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1.
Phytomedicine ; 128: 155376, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38503152

RESUMEN

BACKGROUND: The apoptosis of pulmonary artery endothelial cells (PAECs) is an important factor contributing to the development of pulmonary hypertension (PH), a serious cardio-pulmonary vascular disorder. Salidroside (SAL) is a bioactive compound derived from an herb Rhodiola, but the potential protective effects of SAL on PAECs and the underlying mechanisms remain elusive. PURPOSE: The objective of this study was to determine the role of SAL in the hypoxia-induced apoptosis of PAECs and to dissect the underlying mechanisms. STUDY DESIGN: Male Sprague-Dawley (SD) rats were subjected to hypoxia (10% O2) for 4 weeks to establish a model of PH. Rats were intraperitoneally injected daily with SAL (2, 8, and 32 mg/kg/d) or vehicle. To define the molecular mechanisms of SAL in PAECs, an in vitro model of hypoxic cell injury was also generated by exposed PAECs to 1% O2 for 48 h. METHODS: Various techniques including hematoxylin and eosin (HE) staining, immunofluorescence, flow cytometry, CCK-8, Western blot, qPCR, molecular docking, and surface plasmon resonance (SPR) were used to determine the role of SAL in rats and in PAECs in vitro. RESULTS: Hypoxia stimulation increases AhR nuclear translocation and activates the NF-κB signaling pathway, as evidenced by upregulated expression of CYP1A1, CYP1B1, IL-1ß, and IL-6, resulting in oxidative stress and inflammatory response and ultimately apoptosis of PAECs. SAL inhibited the activation of AhR and NF-κB, while promoted the nuclear translocation of Nrf2 and increased the expression of its downstream antioxidant proteins HO-1 and NQO1 in PAECs, ameliorating the hypoxia-induced oxidative stress in PAECs. Furthermore, SAL lowered right ventricular systolic pressure, and decreased pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-exposed rats. CONCLUSIONS: SAL may attenuate the apoptosis of PAECs by suppressing NF-κB and activating Nrf2/HO-1 pathways, thereby delaying the progressive pathology of PH.


Asunto(s)
Apoptosis , Células Endoteliales , Hemo Oxigenasa (Desciclizante) , Arteria Pulmonar , Transducción de Señal , Animales , Masculino , Ratas , Apoptosis/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Glucósidos/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Hipoxia/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fenoles/farmacología , Arteria Pulmonar/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de Hidrocarburo de Aril/metabolismo , Rhodiola/química , Transducción de Señal/efectos de los fármacos
2.
MedComm (2020) ; 4(5): e338, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37600507

RESUMEN

Aconitum carmichaelii (Fuzi) is a traditional Chinese medicine that has been widely used in the clinic to save the dying life for over several thousand years. However, the medicinal components of Fuzi in treating vascular senescence (VS) and its potential mechanism remain unclear. In this study, a network pharmacology method was used to explore the possible components and further validated by experiments to get a candidate compound, deoxyandrographolide (DA). DA restrains aging biomarkers, such as p16, p21, γH2A.X, and p53 in vitro and in vivo blood co-culture studies. Histone deacetylase 1 (HDAC1), mouse double minute2 (MDM2), cyclin-dependent kinase 4, and mechanistic target of rapamycin kinase (mTOR) are predicted to be the possible targets of DA based on virtual screening. Subsequent bio-layer interferometry results indicated that DA showed good affinity capability with HDAC1. DA enhances the protein expression of HDAC1 in the angiotensin II-induced senescence process by inhibiting its ubiquitination degradation. Loss of HDAC1 by CRISPR/Cas9 leads to the disappearance of DA's anti-aging property. The enhancement of HDAC1 represses H3K4me3 (a biomarker of chromosomal activity) and improves chromosome stability. RNA sequencing results also confirmed our hypothesis. Our evidence illuminated that DA may achieve as a novel compound in the treatment of VS by improving chromosome stability.

3.
Oxid Med Cell Longev ; 2022: 4578381, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36193068

RESUMEN

Traditional Chinese medicine (TCM) has significantly contributed to protecting human health and promoting the progress of world civilization. A total of 2,711 TCMs are included in the 2020 version of the Chinese Pharmacopoeia, which is an integral part of the world's medical resources. Tu Youyou and her team discovered and purified artemisinin. And their contributions made the values and advantageous effects of TCM more and more recognized by the international community. There has been a lot of studies on TCM to treat diseases through antioxidant mechanisms, the reports on the new mechanisms beyond antioxidants of TCM has also increased year by year. Recently, many TCMs appear to have significant effects in regulating ferroptosis. Ferroptosis is an iron-dependent, non-apoptotic, regulated cell death characterized by intracellular lipid peroxide accumulation and oxidative membrane damage. Recently, accumulating studies have demonstrated that numerous organ injuries and pathophysiological process of many diseases are companied with ferroptosis, such as cancer, neurodegenerative disease, acute renal injury, arteriosclerosis, diabetes, and ischemia-reperfusion injury. This work mainly introduces dozens of TCMs that can regulate ferroptosis and their possible mechanisms and targets.


Asunto(s)
Artemisininas , Ferroptosis , Enfermedades Neurodegenerativas , Antioxidantes , Femenino , Humanos , Hierro/metabolismo , Peróxidos Lipídicos , Medicina Tradicional China
4.
Zhongguo Zhong Yao Za Zhi ; 47(2): 461-468, 2022 Jan.
Artículo en Chino | MEDLINE | ID: mdl-35178990

RESUMEN

To investigate the effects of leonurine(Leo) on abdominal aortic constriction(AAC)-induced cardiac hypertrophy in rats and its mechanism. A rat model of pressure overload-induced cardiac hypertrophy was established by AAC method. After 27-d intervention with high-dose(30 mg·kg~(-1)) and low-dose(15 mg·kg~(-1)) Leo or positive control drug losartan(5 mg·kg~(-1)), the cardiac function was evaluated by hemodynamic method, followed by the recording of left ventricular systolic pressure(LVSP), left ventricular end-diastolic pressure(LVESP), as well as the maximum rate of increase and decrease in left ventricular pressure(±dp/dt_(max)). The degree of left ventricular hypertrophy was assessed based on heart weight index(HWI) and left ventricular mass index(LVWI). Myocardial tissue changes and the myocardial cell diameter(MD) were measured after hematoxylin-eosin(HE) staining. The contents of angiotensin Ⅱ(AngⅡ) and angiotensin Ⅱ type 1 receptor(AT1 R) in myocardial tissue were detected by ELISA. The level of Ca~(2+) in myocardial tissue was determined by colorimetry. The protein expression levels of phospholipase C(PLC), inositol triphosphate(IP3), AngⅡ, and AT1 R were assayed by Western blot. Real-time quantitative PCR(qRT-PCR) was employed to determine the mRNA expression levels of ß-myosin heavy chain(ß-MHC), atrial natriuretic factor(ANF), AngⅡ, and AT1 R. Compared with the model group, Leo decreased the LVSP, LVEDP, HWI, LVWI and MD values, but increased ±dp/dt_(max) of the left ventricle. Meanwhile, it improved the pathological morphology of myocardial tissue, reduced cardiac hypertrophy, edema, and inflammatory cell infiltration, decreased the protein expression levels of PLC, IP3, AngⅡ, AT1 R, as well as the mRNA expression levels of ß-MHC, ANF, AngⅡ, AT1 R, c-fos, and c-Myc in myocardial tissue. Leo inhibited AAC-induced cardiac hypertrophy possibly by influencing the RAS system.


Asunto(s)
Cardiomegalia , Hipertrofia Ventricular Izquierda , Angiotensina II/metabolismo , Animales , Cardiomegalia/etiología , Cardiomegalia/genética , Ácido Gálico/análogos & derivados , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/patología , Miocardio/patología , Ratas
5.
Front Cell Infect Microbiol ; 11: 670593, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34422677

RESUMEN

Background: Rheumatoid arthritis (RA) is a long-term autoimmune disorder characterized by chronic inflammation that results in swollen and painful joints and even cartilage and bone damage. The gut microbiota, a novel anti-inflammatory target, is considered an important environmental factor in the development of RA. S-propargyl-cysteine (SPRC), an amino acid analogue, exerts anti-inflammatory, cardioprotective effects, and neuroprotective effects on various diseases. In recent studies, an SPRC treatment exerted anti-inflammatory effects on RA. Meanwhile, gut microbiome dysbiosis in individuals with RA has also been reported by many researchers. However, the relationship between SPRC and gut microbiota in individuals with RA remains unclear. Methods: Thirty male Sprague-Dawley (SD) rats were randomly divided into three groups of 10 each, including the Control, Model, and SPRC groups. Adjuvant-induced arthritis (AIA) rats in SPRC group were treated with SPRC. Measurement of paw volume and serum tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels were applied to evaluate the inflammatory status. Fecal samples were collected on the 14th day and 28th day. Gut microbiota were analyzed using 16S ribosomal RNA (rRNA) gene amplicon sequencing. Untargeted metabolomics on plasma samples was applied to investigate the metabolic changes induced by the altered gut microbiota by using derivatization-UHPLC-Q-TOF/MS. Findings: Using 16S rRNA amplicon sequencing, we found that SPRC significantly altered the gut microbiota structure in AIA rats. In particular, Bifidobacterium, a genus of BSH (Bile Salt Hydrolase)-producing microbes, was overrepresented in SPRC-treated AIA rats. Additionally, a subsequent metabolomics analysis indicated that bile acid metabolism was also altered by SPRC treatment. Interestingly, glycochenodeoxycholic acid (GCDCA) and glycocholic acid (GCA), which are formed with the participation of BSH-producing microbes in the intestine, were identified as crucial biomarkers responding to SPRC treatment with significantly lowered levels. Interpretation: A mechanistic link between the gut microbiota and plasma metabolites was revealed in this study, which provides insights into the mechanism of SPRC treatment for RA from the perspective of the gut microbiota.


Asunto(s)
Artritis Reumatoide , Microbioma Gastrointestinal , Animales , Artritis Reumatoide/tratamiento farmacológico , Ácidos y Sales Biliares , Cisteína , Masculino , ARN Ribosómico 16S/genética , Ratas , Ratas Sprague-Dawley
6.
Drug Deliv ; 28(1): 1031-1042, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34060389

RESUMEN

PURPOSE: S-propargyl-cysteine (SPRC), an excellent endogenous hydrogen sulfide (H2S) donor, could elevate H2S levels via the cystathionine γ-lyase (CSE)/H2S pathway both in vitro and in vivo. However, the immediate release of H2S in vivo and daily administration of SPRC potentially limited its clinical use. METHODS: To solve the fore-mentioned problem, in this study, the dendritic mesoporous silica nanoparticles (DMSN) was firstly prepared, and a sustained H2S delivery system consisted of SPRC and DMSN (SPRC@DMSN) was then constructed. Their release profiles, both in vitro and in vivo, were investigated, and their therapeutical effect toward adjuvant-induced arthritis (AIA) rats was also studied. RESULTS: The spherical morphology of DMSN could be observed under scanning Electron Microscope (SEM), and the transmission electron microscope (TEM) images showed a central-radiational pore channel structure of DMSN. DMSN showed excellent SPRC loading capacity and attaining a sustained releasing ability than SPRC both in vitro and in vivo, and the prolonged SPRC releasing could further promote the release of H2S in a sustained manner through CSE/H2S pathway both in vitro and in vivo. Importantly, the SPRC@DMSN showed promising anti-inflammation effect against AIA in rats was also observed. CONCLUSIONS: A sustained H2S releasing donor consisting of SPRC and DMSN was constructed in this study, and this sustained H2S releasing donor might be of good use for the treatment of AIA.


Asunto(s)
Cisteína/análogos & derivados , Sulfuro de Hidrógeno/metabolismo , Inflamación/tratamiento farmacológico , Nanopartículas/química , Dióxido de Silicio/química , Animales , Supervivencia Celular , Química Farmacéutica , Cistationina gamma-Liasa/efectos de los fármacos , Cisteína/administración & dosificación , Cisteína/farmacología , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/química , Liberación de Fármacos , Inflamación/inducido químicamente , Macrófagos/efectos de los fármacos , Ratones , Tamaño de la Partícula , Distribución Aleatoria , Ratas , Propiedades de Superficie
7.
Chin J Integr Med ; 26(2): 152-160, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31069695

RESUMEN

Leonurus japonicus Houtt, a Chinese traditional herbal medicine, has been widely used to cure gynecological diseases, such as incomplete abortion and menoxenia. Leonurine, a major active alkaloid compound only be found in Leonurus japonicus Houtt, has been successfully extracted and purified. Recent evidence has shown that leonurine can regulate a variety of pathologic processes including oxidative stress, inflammation, fibrosis, apoptosis, and multiple metabolic disorders. Here, we have reviewed the pharmacological actions and biological functions of leonurine, with a focus on the role of leonurine in the amelioration of various pathological processes. Insights into the related signaling pathways and molecular mechanisms have strengthened our understanding on the function of leonurine in the alleviation of multiple pathological states. Our summary of the existing researches should help direct future research into the basic science and clinical applications in related diseases.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Ácido Gálico/análogos & derivados , Extractos Vegetales/farmacología , Femenino , Ácido Gálico/farmacología , Enfermedades de los Genitales Femeninos/tratamiento farmacológico , Humanos
8.
Pharmacol Res ; 144: 90-98, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30959158

RESUMEN

Hydrogen sulfide gas (H2S) has protective effects in the cardiovascular system that includes preventing the development of atherosclerosis when tested in several in vivo models. Plaque instability is a major risk factor for thromboembolism, myocardial infarction, and stroke, so we examined if H2S can promote plaque stability and the potential underlying mechanisms. Apolipoprotein E knockout mice fed an atherogenic diet were administered the exogenous H2S donor sodium hydrosulfide (NaHS) or pravastatin as a positive control daily for 14 weeks. NaHS significantly enhanced plaque stability by increasing fibrous cap thickness and collagen content compared to vehicle-treated controls. NaHS treatment also reduced blood lipid levels and plaque formation. Preservation of plaque stability by NaHS was associated with reductions in vascular smooth muscle cells (VSMCs) apoptosis and expression of the collagen-degrading enzyme matrix metallopeptidase-9 (MMP-9) in plaque. While pravastatin also increased fibrous cap thickness and reduced VSMC apoptosis, but did not enhance plaque collagen or reduce MMP-9 significantly, suggesting distinct mechanisms of plaque stabilization. in vitro, NaHS also decreased MMP-9 expression in macrophages stimulated with tumor necrosis factor-α by inhibiting ERK/JNK phosphorylation and activator protein 1 nuclear translocation. Moreover, H2S reduced caspase-3/9 activity, Bax/Bcl-2 ratio, and LOX-1 mRNA expression in VSMCs stimulated with oxidized low-density lipoprotein. These results suggest that H2S enhances plaque stability and protects against atherogenesis by increasing plaque collagen content and VSMC count. In conclusion, H2S exerts protective effects against atherogenesis at least partly by stabilizing atherosclerotic plaque.


Asunto(s)
Sulfuro de Hidrógeno/uso terapéutico , Músculo Liso Vascular/efectos de los fármacos , Placa Aterosclerótica/tratamiento farmacológico , Sulfuros/uso terapéutico , Animales , Anticolesterolemiantes/uso terapéutico , Apolipoproteínas E/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos del Músculo Liso/efectos de los fármacos , Placa Aterosclerótica/genética , Pravastatina/uso terapéutico , Ratas Wistar
9.
Oxid Med Cell Longev ; 2018: 4010395, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30151069

RESUMEN

The recognition of hydrogen sulfide (H2S) has been evolved from a toxic gas to a physiological mediator, exhibiting properties similar to NO and CO. On the one hand, H2S is produced from L-cysteine by enzymes of cystathionine γ-lyase (CSE) and cystathionine ß-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3MST) in combination with aspartate aminotransferase (AAT) (also called as cysteine aminotransferase, CAT); on the other hand, H2S is produced from D-cysteine by enzymes of D-amino acid oxidase (DAO). Besides sulfide salt, several sulfide-releasing compounds have been synthesized, including organosulfur compounds, Lawesson's reagent and analogs, and plant-derived natural products. Based on garlic extractions, we synthesized S-propargyl-L-cysteine (SPRC) and its analogs to contribute our endeavors on drug development of sulfide-containing compounds. A multitude of evidences has presented H2S is widely involved in the roles of physiological and pathological process, including hypertension, atherosclerosis, angiogenesis, and myocardial infarcts. This review summarizes current sulfide compounds, available H2S measurements, and potential molecular mechanisms involved in cardioprotections to help researchers develop further applications and therapeutically drugs.


Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Desarrollo de Medicamentos/métodos , Sulfuro de Hidrógeno/uso terapéutico , Enfermedades Cardiovasculares/patología , Humanos , Sulfuro de Hidrógeno/farmacología
10.
Trends Pharmacol Sci ; 39(7): 624-634, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29706261

RESUMEN

Garlic (Allium sativum) and allied plant species are rich sources of sulfur compounds. Major roles for garlic and its sulfur constituents include the regulation of vascular homeostasis and the control of metabolic systems linked to nutrient metabolism. Recent studies have indicated that some of these sulfur compounds, such as diallyl trisulfide (DATS), alter the levels of gaseous signalling molecules including nitric oxide (NO), hydrogen sulfide (H2S), and perhaps carbon monoxide (CO) in mammalian tissues. These gases are important in cellular processes associated with the cardiovascular system, inflammation, and neurological functions. Importantly, these studies build on the known biological effects of garlic and associated sulfur constituents. This review highlights our current understanding of the health benefits attributed to edible plants like garlic.


Asunto(s)
Monóxido de Carbono/metabolismo , Ajo/química , Gasotransmisores/metabolismo , Sulfuro de Hidrógeno/metabolismo , Óxido Nítrico/metabolismo , Compuestos Alílicos/farmacología , Animales , Antioxidantes/farmacología , Humanos , Extractos Vegetales/farmacología , Transducción de Señal , Sulfuros/farmacología
11.
Pharmacol Ther ; 188: 26-35, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29360539

RESUMEN

Despite several advances in percutaneous coronary intervention and the discovery of new drugs, the incidence of myocardial infarction and deaths due to cardiovascular diseases (CVD) has not decreased markedly in China. The quality of life is affected seriously, which further results in great social and family burden. Many drugs, from the century-old aspirin to the newly FDA-approved Byvalson, have been proven to be effective in the treatment and prevention of CVD. As clinically reported, those life-saving drugs still have their side effects in regards to the narrow therapeutic indexes influenced by individual genetic variations. Herba Leonuri, also known as Chinese Motherwort, which are naturally present in plants and traditionally are used for the uterotonic action, postpartum blood stasis, breast pain as well as other gynecological disorders in China for thousands of years. Since the last two decades, our group has reported leonurine, a unique alkaloid found in Herba Leonuri, exhibits various bioactivities such as antioxidant, anti-apoptotic effects, free radical scavenging and anti-inflammatory effects, in addition to improving micro-circulation. These bioactivities are related to the underlying mechanisms of ischemic heart diseases and cardiac fibrosis. Pharmacological studies have proven leonurine to be effective in treating CVD in various ways, particularly ischemic heart diseases. Besides the cardio protective effects, which are similar in the central nervous system, more specifically, inhibited mitochondrial reactive oxygen species production together with the restored mitochondrial function and redox state were observed in middle cerebral artery occlusion rats by leonurine treatment, which strongly reveals its neuroprotective effects and carries a therapeutic potential for recovery and prevention of stroke. Based on their mode of action, we propose that leonurine can be developed as drugs to treat ischemic heart diseases. Taking advantage of the most recent findings in pharmacological research including the effects of low toxicity and good pharmacokinetics characteristics, leonurine has a very attractive prospect of clinical application. Our recent promising pharmacological results may be able to eradicate the barrier hindering its sale on market. In sum, from bench to bedside is no longer a long way for leonurine.


Asunto(s)
Ácido Gálico/análogos & derivados , Leonurus/química , Animales , Apoptosis/efectos de los fármacos , Aterosclerosis/tratamiento farmacológico , Descubrimiento de Drogas , Ácido Gálico/síntesis química , Ácido Gálico/farmacocinética , Ácido Gálico/farmacología , Ácido Gálico/uso terapéutico , Humanos , Medicina Tradicional China , Enfermedades Neurodegenerativas/tratamiento farmacológico
12.
J Alzheimers Dis ; 60(s1): S151-S160, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28671133

RESUMEN

With the increase in the proportion of aged population due to the rapid increase of life expectancy, the worldwide prevalence rate of multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease has been increased dramatically. The demographic trend toward an older population has drawn the attention to new drug discovery and treatment on age-related diseases. Although a panel of drugs and/or therapies are currently available for treating the neurodegenerative diseases, side effects or insufficient drug efficacy have been reported. With the long history in prescription of Chinese medicine or natural compounds for modulating aged-related diseases, emerging evidence was reported to support the pharmacological role of Chinese medicine in ameliorating the symptoms, or interfering with the pathogenesis of several neurodegenerative diseases. This review brings evidence about today's trends and development of a list of potential neuroprotective herbal compounds from both the traditional and modern pharmacological point of view. With future projections, the potential hope and implication of using Chinese medicine as an alternative source for novel drug discovery for neurodegenerative diseases is proposed.


Asunto(s)
Medicina Tradicional China/normas , Enfermedades Neurodegenerativas/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Humanos , Medicina Tradicional China/tendencias
13.
Phytomedicine ; 32: 15-23, 2017 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-28732803

RESUMEN

BACKGROUND: Endothelial inflammation is an increasingly prevalent condition in the pathogenesis of many cardiovascular diseases. (-)-7(S)-hydroxymatairesinol (7-HMR), a naturally occurring plant lignan, possesses both antioxidant and anti-cancer properties and therefore would be a good strategy to suppress tumor necrosis factor-α (TNF-α)-mediated inflammation in vascular endothelial cells (VECs). PURPOSE: The objective of this study is to evaluate for its anti-inflammatory effect on TNF-α-stimulated VECs and underling mechanisms. STUDY DESIGN/METHODS: The effect of the 7-HMR on suppression of TNF-α-induced inflammation mediators in VECs were determined by qRT-PCR and Western blot. MAPKs and phosphorylation of Akt, HO-1 and NF-κB p65 were examined using Western blot. Nuclear localisation of NF-κB was also examined using Western blot and immunofluorescence. RESULTS: Here we found that 7-HMR could suppress TNF-α-induced inflammatory mediators, such as vascularcelladhesion molecule-1, interleukin-6 and inducible nitric oxide synthase expression both in mRNA and protein levels, and concentration-dependently attenuated reactive oxidase species generation. We further identified that 7-HMR remarkably induced superoxide dismutase and heme oxygenase-1 expression associated with degradation of Kelch-like ECH-associated protein 1 (keap1) and up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, 7-HMR time- and concentration-dependently attenuated TNF-α-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK) and Akt, but not p38, or c-Jun N-terminal kinase 1/2. Moreover, 7-HMR significantly suppressed TNF-α-mediated nuclear factor-κB (NF-κB) activation by inhibiting phosphorylation and nuclear translocation of NF-κB p65. CONCLUSION: Our results demonstrated that 7-HMR inhibited TNF-α-stimulated endothelial inflammation, at least in part, through inhibition of NF-κB activation and upregulation of Nrf2-antioxidant response element signaling pathway, suggesting 7-HMR might be used as a promising vascular protective drug.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inflamación/tratamiento farmacológico , Lignanos/farmacología , FN-kappa B/metabolismo , Animales , Elementos de Respuesta Antioxidante/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hemo-Oxigenasa 1/metabolismo , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Factor de Necrosis Tumoral alfa/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismo
14.
Molecules ; 22(2)2017 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-28230797

RESUMEN

Nox-dependent signaling plays critical roles in the development of heart failure, cardiac hypertrophy, and myocardial infarction. NADPH oxidase 4 (Nox4) as a major source of oxidative stress in the heart offers a new therapeutic target in cardiovascular disease. In the present work, a novel flavonoid was isolated from Zanthoxylum bungeanum. Its structure was elucidated as Quercetin-3-O-(6''-O-α-l-rhamnopyransoyl)-ß-d-glucopyranoside-7-O-ß-d-glucopyranoside (ZYZ-772) for the first time. ZYZ-772 exhibited significant cardio-protective property against CoCl2 induced H9c2 cardiomyocyte cells injury. In CoCl2 stimulated cardiomyocyte injury, ZYZ-772 inhibited expression of Nox4, and alleviated ROS overproduction. Importantly, ROS triggered MAPKs phosphorylation and P53 signaling mediated apoptosis were restored by ZYZ-772. Our findings present the first piece of evidence for the therapeutic properties of ZYZ-772 in preventing cardiomyocyte injury, which could be attributed to the suppression of Nox4/MAPKs/P53 axis. This will offer a novel therapeutic strategy for the treatment of cardiac ischemia disease.


Asunto(s)
Apoptosis/efectos de los fármacos , Flavonoides/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , NADPH Oxidasas/metabolismo , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Cardiotónicos/química , Cardiotónicos/farmacología , Línea Celular , Flavonoides/química , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Estructura Molecular , Extractos Vegetales/química , Ratas
15.
Pharmacol Res ; 115: 25-44, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27838509

RESUMEN

Pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are closely related to the formation of protein aggregates and inclusion body. For instance, active autophagic components from Chinese herbal medicines (CHMs) are highlighted to modulate neurodegeneration via degradation of disease proteins. In this study, the neuroprotective effect of the purified Hedera helix (HH) fraction containing both hederagenin and α-hederin, is confirmed by the improvement of motor deficits in PD mice model. Furthermore, hederagenin and α-hederin derived from HH are confirmed as novel autophagic enhancers. Both compounds reduce the protein level of mutant huntingtin with 74 CAG repeats and A53T α-synuclein, and inhibit the oligomerization of α-synuclein and inclusion formation of huntingtin, via AMPK-mTOR dependent autophagy induction. Both hederagenin and α-hederin induce autophagy and promote the degradation of neurodegenerative mutant disease proteins in vitro, suggesting the therapeutic roles of HH in neurodegenerative disorders.


Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacología , Adenilato Quinasa/metabolismo , Animales , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Femenino , Hedera/química , Proteína Huntingtina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades Neurodegenerativas/metabolismo , Ácido Oleanólico/farmacología , Células PC12 , Ratas , Serina-Treonina Quinasas TOR/metabolismo , alfa-Sinucleína/metabolismo
16.
Redox Biol ; 10: 157-167, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27744121

RESUMEN

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder. Hydrogen sulfide (H2S), the third physiological gasotransmitter, is well recognized as an anti-inflammatory mediator in various inflammatory conditions. Herein, we explored the protective effects of S-propargyl-cysteine (SPRC, also known as ZYZ-802), an endogenous H2S modulator, on RA and determined the underlying mechanisms. In the present study, SPRC concentration-dependently attenuated inflammatory mediator expression, reactive oxidase species generation, and the expression and activity of matrix metalloproteinases (MMP)-9 in interleukin (IL)-1ß-induced human rheumatoid fibroblast-like synoviocytes MH7A. In addition, SPRC blocked IL-1ß-mediated migration and invasion of MH7A cells. As expected, the protective effects of SPRC were partially abrogated by DL-propargylglycine (PAG, a H2S biosynthesis inhibitor). In vivo study also demonstrated that SPRC treatment markedly ameliorated the severity of RA in adjuvant-induced arthritis rats, and this effect was associated with the inhibition of inflammatory response. We further identified that SPRC remarkably induced heme oxygenase-1 expression associated with the degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2); this effect was attributed to the sulfhydrylation of the cysteine residue of Keap1. Our data demonstrated for the first time that SPRC, an endogenous H2S modulator, exerted anti-inflammatory properties in RA by upregulating the Nrf2-antioxidant response element (ARE) signaling pathway.


Asunto(s)
Antiinflamatorios/administración & dosificación , Elementos de Respuesta Antioxidante/efectos de los fármacos , Artritis Reumatoide/tratamiento farmacológico , Cisteína/análogos & derivados , Factor 2 Relacionado con NF-E2/genética , Animales , Antiinflamatorios/farmacología , Artritis Reumatoide/genética , Línea Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular , Cisteína/administración & dosificación , Cisteína/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba
17.
PLoS One ; 11(9): e0163289, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27649298

RESUMEN

Anemia of inflammation (AI) is clinically prevalent and greatly threatens public health. Traditional remedies have raised controversy during clinical practice, calling for alternative therapies. We have recently found that hydrogen sulfide (H2S) inhibits inflammatory hepcidin, the critical mediator of AI. However, due to the chemical property of H2S, there remains an urgent need for a stable H2S donor in AI treatment. Here we reported that S-propargyl-cysteine (SPRC), a novel water-soluble H2S donor, suppressed hepatic hepcidin and corrected hypoferremia induced by lipopolysaccharide. The effects of SPRC were reversed by inhibition of cystathionine γ-lyase, one of the major endogenous H2S synthases. Moreover, SPRC reduced serum hepcidin, improved transferrin saturation, and maintained erythrocyte membrane integrity in a chronic mouse AI model. Consistently, splenomegaly was ameliorated and splenic iron accumulation relieved. Mechanism study indicated that serum IL-6 content and hepatic Il-6 mRNA were decreased by SPRC, in parallel with reduced hepatic JAK2/STAT3 activation. On the whole, our data reveal the inhibition of inflammatory hepcidin by SPRC, and suggest SPRC as a potential remedy against AI.


Asunto(s)
Anemia/tratamiento farmacológico , Cisteína/análogos & derivados , Hepcidinas/metabolismo , Sulfuro de Hidrógeno/metabolismo , Inflamación/tratamiento farmacológico , Interleucina-6/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Anemia/metabolismo , Animales , Cisteína/farmacología , Cisteína/uso terapéutico , Modelos Animales de Enfermedad , Inflamación/inducido químicamente , Inflamación/metabolismo , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL
18.
Antioxid Redox Signal ; 25(5): 268-81, 2016 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-27296720

RESUMEN

AIMS: Macrophages are of key importance for tissue repair after myocardial infarction (MI). Hydrogen sulfide (H2S) has been shown to exert cardioprotective effects in MI. However, the mechanisms by which H2S modulates cardiac remodeling and repair post-MI remain to be clarified. RESULTS: In our current study, we showed that H2S supplementation ameliorated pathological remodeling and dysfunction post-MI in wild-type (WT) and CSE KO mice, resulting in decreased infarct size and mortality, accompanied by an increase in the number of M2-polarized macrophages at the early stage of MI. Strikingly, adoptive transfer of NaHS-treated bone marrow-derived macrophages into WT and CSE KO mice with depleted macrophages also ameliorated MI-induced cardiac functional deterioration. Further mechanistic studies demonstrated that NaHS-induced M2 polarization was achieved by enhanced mitochondrial biogenesis and fatty acid oxidation. INNOVATION AND CONCLUSION: Our study shows (for the first time) that H2S may have the potential as a therapeutic agent for MI via promotion of M2 macrophage polarization. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16:293-296, 2012) with the following serving as open reviewers: Hideo Kimura, Chaoshu Tang, Xiaoli Tian, and Kenneth Olson. Antioxid. Redox Signal. 25, 268-281.


Asunto(s)
Sulfuro de Hidrógeno/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/fisiología , Infarto del Miocardio/etiología , Infarto del Miocardio/metabolismo , Biogénesis de Organelos , Animales , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Pruebas de Función Cardíaca , Lipólisis , Masculino , Ratones , Ratones Noqueados , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/mortalidad , Miocitos Cardíacos , Oxidación-Reducción , Disfunción Ventricular/tratamiento farmacológico
19.
Nat Prod Commun ; 11(11): 1757-1761, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30475522

RESUMEN

Herba Leonuri, also named Chinese Motherwort, has been extensively investigated as an effective agent on the uterus system. Our group has been studying the natural products of Herba Leonuri for several years, and during this period, many biological activities of the drug were recognized. Leonurine (4-guanidino-N- butyl-syringate) is an alkaloid present in Herba Leonuri. Recently, growing evidence has highlighted the therapeutic potential of leonurine in multiple diseases, especially cardiovascular. In this review, we discuss the biological activities of leonurine, as well as recent advances involving this alkaloid.


Asunto(s)
Ácido Gálico/análogos & derivados , Leonurus/química , Medicina Tradicional China , Ácido Gálico/química , Ácido Gálico/farmacología , Humanos , Estructura Molecular , Fitoterapia
20.
Antioxid Redox Signal ; 24(2): 70-83, 2016 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-26154696

RESUMEN

AIMS: Anemia of inflammation is quite prevalent in hospitalized patients with poor prognosis. Concerns about the effectiveness and safety of iron supplementation have arisen, driving the demand for alternative therapies. Induction of hepatic hepcidin, the master hormone of iron homeostasis, causes anemia under inflammatory conditions. Previous studies indicated that hydrogen sulfide (H2S), the third gasotransmitter and a well-known regulator of inflammation, may inhibit the secretion of inflammatory cytokines. We thus investigated the effect of H2S on inflammatory hepcidin induction. RESULTS: H2S suppressed lipopolysaccharide (LPS)-induced hepcidin production and regulated iron homeostasis in mice by decreasing serum interleukin-6 (IL-6) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) activation; similar results were obtained in Huh7 cells exposed to conditioned medium from LPS-challenged THP-1 macrophages. Intriguingly, we found H2S also attenuated hepcidin levels in Huh7 cells and mouse primary hepatocytes in a sirtuin 1 (SIRT1)-dependent manner. By promoting SIRT1 expression and stabilizing SIRT1-STAT3 interactions, H2S ameliorated IL-6-induced STAT3 acetylation, resulting in reduced hepcidin production. Inhibition and silencing of SIRT1 diminished H2S-mediated suppression of hepcidin, as opposed to SIRT1 activation and overexpression. Consistent results were observed in vivo. Furthermore, knockout of cystathionine γ-lyase (CSE), an endogenous H2S synthase, exaggerated inflammatory hepcidin expression in mice. INNOVATION: For the first time, we elucidated the effects and possible mechanisms of H2S on inflammatory hepcidin and established a novel regulatory link between SIRT1 and hepcidin. CONCLUSION: Our work demonstrates that H2S attenuates inflammation-induced hepatic hepcidin via multipathways and suggests new treatment strategies for anemia of inflammation.


Asunto(s)
Sulfuro de Hidrógeno/uso terapéutico , Inflamación/tratamiento farmacológico , Interleucina-6/metabolismo , Factor de Transcripción STAT3/metabolismo , Sirtuina 1/metabolismo , Acetilación , Animales , Células Cultivadas , Hepcidinas , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL
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