Search

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diabetes, being the most widespread illness, poses a serious threat to global public health. It seems that inflammation plays a critical role in the pathophysiology of diabetes. This review aims to demonstrate a probable link between type 2 diabetes mellitus (T2DM) and chronic inflammation during its development. Additionally, the current review examined the bioactivity of natural flavones and the possible molecular mechanisms by which they influence diabetes and inflammation. While natural flavones possess remarkable anti-diabetic and anti-inflammatory bioactivities, their therapeutic use is limited by the low oral bioavailability. Several factors contribute to the low bioavailability, including poor water solubility, food interaction, and unsatisfied metabolic behaviors, while the diseases (diabetes, inflammation, etc.) causing even less bioavailability. Throughout the years, different strategies have been developed to boost flavones' bioavailability, including structural alteration, biological transformation, and innovative drug delivery system design. This review addresses current advancements in improving the bioavailability of flavonoids in general, and flavones in particular. Clinical trials were also analyzed to provide insight into the potential application of flavonoids in diabetes and inflammatory therapies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]