechanisms were investigated using Western blot, q-PCR, co-immunoprecipitation, and immunocytochemistry for junction protein expression, miR-200a/Keap1/Nrf2 pathway regulation. RESULTS: HDAC3 expression and activity were significantly increased in the hippocampus and cortex of db/db mice. Specific HDAC3 inhibition significantly ameliorated BBB permeability and junction protein downregulation in db/db mice. In cultured HBMEC, HG-IL1ß insult significantly increased transendothelial permeability and reduced junction protein expression. HDAC3 inhibition significantly attenuated the transendothelial permeability and junction protein downregulation. Moreover, we demonstrated the underlying mechanism was at least in part attributed by HDAC3 inhibition-mediated miR-200a/Keap1/Nrf2 signaling pathway and downstream targeting junction protein expression in T2DM db/db mice. CONCLUSIONS: Our experimental results show that HDAC3 might be a new therapeutic target for BBB damage in T2DM.

7.
J Cell Mol Med ; 23(7): 4666-4678, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31033175

RESUMO

The traditional Chinese herb Lonicerae Japonicae Flos has shown significant clinical benefits in the treatment of heart failure, but the mechanism remains unclear. As the main active ingredient found in the plasma after oral administration of Lonicerae Japonicae Flos, chlorogenic acid (CGA) has been reported to possess anti-inflammatory, anti-oxidant and anti-apoptosis function. We firstly confirmed the cardioprotective effects of CGA in transverse aortic constriction (TAC)-induced heart failure mouse model, through mitigating the TNF-α-induced toxicity. We further used TNF-α-induced cardiac injury in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to elucidate the underlying mechanisms. CGA pre-treatment could reverse TNF-α-induced cellular injuries, including improved cell viability, increased mitochondrial membrane potential and inhibited cardiomyocytes apoptosis. We then examined the NF-κB/p65 and major mitogen-activated protein kinases (MAPKs) signalling pathways involved in TNF-α-induced apoptosis of hiPSC-CMs. Importantly, CGA can directly inhibit NF-κB signal by suppressing the phosphorylation of NF-κB/p65. As for the MAPKs, CGA suppressed the activity of only c-Jun N-terminal kinase (JNK), but enhanced extracellular signal-regulated kinase1/2 (ERK1/2) and had no effect on p38. In summary, our study revealed that CGA has profound cardioprotective effects through inhibiting the activation of NF-κB and JNK pathway, providing a novel therapeutic alternative for prevention and treatment of heart failure.

9.
Stroke ; 49(12): 3039-3049, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30571410

RESUMO

Background and Purpose- The complexity and heterogeneity of stroke, as well as the associated comorbidities, may render neuroprotective drugs less efficacious in clinical practice. Therefore, the development of targeted therapies to specific patient subsets has become a high priority in translational stroke research. Ischemic stroke with type 2 diabetes mellitus has a nearly double mortality rate and worse neurological outcomes. In the present study, we tested our hypothesis that rFGF21 (recombinant human fibroblast growth factor 21) administration is beneficial for improving neurological outcomes of ischemic stroke with type 2 diabetes mellitus. Methods- Type 2 diabetes mellitus db/db and nondiabetic genetic control db/+ mice were subjected into permanent focal ischemia of distal middle cerebral artery occlusion, we examined the effects of poststroke administration with rFGF21 in systemic metabolic disorders, inflammatory gatekeeper PPARγ (peroxisome proliferator-activated receptor γ) activity at 3 days, mRNA expression of inflammatory cytokines and microglia/macrophage activation at 7 days in the perilesion cortex, and last neurological function deficits, ischemic brain infarction, and white matter integrity up to 14 days after stroke of db/db mice. Results- After permanent focal ischemia, diabetic db/db mice presented confounding pathological features, including metabolic dysregulation, more severe brain damage, and neurological impairment, especially aggravated proinflammatory response and white matter integrity loss. However, daily rFGF21 treatment initiated at 6 hours after stroke for 14 days significantly normalized systemic metabolic disorders, rescued PPARγ activity decline, inhibited proinflammatory cytokine mRNA expression, and M1-like microglia/macrophage activation in the brain. Importantly, rFGF21 also significantly reduced white matter integrity loss, ischemic brain infarction, and neurological function deficits up to 14 days after stroke. The potential mechanisms of rFGF21 may in part consist of potent systematic metabolic regulation and PPARγ-activation promotion-associated antiproinflammatory roles in the brain. Conclusions- Taken together, these results suggest rFGF21 might be a novel and potent candidate of the disease-modifying strategy for treating ischemic stroke with type 2 diabetes mellitus.


Assuntos
Isquemia Encefálica , Encéfalo/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Diabetes Mellitus Tipo 2 , Fatores de Crescimento de Fibroblastos/farmacologia , PPAR gama/efeitos dos fármacos , Acidente Vascular Cerebral , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/genética , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Microglia/efeitos dos fármacos , PPAR gama/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Proteínas Recombinantes , Substância Branca/efeitos dos fármacos , Substância Branca/patologia
10.
Zhongguo Zhong Yao Za Zhi ; 43(18): 3787-3794, 2018 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-30384547

RESUMO

Heat-clearing and detoxifying Chinese herbs (HDCHs) are mainly used to treat carbuncle, sore throat, erysipelas, gills, dysentery and other diseases induced by heat-toxicity. Inflammation is a defensive response to damaging factors in living organism with vascular system. In recent years, a large amount of experimental and clinical studies showed that HDCHs had good therapeutic effect on inflammation. This review analyzed the anti-inflammatory mechanism of 11 HDCHs by retrieving literature in past 5 years, including Lonicerae Japonicae Flos (Jinyinhua), Lonicerae Flos (Jinyinhua), Lonicerae Japonicae Caulis (Rendongteng), Forsythiae Fructus (Lianqiao), Rhizoma Coptidis(Huanglian), Gardeniae Fructus (Zhizi), Andrographis Herba (Chuanxinlian), Taraxaci Herba (Pugongying), Scrophulariae Radix (Xuanshen), Pulsatillae Radix (Baitouweng), and Agrimoniae Herba (Xianhecao). The data showed that the regulatory effect of HDCHs on inflammation may be involved mainly in the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK) or janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, with similarity of action links among these three. Based upon the analysis of literature, we proposed some promising directions in this research field, providing a reliable theoretical basis for both experimental researches and clinical practices of HDCHs.

11.
J Cereb Blood Flow Metab ; 38(12): 2236-2250, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30152713

RESUMO

In the context of ischemic stroke, rescuing neurons can be theoretically achieved with either reperfusion or neuroprotection. Reperfusion works via the rapid restoration of oxygen and glucose delivery. Neuroprotection comprises molecular strategies that seek to block excitotoxicity, oxidative stress or various cell death pathways. Here, we propose the hypothesis that neurons rescued with reperfusion are different from neurons rescued with molecular neuroprotection. Neurons were subjected to oxygen-glucose deprivation (OGD) and then treated with "in vitro reperfusion" (i.e. energetic rescue via restoration of oxygen and glucose) or Z-VADfmk (to block apoptosis) or MK-801 (to block excitotoxicity). Levels of injury were titrated so that equivalent levels of neuronal salvage were achieved with reperfusion or neuroprotection. Gene arrays showed that OGD significantly altered the transcriptomic profiles of surviving neurons. Pathway analysis confirmed that a large spectrum of metabolic, inflammation, and signaling genes were perturbed. In spite of the fact that equal levels of neuronal salvage were achieved, energetic rescue renormalized the transcriptomic profiles in surviving neurons to a larger degree compared to neuroprotection with either Z-VADfmk or MK-801. These findings suggest that upstream reperfusion may bring salvaged neurons back "closer to normal" compared to downstream molecular neuroprotection.

12.
Molecules ; 23(7)2018 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30041436

RESUMO

Qishen granules (QSG) have beneficial therapeutic effects for heart failure, but the effects of decomposed recipes, including Wenyang Yiqi Huoxue (WYH) and Qingre Jiedu (QJ), are not clear. In this study, the efficacy of WYH and QJ on heart failure is evaluated by using transverse aortic constriction (TAC) induced mice and the significantly changed genes in heart tissues were screened with a DNA array. Furthermore, a new quantitative pathway analysis tool is developed to evaluate the differences of pathways in different groups and to identify the pharmacological contributions of the decomposed recipes. Finally, the related genes in the significantly changed pathways are verified by a real-time polymerase chain reaction and a Western blot. Our data show that both QJ and WYH improve the left ventricular ejection fraction, which explain their contributions to protect against heart failure. In the energy metabolism, QJ achieves the therapeutic effects of QSG through nicotinamide nucleotide transhydrogenase (Nnt)-mediated mechanisms. In ventricular remodeling and inflammation reactions, QJ and WYH undertake the therapeutic effects through 5'-nucleotidase ecto (Nt5e)-mediated mechanisms. Together, QJ and WYH constitute the therapeutic effects of QSG and play important roles in myocardial energy metabolism and inflammation, which can exert therapeutic effects for heart failure.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Animais , Biomarcadores , Modelos Animais de Doenças , Ecocardiografia , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos , Transcriptoma , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular
13.
Neurobiol Dis ; 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30031157

RESUMO

The emerging concept of the vasculome suggests that microvessels contribute to function and dysfunction in every organ. In the brain, aging and comorbidities such as hypertension and diabetes significantly influence a wide variety of neurodegenerative and cerebrovascular disorders, but the underlying mechanisms are complex and remain to be fully elucidated. Here, we hypothesize that aging, hypertension and diabetes perturb gene networks in the vasculome. Microvascular endothelial cells were isolated from mouse brain and heart, and their transcriptomes were profiled with microarrays. For aging, we compared 5 mo vs 15 mo old C57BL6 male mice. For hypertension, we compared 4 mo old normotensive BPN vs hypertensive BPH male mice. For diabetes, we compared 3 mo old diabetic db/db mice with their matching C57BLKS controls. Four overall patterns arose from these comparative analyses. First, organ differences between brain and heart were larger than effects of age and co-morbidities per se. Second, across all conditions, more genes were altered in the brain vasculome compared with the heart. Third, age, hypertension and diabetes perturbed the brain and heart vasculomes in mostly distinct ways, with little overlap. Fourth, nevertheless, a few common pathways were detected in the brain, expressed mostly as a suppression of immune response. These initial drafts of the brain and heart vasculomes in the context of aging and vascular comorbidities should provide a framework for designing future investigations into potential targets and mechanisms in CNS disease.

14.
J Neurotrauma ; 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-29768967

RESUMO

Important differences in the biology of focal and diffuse traumatic brain injury (TBI) subtypes may result in unique pathophysiological responses to shared molecular mechanisms. Interleukin-1 (IL-1) signaling has been tested as a potential therapeutic target in preclinical models of cerebral contusion and diffuse TBI, and in a phase II clinical trial, but no published studies have examined IL-1 signaling in an impact/acceleration closed head injury (CHI) model. We hypothesized that genetic deletion of IL-1 receptor-1 (IL-1R1 KO) would be beneficial in focal (contusion) and CHI in mice. Wild type and IL-1R1 KO mice were subjected to controlled cortical impact (CCI), or to CHI. CCI produced brain leukocyte infiltration, HMGB1 translocation and release, edema, cell death, and cognitive deficits. CHI induced peak rotational acceleration of 9.7 × 105 ± 8.1 × 104 rad/s2, delayed time to righting reflex, and robust Morris water maze deficits without deficits in tests of anxiety, locomotion, sensorimotor function, or depression. CHI produced no discernable acute plasmalemma damage or cell death, blood-brain barrier permeability to IgG, or brain edema and only a modest increase in brain leukocyte infiltration at 72 h. In both models, mature (17 kDa) interleukin-1 beta (IL-1ß) was induced by 24 h in CD31+ endothelial cells isolated from injured brain but was not induced in CD11b+ cells in either model. High mobility group box protein-1 was released from injured brain cells in CCI but not CHI. Surprisingly, cognitive outcome in mice with global deletion of IL-1R1 was improved in CHI, but worse after CCI without affecting lesion size, edema, or infiltration of CD11b+/CD45+ leukocytes in CCI. IL-1R1 may induce unique biological responses, beneficial or detrimental to cognitive outcome, after TBI depending on the pathoanatomical subtype. Brain endothelium is a hitherto unrecognized source of mature IL-1ß in both models.

16.
Zhongguo Zhong Yao Za Zhi ; 42(10): 1991-1995, 2017 May.
Artigo em Chinês | MEDLINE | ID: mdl-29090562

RESUMO

In this paper, the funding situation of traditional Chinese medicine oncology research projects supported by National Natural Science Fund from 1986-2016 was reviewed. The characteristics of funded projects were summarized from funding amount, funding expenses, funding category, and the main research contents of projects, etc. At the same time, the main problems in the projects were analyzed in this paper, in order to provide reference for the relevant fund applicants.

17.
Transl Stroke Res ; 8(6): 549-559, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28580536

RESUMO

Previous studies showed recombinant annexin A2 (rA2) in combination with low-dose tissue-type plasminogen activator (tPA) improved thrombolytic efficacy and long-term neurological outcomes after embolic focal ischemia in rats. The objective of this study was to investigate the effects and mechanisms of the combination in early BBB integrity and cerebrovascular patency in the rat focal embolic stroke model. Ischemic brain infarct volume and hemorrhagic transformation were quantified at 24 h after stroke. At an earlier time point, 16 h after stroke, BBB integrity was evaluated by IgG extravasation, and the involved mechanisms were assessed for tight junction ZO-1 and adhesion junction ve-cadherin protein expression, matrix metalloproteinase activation, extracellular matrix collagen IV and endothelial barrier antigen expression, and activation of microglia/macrophages and astrocytes. While at the same time point, cerebrovascular patency was assessed by intravascular fibrin and platelet depositions. At 24 h after stroke, the combination showed significant reduction in brain infarction and intracerebral hemorrhage. At 16 h after stroke onset, the combination therapy significantly reduced BBB disruption, and improved preservation of the junction proteins ZO-1 and ve-cadherin, decreased activation of matrix metalloproteinase, inhibited degradation of extracellular matrix collagen IV and endothelial barrier antigen, and reduced microglia/macrophage and astrocytes activations. Meanwhile, the combination also significantly improved cerebrovascular patency by reducing intravascular fibrin and platelet depositions in the peri-infarct brain tissues. These results suggest the beneficial effects of the rA2 plus low-dose tPA combination may be mediated in part by the amelioration of BBB disruption and improvement of cerebrovascular patency.


Assuntos
Anexina A2/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Acidente Vascular Cerebral/patologia , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Encéfalo/patologia , Permeabilidade Capilar/efeitos dos fármacos , Quimioterapia Combinada , Embolia Intracraniana , Masculino , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologia
18.
J Ethnopharmacol ; 202: 162-171, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28315720

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Euonymus alatus, Radix trichosanthis, Panax notoginseng and Coptis chinensis are popular plants used in traditional Chinese medicine to treat diabetes. AIM OF THE STUDY: The aim of the study is to investigate the therapeutic effect of the active components of Euonymus alatus, Radix trichosanthis, Panax notoginseng and Coptis chinensis (cERPC) on diabetic peripheral neuropathy in the rats and explore the underlying mechanism involved. METHODS: After diabetes was induced in rats for 20 weeks, cERPC or water was administered for 12 weeks. After a hot plate test, motor nerve conduction velocity and sciatic nerve blood flow were determined; the sciatic nerves were isolated for toluidine blue staining; and the fibre area, fibre diameter, axon area, axon diameter and myelin thickness were evaluated. The levels of the myelin basic protein, myelin protein zero, Oct6 and Krox20 were measured by western blot or immunofluorescence. RESULTS: cERPC was efficient in reducing the response latency, increasing motor nerve conduction velocity, enhancing sciatic nerve blood flow and ameliorating the pathological changes in diabetic rats. cERPC also had a role in increasing the levels of myelin basic protein and myelin protein zero and improving the expression of Oct6 and Krox20 in sciatic nerves of diabetic rats. CONCLUSIONS: cERPC ameliorates diabetic peripheral neuropathy by attenuating electrophysiological, circulatory and morphological alterations, which is mediated by the Oct6-Krox20 pathway.


Assuntos
Neuropatias Diabéticas/prevenção & controle , Medicamentos de Ervas Chinesas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Axônios/ultraestrutura , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/patologia , Masculino , Neurônios Motores/efeitos dos fármacos , Proteínas da Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Bainha de Mielina/ultraestrutura , Condução Nervosa/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Nervo Isquiático/irrigação sanguínea
19.
Curr Pharm Des ; 23(7): 1077-1097, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27748194

RESUMO

Salvia miltiorrhiza Bunge, also known as Danshen in Chinese, has been widely used to treat cardiovascular diseases (CVD) in China and other Asia countries. Here, we summarize literatures of the historical traditional Chinese medicine (TCM) interpretation of the action of Salvia miltiorrhiza, its use in current clinical trials, its main phytochemical constituents and its pharmacological findings by consulting Pubmed, China Knowledge Resource Integrated, China Science and Technology Journal, and the Web of Science Databases. Since 2000, 39 clinical trials have been identified that used S. miltiorrhiza in TCM prescriptions alone or with other herbs for the treatment of patients with CVD. More than 200 individual compounds have been isolated and characterized from S. miltiorrhiza, which exhibited various pharmacological activities targeting different pathways for the treatment of CVD in various animal and cell models. The isolated compounds may provide new perspectives in alternative treatment regimes and reveal novel chemical scaffolds for the development of anti-CVD drugs. Meanwhile, there are also some rising concerns of the potential side effects and drug-drug interactions of this plant. The insights gained from this study will help us to better understanding of the actions of this herb for management of cardiovascular disorders. As an herb of red root, S. miltiorrhiza will act as a potential red light to prevent the development of CVD.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Extratos Vegetais/uso terapêutico , Salvia miltiorrhiza/química , Animais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Humanos , Medicina Tradicional Chinesa , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
20.
Int J Genomics ; 2017: 4832125, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29318137

RESUMO

HuoXueJieDu (HXJD) formula exerts protective effects against diabetic retinopathy (DR) in rats, but its underlying mechanism remains unknown. In the present study, the diabetic rats were established using streptozocin. The administration of HXJD was initiated at 20 weeks after diabetes induction and continued for 12 weeks. Whole genome expression profiles in rat retinas were examined using microarray technology. Differential gene expression and pathway enrichment analysis were conducted on the microarray data, with validation through real-time PCR and immunohistochemical staining. The results showed that 170 genes and several IPA canonical pathways related to inflammation, matrix metabolism, and phototransduction were regulated by HXJD. PCR validation of selected genes, including SOCS3, STAT3, TIMP1, and A2M, confirmed the gene expression changes influenced by HXJD. In addition, the immunohistochemical staining results suggested that critical members of the SOCS3-STAT3 pathway were also affected by HXJD. Taken together, these results indicated that SOCS3-STAT3 and TIMP1-A2M pathways might mediate the alleviation of HXJD activities in rats with diabetic retinopathy.

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