Glucagon-like peptide-1 (GLP-1) receptor activation in the brain provides neuroprotection. Exendin-4 (Ex-4), a GLP-1 analog, has seen limited clinical usage because of its short half-life. We developed long-lasting Ex-4-loaded poly(D,L-lactide-co-glycolide) microspheres (PEx-4) and explored its neuroprotective potential against cerebral ischemia in diabetic rats. Compared with Ex-4, PEx-4 in the gradually degraded microspheres sustained higher Ex-4 levels in the plasma and cerebrospinal fluid for at least 2 weeks and improved diabetes-induced glycemia after a single subcutaneous administration (20 μg/day). Ten minutes of bilateral carotid artery occlusion (CAO) combined with hemorrhage-induced hypotension (around 30 mm Hg) significantly decreased cerebral blood flow and microcirculation in male Wistar rats subjected to streptozotocin-induced diabetes. CAO increased cortical O 2 − levels by chemiluminescence amplification and prefrontal cortex edema by T2-weighted magnetic resonance imaging analysis. CAO significantly increased aquaporin 4 and glial fibrillary acidic protein expression and led to cognition deficits. CAO downregulated phosphorylated Akt/endothelial nitric oxide synthase (p-Akt/p-eNOS) signaling and enhanced nuclear factor (NF)-κBp65/ intercellular adhesion molecule-1 (ICAM-1) expression, endoplasmic reticulum (ER) stress, and apoptosis in the cerebral cortex. PEx-4 was more effective than Ex-4 to improve CAO-induced oxidative injury and cognitive deficits. The neuroprotection provided by PEx-4 was through p-Akt/p-eNOS pathways, which suppressed CAO-enhanced NF-κB/ICAM-1 signaling, ER stress, and apoptosis.

High shear stress that develops in the arteriovenous fistula of chronic kidney diseases (CKD) may increase H2O2 and thromboxane A2 (TXA2) release, thereby exacerbating endothelial dysfunction, thrombosis, and neointimal hyperplasia. We investigated whether glucagon-like peptide-1 receptor agonist/exendin-4, a potentially cardiovascular protective agent, could improve TXA2-induced arteriovenous fistula injury in CKD. TXA2 administration to H2O2-exposed human umbilical vein endothelial cells increased apoptosis, senescence, and detachment; these phenotypes were associated with the downregulation of phosphorylated endothelial nitric oxide synthase/heme oxygenase-1 (eNOS/HO-1) signalling. Exendin-4 reduced H2O2/TXA2-induced endothelial injury via inhibition of apoptosis-related mechanisms and restoration of phosphorylated eNOS/HO-1 signalling. Male Wistar rats subjected to right common carotid artery-external jugular vein anastomosis were treated with exendin-4 via cervical implant osmotic pumps for 16-42 days. High shear stress induced by the arteriovenous fistula significantly increased venous haemodynamics, blood and tissue H2O2 and TXB2 levels, macrophage/monocyte infiltration, fibrosis, proliferation, and adhesion molecule-1 expression. Apoptosis was also increased due to NADPH oxidase gp91 activation and mitochondrial Bax translocation in the proximal end of the jugular vein of CKD rats. Exendin-4-treatment of rats with CKD led to the restoration of normal endothelial morphology and correction of arteriovenous fistula function. Exendin-4 treatment or thromboxane synthase gene deletion in CKD mice markedly reduced ADP-stimulated platelet adhesion to venous endothelium, and prevented venous occlusion in FeCl3-injured vessels by upregulation of HO-1. Together, these data reveal that the use of glucagon-like peptide-1 receptor agonists is an effective strategy for treatment of CKD-induced arteriovenous fistula failure.

Increased oxidative stress induces inflammation to several tissues/organs leading to cell death and long-term injury. Traditional Chinese Medicine (TCM) with antioxidant, anti-inflammatory, anti-apoptotic, and autophagic regulatory functions has been widely used as preventive or therapeutic strategy in modern medicine. Oxidative stress and inflammation have been widely reported to contribute to cigarette smoke-induced lung inflammation, hepatotoxicity, or sympathetic activation-induced liver inflammation, lipopolysaccharide-induced renal inflammation, and substance P-mediated neurogenic hyperactive bladder based on clinical findings. In this review, we introduce several evidences for TCM treatment including Monascus adlay (MA) produced by inoculating adlay (Cois lachrymal-jobi L. var. ma-yuen Stapf) with Monascus purpureus on lung injury, Amla (Emblica officinalis Gaertn. of Euphorbiaceae family) on hepatotoxin-induced liver inflammation, Virgate Wormwood Decoction (Yīn Chén Hāo tāng) and its active component genipin on sympathetic activation–induced liver inflammation, and green tea extract and its active components, catechins, or a modified TCM formula Five Stranguries Powder (Wǔ Lén Sǎn) plus Crataegi Fructus (Shān Zhā) on hyperactive bladder. The pathophysiologic and molecular mechanisms of TCM on ameliorating inflammatory diseases are discussed in the review.

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