PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer's disease mice with cerebral microinfarcts.

Background: Current evidence suggests that microvessel disease is involved in Alzheimer's disease (AD). Cerebrovascular disease correlates with cardiovascular disease and is complicated in ≈40% of AD patients. The protein kinase C (PKC) ε activator DCPLA can stimulate human antigen (Hu) R that prevents degradation and promotes the translation of mitochondrial Mn-superoxide dismutase (MnSOD) and vascular endothelial growth factor-A (VEGF) mRNAs.

Association of Apolipoprotein E4-related Microvascular Disease in the Alzheimer's Disease Hippocampal CA1 Stratum Radiatum.

Current data suggest a hypothesis of vascular pathogenesis for the development and progression of Alzheimer's disease (AD). To investigate this, we studied the association of apolipoprotein E4 (APOE4) gene on microvessels in human autopsy-confirmed AD with and without APOE4, compared with age/sex-matched control (AC) hippocampal CA1 stratum radiatum. AD arterioles (without APOE4 gene) had mild oxidative stress and loss of vascular endothelial growth factor (VEGF) and endothelial cell density, reflecting aging progression.

HIV Promotes Neurocognitive Impairment by Damaging the Hippocampal Microvessels.

Current evidence suggests that mild cerebrovascular changes could induce neurodegeneration and contribute to HIV-associated neurocognitive disease (HAND) in HIV patients. We investigated both the quantitative and qualitative impact of HIV infection on brain microvessels, especially on hippocampal microvessels, which are crucial for optimal O supply, and thus for maintaining memory and cognitive abilities. The results obtained using cultured human brain microvascular endothelial cells (HBMEC) were reproduced using a suitable mouse model and autopsied human HIV hippocampus.

PKCε Activation Restores Loss of PKCε, Manganese Superoxide Dismutase, Vascular Endothelial Growth Factor, and Microvessels in Aged and Alzheimer's Disease Hippocampus.

Vascular endothelial dysfunction and capillary loss are currently considered to be a primary phenotype of normal human aging and Alzheimer's disease (AD). Activation of protein kinase C (PKCε) improves several molecular, cellular, physiological, and behavioral endpoints, yet it is not known whether a loss of PKCε activity occurs in the microvascular endothelium in aged and AD hippocampi, whether this loss contributes to microvascular change, or whether activation of PKCε protects against microvascular damage, an early change that induces age-associated memory defect and AD. We investigated the effect of the PKCε activation on microvascular loss in the hippocampus, important for memory storage.

Resveratrol Improves Recovery and Survival of Diet-Induced Obese Mice Undergoing Extended Major (80%) Hepatectomy.

Introduction: Loss of hepatic epidermal growth factor receptor (EGFR) expression is a cause for the increased perioperative risk for complications and death in patients with obesity and fatty liver undergoing liver resection. Herein, we set out to identify agents that might increase EGFR expression and improve recovery for patients with fatty liver undergoing resection. Using the diet-induced obese (DIO) mouse model of fatty liver, we examined resveratrol as a therapy to induce EGFR expression and improve outcomes following 80% partial hepatectomy (PH) in a murine model.

Meloxicam increases epidermal growth factor receptor expression improving survival after hepatic resection in diet-induced obese mice.

Background: Patients with fatty liver have delayed regenerative responses, increased hepatocellular injury, and increased risk for perioperative mortality. Currently, no clinical therapy exists to prevent liver failure or improve regeneration in patients with fatty liver. Previously we demonstrated that obese mice have markedly reduced levels of epidermal growth factor receptor in liver.

Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice.

Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction.

JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia.

Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass.

Interleukin-6 is an important in vivo inhibitor of intestinal epithelial cell death in mice.

Background And Aims: Interleukin-6 (IL-6) is a well-recognised mediator of liver disease and regeneration. However, the in vivo effects of IL-6 on enterocytes and the intestinal tract have not been elucidated. We sought to determine the in vivo effects of IL-6 on enterocytes.

Interleukin-6 inhibits oxidative injury and necrosis after extreme liver resection.

Unlabelled: Extreme hepatectomy or resection of more than 80% of liver mass often leads to liver failure and death and is a major limitation to therapeutic liver resection for patients with liver tumors. We sought to define the mechanisms leading to liver failure and to determine the utility of interleukin-6 (IL-6) administration to improve outcomes. Mice were injected with Chinese hamster ovary cells expressing human IL-6 or no recombinant protein, or were administered recombinant IL-6 or carrier by osmotic mini-pump.

Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair.

Interleukin-6 (IL-6) is an important mediator of liver regeneration and repair that is also elevated in chronic liver diseases, including fatty liver of obesity and cirrhosis. IL-6 has been reported both to delay and accelerate liver regeneration. We examined the effects on liver injury and regeneration of a continuous administration of exogenous IL-6 to mice by injection of an IL-6-expressing CHO-cell line in athymic nude mice and by osmotic mini-pump delivery of recombinant murine IL-6.