Disrupting Mechanisms that Regulate Genomic Repeat Elements to Combat Cancer and Drug Resistance.

Despite advancements in understanding cancer pathogenesis and the development of many effective therapeutic agents, resistance to drug treatment remains a widespread challenge that substantially limits curative outcomes. The historical focus on genetic evolution under drug "pressure" as a key driver of resistance has uncovered numerous mechanisms of therapeutic value, especially with respect to acquired resistance. However, recent discoveries have also revealed a potential role for an ancient evolutionary balance between endogenous "viral" elements in the human genome and diverse factors involved in their restriction in tumor evolution and drug resistance. It has long been appreciated that the stability of genomic repeats such as telomeres and centromeres affect tumor fitness, but recent findings suggest that de-regulation of other repetitive genome elements, including retrotransposons, might also be exploited as cancer therapy. This review aims to present an overview of these recent findings.

Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice.

Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL/6 mice. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically relevant measurements. We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits. By simultaneously reducing frailty and enhancing longevity, AKG, at least in the murine model, results in a compression of morbidity.

Chemical activation of a food deprivation signal extends lifespan.

Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology.

Benefit of Aloe vera and Matricaria recutita mixture in rat irritable bowel syndrome: Combination of antioxidant and spasmolytic effects.

OBJECTIVE: To evaluate the beneficial effects of a mixture of Aloe vera (AV) and Matricaria recutita (German chamomile, GC) in an experimental model of irritable bowel syndrome (IBS). METHODS: IBS was induced by a 5-day restraint stress in rats including the groups of control (water), GC (300 mg/kg), loperamide (10 mg/kg), mixed AV and GC (50: 50 at doses of 150, 300 or 450 mg/kg assigned as Mix-150, Mix-300 and Mix-450, respectively) and the sham group which did not receive any restraint stress and was fed with saline. All medications were administered intragastrically by gavage for 7 days, 2 days as pre-treatment followed by 5 days during induction of IBS every day before restraining. RESULTS: The increased tumor necrosis factor alpha (TNF-α), myeloperoxidase (MPO) activity, and lipid peroxidation (LPO) in colonic cells in the control group were significantly decreased in the treatment groups. GC inhibited only small bowel transit while the AV/GC mixture delayed gastric emptying at the doses of 150 and 300 mg/kg. The AV/GC mixture also reduced colonic transit and small bowel transit at the dose of 150 mg/kg. CONCLUSIONS: The severity of stress-induced IBS was diminished by the AV/GC mixture at all doses used but not dose-dependently, via inhibiting colonic MPO activity and improving oxidative stress status. The effect of the mixture was more effective than GC alone. The present results support effectiveness of the AV and GC combination in IBS.

Effects of Hypericum perforatum extract on rat irritable bowel syndrome.

CONTEXT: In irritable bowel syndrome (IBS), disturbance of bowel motility is associated with infiltration of inflammatory mediators and cytokines into the intestine, such as neutrophils, myeloperoxidase (MPO), tumor necrosis factor alfa (TNF-α), and lipid peroxide. AIMS: Regarding promising anti-inflammatory and anti-oxidative effects of Hypericum perforatum (HP) extract, besides its anti-depressant effect, this study was designed to evaluate the effects of HP in an experimental model of IBS. SETTINGS AND DESIGN: IBS was induced by a 5-day restraint stress in rats. The HP extract was administered by gavage in doses of 150, 300, and 450 mg/kg for 26 days. Fluoxetine and loperamide were used as positive controls. Gastric emptying and small bowel and colon transit, besides the levels of TNF-α, MPO, lipid peroxidation, and antioxidant power, were determined in colon homogenates. STATISTICAL ANALYSIS USED: Data were analyzed by one-way ANOVA followed by Tukey's post hoc test for multiple comparisons. RESULTS: A significant reduction in small bowel and colonic transit (450 mg/kg), TNF-α, MPO, and lipid peroxidation and an increase in antioxidant power in all HP-treated groups (150, 300, and 450 mg/kg) were seen as compared with the control group. Gastric emptying did not alter significantly when compared with the control group. Treatment with loperamide (10 mg/kg) significantly inhibited gastric emptying and small bowel and colonic transit, while flouxetine (10 mg/kg) decreased gastric emptying, TNF-α, MPO, and lipid peroxidation and increased the antioxidant power of the samples in comparison with the control group. CONCLUSIONS: HP diminished the recruitment of inflammatory cells and TNF-α following restraint stress not in a dose-dependent manner, possibly via inhibition of MPO activity and increasing colon antioxidant power, without any difference with fluoxetine. The HP extract inhibits small bowel and colonic transit acceleration like loperamide but has minimal effect on gastric emptying.