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Blood-brain barrier (BBB) disruption is a major pathophysiological event of ischemic stroke. Brain microvascular endothelial cells are critical to maintain homeostasis between central nervous system and periphery. Resveratrol protects against ischemic stroke. 3,3',4,5'-tetramethoxy-trans-stilbene (3,3',4,5'-TMS) and 3,4',5-trimethoxy-trans-stilbene (3,4',5-TMS) are resveratrol derivatives with addition of methoxy groups, showing better pharmacokinetic performance. We aimed to explore their protective effects and underlying mechanisms. Oxygen-glucose deprivation (OGD) model was applied in bEnd.3 cell line, mouse brain microvascular endothelium to mimic ischemia. The cells were pre-treated with 3,3',4,5'-TMS or 3,4',5-TMS (1 and 5 µM, 24 h) and then subjected to 2-h OGD injury. Cell viability, levels of proinflammatory cytokines and reactive oxygen species (ROS), and protein expressions were measured by molecular assays and fluorescence staining. OGD injury triggered cell death, inflammatory responses, ROS production and nuclear factor-kappa B (NF-κB) signalling pathway. These impairments were remarkably attenuated by the two stilbenes, 3,3',4,5'-TMS and 3,4',5-TMS. They also alleviated endothelial barrier injuries through upregulating the expression of tight junction proteins. Moreover, 3,3',4,5'-TMS and 3,4',5-TMS activated 5' adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Overall, 3,3',4,5'-TMS and 3,4',5-TMS exert protective effects against OGD damage through suppressing cell death, inflammatory responses, oxidative stress, as well as BBB disruption on bEnd.3 cells.
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Encéfalo , Supervivencia Celular , Células Endoteliales , Glucosa , Oxígeno , Especies Reactivas de Oxígeno , Estilbenos , Estilbenos/farmacología , Animales , Glucosa/metabolismo , Ratones , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Oxígeno/metabolismo , Línea Celular , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Supervivencia Celular/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Estrés Oxidativo/efectos de los fármacos , Citocinas/metabolismo , Transducción de Señal/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacosRESUMEN
Gut microbiota dysbiosis and gut barrier disruption are key events associated with high-fat diet (HFD)-induced systemic metabolic disorders. Gymnemic acid (GA) has been reported to have an important role in alleviating HFD-induced disorders of glycolipid metabolism, but its regulatory role in HFD-induced disorders of the gut microbiota and gut barrier function has not been elucidated. Here we showed that GA intervention in HFD-induced hamsters increased the relative abundance of short-chain fatty acid (SCFA)-producing microbes including Lactobacillus (P<.05) and Lachnoclostridium (P<.01) in the gut, and reduced the relative abundance of lipopolysaccharide (LPS)-producing microbes including Enterococcus (P<.05) and Bacteroides (P<.05), subsequently improving HFD-induced intestinal barrier dysfunction and systemic inflammation. Specifically, GA intervention reduced mRNA expression of inflammatory cytokines, including IL-1ß, IL-6, and TNF-α (P<.01), increased mRNA expression of antioxidant-related genes, including Nfe2l2, Ho-1, and Nqo1 (P<.01), and increased mRNA expression of intestinal tight junction proteins, including Occludin and Claudin-1 (P<.01), thereby improving gut barrier function of HFD hamsters. This ameliorative effect of GA on the gut of HFD hamsters may further promote lipid metabolic balance in liver and adipose tissue by regulating the Toll-like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) signaling pathway. Taken together, these results systematically revealed the important role of GA in regulating HFD-induced gut microbiota disturbance and gut barrier function impairment, providing a potential clinical theoretical basis for targeted treatment of HFD-induced microbiota dysbiosis.
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Recently, malignant neoplasms have growingly caused human morbidity and mortality. Head and neck cancer (HNC) constitutes a substantial group of malignancies occurring in various anatomical regions of the head and neck, including lips, mouth, throat, larynx, nose, sinuses, oropharynx, hypopharynx, nasopharynx, and salivary glands. The present study addresses the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway as a possible therapeutic target in cancer therapy. Finding new multitargeting agents capable of modulating PI3K/Akt/mTOR and cross-linked mediators could be viewed as an effective strategy in combating HNC. Recent studies have introduced phytochemicals as multitargeting agents and rich sources for finding and developing new therapeutic agents. Phytochemicals have exhibited immense anticancer effects, including targeting different stages of HNC through the modulation of several signaling pathways. Moreover, phenolic/polyphenolic compounds, alkaloids, terpenes/terpenoids, and other secondary metabolites have demonstrated promising anticancer activities because of their diverse pharmacological and biological properties like antiproliferative, antineoplastic, antioxidant, and anti-inflammatory activities. The current review is mainly focused on new therapeutic strategies for HNC passing through the PI3K/Akt/mTOR pathway as new strategies in combating HNC.
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Neoplasias de Cabeza y Cuello , Fosfatidilinositol 3-Quinasas , Fitoquímicos , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Fitoquímicos/farmacología , Fitoquímicos/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Antineoplásicos Fitogénicos/farmacologíaRESUMEN
Hyperglycemia induces chronic stresses, such as oxidative stress and endoplasmic reticulum (ER) stress, which can result in [Formula: see text]-cell dysfunction and development of Type 2 Diabetes Mellitus (T2DM). Ginsenoside Rk1 is a minor ginsenoside isolated from Ginseng. It has been shown to exert anti-cancer, anti-inflammatory, anti-oxidant, and neuroprotective effects; however, its effects on pancreatic cells in T2DM have never been studied. This study aims to examine the novel effects of Ginsenoside Rk1 on ER stress-induced apoptosis in a pancreatic [Formula: see text]-cell line MIN6 and HFD-induced diabetic pancreas, and their underlying mechanisms. We demonstrated that Ginsenoside Rk1 alleviated ER stress-induced apoptosis in MIN6 cells, which was accomplished by directly targeting and activating insulin-like growth factor 1 receptor (IGF-1R), thus activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Bcl-2-associated agonist of cell death (Bad)-B-cell lymphoma-2 (Bcl-2) pathway. This pathway was also confirmed in an HFD-induced diabetic pancreas. Meanwhile, the use of the IGF-1R inhibitor PQ401 abolished this anti-apoptotic effect, confirming the role of IGF-1R in mediating anti-apoptosis effects exerted by Ginsenoside Rk1. Besides, Ginsenoside Rk1 reduced pancreas weights and increased pancreatic insulin contents, suggesting that it could protect the pancreas from HFD-induced diabetes. Taken together, our study provided novel protective effects of Ginsenoside Rk1 on ER stress-induced [Formula: see text]-cell apoptosis and HFD-induced diabetic pancreases, as well as its direct target with IGF-1R, indicating that Ginsenoside Rk1 could be a potential drug for the treatment of T2DM.
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Apoptosis , Estrés del Retículo Endoplásmico , Ginsenósidos , Páncreas , Receptor IGF Tipo 1 , Ginsenósidos/farmacología , Animales , Apoptosis/efectos de los fármacos , Receptor IGF Tipo 1/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones , Páncreas/patología , Páncreas/citología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Línea Celular , Ratones Endogámicos C57BL , Fitoterapia , Transducción de Señal/efectos de los fármacosRESUMEN
Ginsenoside Rk1, one kind of ginsenoside, is a minor ginsenoside found in Panax ginseng and used as traditional Chinese medicine for centuries. It exhibits anti-tumor and anti-aggregation effects. However, little research has been done on its effect on endothelial function. This study investigated whether ginsenoside Rk1 improved endothelial dysfunction in diabetes and the underlying mechanisms in vivo and in vitro. Male C57BL/6 mice were fed with a 12 week high-fat diet (60% kcal % fat), whereas treatment groups were orally administered with ginsenoside Rk1 (10 and 20 mg per kg per day) in the last 4 weeks. Aortas isolated from C57BL/6 mice were induced by high glucose (HG; 30 mM) and co-treated with or without ginsenoside Rk1 (1 and 10 µM) for 48 h ex vivo. Moreover, primary rat aortic endothelial cells (RAECs) were cultured and stimulated by HG (44 mM) to mimic hyperglycemia, with or without the co-treatment of ginsenoside Rk1 (10 µM) for 48 h. Endothelium-dependent relaxations of mouse aortas were damaged with elevated oxidative stress and downregulation of three isoforms of peroxisome proliferator-activated receptors (PPARs), PPAR-α, PPAR-ß/δ, and PPAR-γ, as well as endothelial nitric oxide synthase (eNOS) phosphorylation due to HG or high-fat diet stimulation, which also existed in RAECs. However, after the treatment with ginsenoside Rk1, these impairments were all ameliorated significantly. Moreover, the vaso-protective and anti-oxidative effects of ginsenoside Rk1 were abolished by PPAR antagonists (GSK0660, GW9662 or GW6471). In conclusion, this study reveals that ginsenoside Rk1 ameliorates endothelial dysfunction and suppresses oxidative stress in diabetic vasculature through activating the PPAR/eNOS pathway.
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Endotelio Vascular , Ginsenósidos , Ratones Endogámicos C57BL , Receptores Activados del Proliferador del Peroxisoma , Ginsenósidos/farmacología , Animales , Masculino , Ratones , Ratas , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Estrés Oxidativo/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Aorta/efectos de los fármacos , Aorta/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Panax/química , Dieta Alta en GrasaRESUMEN
Resveratrol has profound benefits against diabetes. However, whether its methylated derivative 3,4',5-trimethoxy-trans-stilbene (3,4',5-TMS) also plays a protective role in glucose metabolism is not characterized. We aimed to study the anti-diabetic effects of 3,4',5-TMS in vitro and in vivo. Insulin-resistant HepG2 cells (IR-HepG2) were induced by high glucose plus dexamethasone whilst six-week-old male C57BL/6J mice received a 60 kcal% fat diet for 14 weeks to establish an obese diabetic model. 3,4',5-TMS did not reduce the cell viability of IR-HepG2 cells at concentrations of 0.5 and 1 µM, which enhanced the capability of glycogen synthesis and glucose consumption in IR-HepG2 cells. Four-week oral administration of 3,4',5-TMS at 10 mg kg-1 day-1 ameliorated insulin sensitivity and glucose tolerance of diet-induced obese (DIO) mice. 3,4',5-TMS activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway by inhibiting phosphorylation of insulin receptor substrate (IRS)-1 at Ser307 and increasing the protein levels of IRS-1 and IRS-2 to restore the insulin signaling pathway in diabetes. 3,4',5-TMS also upregulated the phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) at Ser9. 3,4',5-TMS suppressed oxidative stress by increasing the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H : quinone oxidoreductase 1 (NQO1) and antioxidant enzyme activity. In summary, 3,4',5-TMS alleviated hepatic insulin resistance in vitro and in vivo, by the activation of the insulin signaling pathway, accomplished by the suppression of oxidative stress.
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Diabetes Mellitus , Resistencia a la Insulina , Estilbenos , Animales , Ratones , Masculino , Insulina/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Ratones Obesos , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Glucosa/metabolismo , Estrés Oxidativo , Antioxidantes/farmacología , Obesidad/tratamiento farmacológicoRESUMEN
BACKGROUND: Diabetes belongs to the most prevalent metabolic diseases worldwide, which is featured with insulin resistance, closely associated with obesity and urgently needs to be treated. Baicalin, belonging to natural flavonoids, has been reported to inhibit oxidative stress or inflammatoin. PURPOSE: This study investigated the properties of baicalin on modulating abnormal glucolipid metabolism, as well as the underlying in-vitro and in-vivo mechanisms. METHODS: Insulin-resistant (IR)-HepG2 cells were stimulated by dexamethasone (20 µM) and high glucose (50 mM) for 48 h and incubated with or without baicalin or metformin for another 16 h. Male C57BL/6 J mice were fed with a high-fat diet (HFD, 60 % kcal% fat) during the total 14 weeks. Obese mice were then administered with baicalin (50 and 100 mg/kg) or vehicle solution everyday through oral gavage during the last 4-week period. Moreover, baicalin metabolisms in vitro and in vivo were determined using UPLC/MS/MS to study its metabolism situation. RESULTS: Exposure to dexamethasone and high glucose damaged the abilities of glycogen synthesis and glucose uptake with elevated oxidative stress and increased generation levels of advanced glycation end-products (AGEs) in HepG2 cells. These impairments were basically reversed by baicalin treatment. Four-week oral administration with baicalin ameliorated hyperglycemia and dyslipidemia in HFD-induced obese and pre-diabetic mice. Downregulation of IRS/PI3K/Akt signaling pathway accomplished with reduced GLUT4 expression and enhanced GSK-3ß activity was observed in insulin resistant HepG2 cells as well as liver tissues from pre-diabetic mice; and such effect was prevented by baicalin. Moreover, baicalin and its matabolites were detected in IR-HepG2 cells and mouse plasma. CONCLUSION: The study illustrated that baicalin alleviated insulin resistance by activating insulin signaling pathways and inhibiting oxidative stress and AGEs production, revealing the potential of baicalin to be a therapeutic natural flavonoid against hepatic insulin and glucose-lipid metabolic disturbance in pre-diabetes accompanied with obesity.
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Diabetes Mellitus Experimental , Resistencia a la Insulina , Estado Prediabético , Masculino , Ratones , Animales , Glucosa/metabolismo , Insulina/metabolismo , Estado Prediabético/tratamiento farmacológico , Ratones Obesos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Espectrometría de Masas en Tándem , Ratones Endogámicos C57BL , Flavonoides/uso terapéutico , Transducción de Señal , Hígado , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Dexametasona/farmacología , Dieta Alta en Grasa/efectos adversosRESUMEN
6-benzylaminopurine (6-BA), a multifunctional plant growth regulator, which is frequently used worldwide to improve qualities of various crops, is an important ingredient in production of "toxic bean sprouts." Although there is no direct evidence of adverse effects, its hazardous effects, as well as joint toxicity with other chemicals, have received particular attention and aroused furious debate between proponents and environmental regulators. By use of human umbilical vein endothelial cells (HUVECs), adverse effects of 6-BA to human-derived cells were first demonstrated in this study. A total of 25-50 mg 6-BA/L inhibited proliferation, migration, and formation of tubular-like structures by 50% in vitro. Results of Western blot analyses revealed that exposure to 6-BA differentially modulated the MAPK signal transduction pathway in HUVECs. Specifically, 6-BA decreased phosphorylation of MEK and ERK, but increased phosphorylation of JNK and P38. In addition, 6-BA exacerbated atorvastatin-induced cerebral hemorrhage via increasing hemorrhagic occurrence by 60% and areas by 4 times in zebrafish larvae. In summary, 6-BA elicited toxicity to the endothelial system of HUVECs and zebrafish. This was due, at least in part, to discoordination of MAPK signaling pathway, which should pose potential risks to the cerebral vascular system.
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Compuestos de Bencilo , Hemorragia Cerebral , Purinas , Pez Cebra , Animales , Humanos , Atorvastatina/metabolismo , Atorvastatina/farmacología , Pez Cebra/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Hemorragia Cerebral/metabolismoRESUMEN
Portulaca oleracea L. (purslane) is a food and a traditional drug worldwide. It exhibits anti-inflammatory, anti-oxidative, anti-tumor, and anti-diabetic bioactivities; but its activity on diabetic-associated endothelial dysfunction is unknown. This study aimed to investigate the effect of purslane on endothelial function and the underlying mechanisms. Male C57BL/6 mice had 14-week ad libitum access to a high-fat rodent diet containing 60% kcal% fat to induce obesity and diabetes whereas purslane extract (200 mg/kg/day) was administered during the last 4 weeks via intragastric gavage. Primary rat aortic endothelial cells and isolated mouse aortas were cultured with a risk factor, high glucose or tunicamycin, together with purslane extract. By ESI-QTOF-MS/MS, flavonoids and their glycoside products were identified in the purslane extract. Exposure to high glucose or tunicamycin impaired acetylcholine-induced endothelium-dependent relaxations in aortas and induced endoplasmic reticulum (ER) stress and oxidative stress with the downregulation of 5' AMP-activated protein kinase (AMPK)/ endothelial nitric oxide synthase (eNOS) signaling. Co-incubation with purslane significantly ameliorated these impairments. The effects of purslane were abolished by Compound C (AMPK inhibitor). Four-week purslane treatment ameliorated aortic relaxations, ER stress, and oxidative stress in diabetic obese mice. This study supported that purslane protected endothelial function, and inhibited ER stress and oxidative stress in vasculature through AMPK/eNOS activation, revealing its therapeutic potential against vascular complications in diabetes.
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Flavonoids are essential substances with antioxidant properties and high medicinal value. Citrus reticulata 'Chachi' peel (CRCP) is rich in flavonoids and has numerous health benefits. The different maturity periods of CRCP can affect the flavonoid contents and pharmacological effects. In this study, we successfully performed UPLC-ESI-MS/MS-based metabolic analysis to compare the metabolites of CRCP at different harvesting periods (Jul, Aug, Sep, Oct, Nov, and Dec) using a systematic approach. The results revealed the identification of a total of 168 flavonoid metabolites, including 61 flavones, 54 flavonols, 14 flavone C-glycosides, 14 dihydroflavones, 9 flavanones, 8 isoflavones, 3 flavanols, 3 dihydroflavonols, and 2 chalcones. Clustering analysis and PCA were used to separate the CRCP samples collected at different stages. Furthermore, from July to December, the relative contents of isoflavones, dihydroflavones, and dihydroflavonols gradually increased and flavanols gradually decreased over time. The relative content of flavonoid C-glycosides showed an increasing and then decreasing trend, reaching the highest value in August. This study contributes to a better understanding of flavonoid metabolites in CRCP at different harvesting stages and informs their potential future utilization.
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Metabolic disorders are complex abnormalities involving impaired glucose and lipid metabolism, associated with complications such as kidney disease, cardiovascular disease, foot ulcer, retinopathy, and neuropathy [...].
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AIMS: Excess dietary sodium intake and retention lead to hypertension. Impaired dermal lymphangiogenesis and lymphatic dysfunction-mediated sodium and fluid imbalance are pathological mechanisms. The adenosine A2A receptor (A2AR) is expressed in lymphatic endothelial cells (LECs), while the roles and mechanisms of LEC-A2AR in skin lymphangiogenesis during salt-induced hypertension are not clear. METHODS AND RESULTS: The expression of LEC-A2AR correlated with lymphatic vessel density in both high-salt diet (HSD)-induced hypertensive mice and hypertensive patients. Lymphatic endothelial cell-specific A2AR knockout mice fed HSD exhibited 17 ± 2% increase in blood pressure and 17 ± 3% increase in Na+ content associated with decreased lymphatic density (-19 ± 2%) compared with HSD-WT mice. A2AR activation by agonist CGS21680 increased lymphatic capillary density and decreased blood pressure in HSD-WT mice. Furthermore, this A2AR agonist activated MSK1 directly to promote VEGFR2 activation and endocytosis independently of VEGF as assessed by phosphoprotein profiling and immunoprecipitation assays in LECs. VEGFR2 kinase activity inhibitor fruquintinib or VEGFR2 knockout in LECs but not VEGF-neutralizing antibody bevacizumab suppressed A2AR activation-mediated decrease in blood pressure. Immunostaining revealed phosphorylated VEGFR2 and MSK1 expression in the LECs were positively correlated with skin lymphatic vessel density and A2AR level in hypertensive patients. CONCLUSION: The study highlights a novel A2AR-mediated VEGF-independent activation of VEGFR2 signaling in dermal lymphangiogenesis and sodium balance, which might be a potential therapeutic target in salt-sensitive hypertension.
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Hipertensión , Linfangiogénesis , Ratones , Animales , Receptor de Adenosina A2A/metabolismo , Células Endoteliales/metabolismo , Inhibidores de Proteínas Quinasas , Sodio/metabolismoRESUMEN
Neuroblastoma is the most prevalent extracranial solid tumor in pediatric patients, originating from sympathetic nervous system cells. Metastasis can be observed in approximately 70% of individuals after diagnosis, and the prognosis is poor. The current care methods used, which include surgical removal as well as radio and chemotherapy, are largely unsuccessful, with high mortality and relapse rates. Therefore, attempts have been made to incorporate natural compounds as new alternative treatments. Marine cyanobacteria are a key source of physiologically active metabolites, which have recently received attention owing to their anticancer potential. This review addresses cyanobacterial peptides' anticancer efficacy against neuroblastoma. Numerous prospective studies have been carried out with marine peptides for pharmaceutical development including in research for anticancer potential. Marine peptides possess several advantages over proteins or antibodies, including small size, simple manufacturing, cell membrane crossing capabilities, minimal drug-drug interactions, minimal changes in blood-brain barrier (BBB) integrity, selective targeting, chemical and biological diversities, and effects on liver and kidney functions. We discussed the significance of cyanobacterial peptides in generating cytotoxic effects and their potential to prevent cancer cell proliferation via apoptosis, the activation of caspases, cell cycle arrest, sodium channel blocking, autophagy, and anti-metastasis behavior.
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Usually, in aerobic metabolism, natural materials including nucleic acids, proteins, and lipids can experience auxiliary injury by oxidative responses. This damage produced by reactive oxygen/nitrogen species has been identified as "oxidative stress." As a natural polyphenol got from red wine and peanuts, resveratrol is one of the most eminent anti-aging mixtures. Based on many studies', resveratrol hinders destructive effects of inflammatory causes and reactive oxygen radicals in several tissues. The nuclear erythroid 2-related factor 2 is a factor related to transcription with anti-inflammatory, antioxidant possessions which is complicated by enzyme biotransformation and biosynthesis of lipids and carbohydrates. This review provides current understanding and information about the character of resveratrol against oxidative stress and regulation of inflammation via Nrf2 signaling pathway.
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Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Humanos , Resveratrol/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Inflamación/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Especies de Nitrógeno Reactivo , LípidosRESUMEN
Dried tangerine peel (Citri reticulatae Pericarpium, CRP; Chenpi in Chinese) possesses medicine and food homology with hypolipidemic, anti-inflammatory and antioxidant activities. This study aimed to explore the protective effect of CRP extract on endothelial function and inflammation in type 2 diabetic rats and the related mechanisms. Type 2 diabetes mellitus was induced by high-fat diet (HFD)/streptozotocin (STZ) in male Sprague Dawley rats, and CRP extract was orally administered at 400 mg/kg/day for 4 weeks. Rat and mouse aortas were treated with high glucose and CRP extract ex vivo. The data showed that the ethanolic extract of CRP normalized blood pressure and the plasma lipid profile as well as the plasma levels of liver enzymes in diabetic rats. Impaired endothelium-dependent relaxations in aortas, carotid arteries and renal arteries were improved. CRP extract suppressed vascular inflammatory markers and induced AMPK activation in aortas of diabetic rats. Exposure to high glucose impaired vasodilation in aortas of rats and mice, and this impairment was prevented by co-incubation with CRP extract. In conclusion, our findings suggest that CRP extract protects endothelial function by inhibiting the vascular inflammatory state on activation of AMPK in diabetic rats.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Enfermedades Vasculares , Ratas , Masculino , Ratones , Animales , Ratas Sprague-Dawley , Diabetes Mellitus Experimental/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP , Inflamación/tratamiento farmacológico , GlucosaRESUMEN
Jatrorrhizine (JAT) is one of the major bioactive protoberberine alkaloids found in rhizoma coptidis, which has hypoglycemic and hypolipidemic potential. This study aimed to evaluate the vasoprotective effects of JAT in diabetes and obesity and the underlying mechanism involved. Mouse aortas, carotid arteries and human umbilical cord vein endothelial cells (HUVECs) were treated with risk factors (high glucose or tunicamycin) with and without JAT ex vivo and in vitro. Furthermore, aortas were obtained from mice with chronic treatment: (1) control; (2) diet-induced obese (DIO) mice fed a high-fat diet (45% kcal% fat) for 15 weeks; and (3) DIO mice orally administered JAT at 50 mg/kg/day for the last 5 weeks. High glucose or endoplasmic reticulum (ER) stress inducer tunicamycin impaired acetylcholine-induced endothelium-dependent relaxations (EDRs) in mouse aortas, induced oxidative stress in carotid arteries and HUVECs, downregulated phosphorylations of Akt at Ser473 and eNOS at Ser1177 and enhanced ER stress in mouse aortas and HUVECs, and these impairments were reversed by cotreatment with JAT. JAT increased NO release in high-glucose-treated mouse aortas and HUVECs. In addition, chronic JAT treatment restored endothelial function with EDRs comparable to the control, increased Akt/eNOS phosphorylation, and attenuated ER stress and oxidative stress in aortas from DIO mice. Blood pressure, glucose sensitivity, fatty liver and its morphological change, as well as plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and plasma lipid profile, were also normalized by JAT treatment. Collectively, our data may be the first to reveal the vasoprotective effect of JAT that ameliorates endothelial dysfunction in diabetes and obesity through enhancement of the Akt/eNOS pathway and NO bioavailability, as well as suppression of ER stress and oxidative stress.
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Diabetes Mellitus , Medicamentos Herbarios Chinos , Ratones , Humanos , Animales , Estrés del Retículo Endoplásmico , Tunicamicina/farmacología , Endotelio Vascular/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Acetilcolina/metabolismo , Alanina Transaminasa/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ratones Endogámicos C57BL , Diabetes Mellitus/metabolismo , Estrés Oxidativo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Obesidad/metabolismo , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Aspartato Aminotransferasas/metabolismo , Lípidos/farmacologíaRESUMEN
Nine-processed tangerine peel (Jiuzhi Chenpi in Chinese) is a famous Chinese traditional snack. The composition and contents of volatile substances during its processing is unclear. Gas chromatography combined with ion mobility spectrometry (GC-IMS) was applied to determine the characteristic changes of volatile components throughout the production process. Four stages such as untreated dry tangerine peel (raw material), debittered tangerine peel, pickled tangerine peel, and final product were examined. A total of 110 flavor compounds including terpenes, alcohols, aldehydes, ketones, esters, acids, and two others were successfully detected in tangerine peel samples across the various production stages. There were abundant amounts of terpenes contributing to the flavor, including limonene, gamma-terpinene, alpha-pinene, myrcene, beta-pinene, and alpha-thujene which were reduced at the later stage of production. Large amounts of esters and alcohols such as methyl acetate, furfuryl acetate, ethyl acetate, benzyl propionate, 2-hexanol, linalool, and isopulegol, were diminished at the early stage of processing, i.e., soaking for debittering. One the other hand, the final product contained increased amount of aldehydes and ketones including pentanal, hexanal, 2-hexenal, 2-heptenal (E), 2-pentenal (E), 1-penten-3-one, 6-methyl-5-hepten-2-one, 2-methyl-2-propenal, and 2-cyclohexen-1-one, and very high level of acetic acid. Present findings help to understand the formation of the unique flavor of nine-processed tangerine peel and provide a scientific basis for the optimization of processing methods and quality control.
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BACKGROUND: Inflammation contributes to various diseases and soybeans and legumes are shown to reduce inflammation. However, the bioactive ingredients involved and mechanisms are not completely known. We hypothesized that soy isoflavones daidzin and daidzein exhibit anti-inflammatory effect in lipopolysaccharides (LPS)-stimulated RAW264.7 macrophage cell model and that activation mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways may mediate the effect. METHODS: Cell viability and nitric oxide (NO) level were determined by 3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Griess reagent respectively. ELISA kits and Western blotting respectively assessed the generations of pro-inflammatory cytokines and protein expressions of signaling molecules. p65 nuclear translocation was determined by immunofluorescence assay. RESULTS: The in vitro results showed that both isoflavones did not affect cell viability at the concentrations being tested and significantly reduced levels of NO, pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), and inflammatory indicators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in RAW264.7 cells. Daidzin and daidzein partially suppressed MAPK signaling pathways, reducing the phosphorylation of p38 and ERK; whilst phosphorylation of JNK was mildly but not significantly decreased. For the involvement of NF-κB signaling pathways, daidzin only reduced the phosphorylation of p65 whereas daidzein effectively inhibited the phosphorylation of IKKα/ß, IκBα and p65. Daidzin and daidzein inhibited p65 nuclear translocation, comparable with dexamethasone (positive control). CONCLUSION: This study supports the anti-inflammatory effects of isoflavones daidzin and daidzein, which were at least partially mediated through inactivation of MAPK and/or NF-κB signaling pathways in macrophages.
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3,4',5-trimethoxy-trans-stilbene (TMS) is a methoxylated derivative of resveratrol. Previous studies showed the vaso-protective effects of resveratrol; nevertheless, research on this derivative is scarce. The current study aimed to explore whether TMS can alleviate endothelial dysfunction in diabetic and obese mice, along with the underlying mechanisms. Thoracic aortas isolated from male C57BL/6J mice and primary cultures of rat aortic endothelial cells were treated with high glucose with or without TMS. High glucose exposure impaired acetylcholine-induced endothelium-dependent relaxations, down-regulated NO bioavailability and the AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1)/endothelial nitric oxide synthase (eNOS) pathway, increased endoplasmic reticulum (ER) stress and oxidative stress, which were reversed by TMS treatment. Moreover, the protective effects of TMS were abolished by Compound C (AMPK inhibitor), and EX527 (SIRT1 inhibitor). The mice were fed with high-fat diet (60% kcal% fat) for 14 weeks to establish a diabetic and obese model, and were orally administered TMS (10 mg/kg/day) in the last 4 weeks. Chronic TMS treatment alleviated endothelial dysfunction via enhancing the AMPK/SIRT1/eNOS pathway and attenuated oxidative stress and ER stress in aortas of diet-induced obese mice. In summary, our study reveals the potent vaso-protective effect of TMS and its therapeutic potential against endothelial dysfunction in metabolic disorders.