The role of the heterochronic microRNA let-7 in the progression of aging

Aging results in reduced tissue homeostasis and declined ability to replace damaged cells by new functional ones. In many tissues, homeostasis and repair are supported by tissue-specific stem cells that induce to generate differentiated cells in accordance with physiological requirements. Heterochronic genes, initially described in worms, specify the timing of fate decisions in each cell type and thus ensure a synchronized program of development throughout the animal. The heterochronic let-7 microRNA plays an important role in development by repressing cell fate regulators to promote stage progression. Recent studies reveal a new role of let-7 which occurs much later in life and regulates aging of several tissues, across species. In this article I review the current knowledge on the fate mechanisms of tissue stem cells during aging that are modulate by let-7, as well as its co-partners and its target genes. I also discuss the therapeutic potential of controlling heterochronic events as a possible treatment for aging‐related disorders. Timing is a clear dimension of organisms' development that may be difficult to witness in aging stages that are not as defined as in embryonic development. Exploring the regulation of stem cell aging by let-7 may ultimately reveal novel timing mechanisms.     

Vaccination with autoantigen protects against aggregated beta-amyloid and glutamate toxicity by controlling microglia: effect of CD4+CD25+ T cells

Neurodegenerative diseases differ in etiology but are propagated similarly. We show that neuronal loss caused by intraocular injection of aggregated beta-amyloid was significantly greater in immunodeficient mice than in normal mice. The neurodegeneration was attenuated or augmented by elimination or addition, respectively, of naturally occurring CD4(+)CD25(+) regulatory T cells (Treg). Vaccination with retina-derived antigens or with the synthetic copolymer glatiramer acetate (Copolymer-1, Cop-1), but not with beta-amyloid, reduced the ocular neuronal loss. In mouse hippocampal slices, microglia encountering activated T cells overcame the cytotoxicity of aggregated beta-amyloid. These findings support the concept of "protective autoimmunity", show that a given T cell-based vaccination is protective at a particular site irrespective of toxicity type, and suggest that locally activated T cells induce a microglial phenotype that helps neurons withstand the insult. Alzheimer's and other neurodegenerative diseases might be arrested or retarded by vaccination with Cop-1 or related compounds or by treatment with compounds that weaken Treg suppression.     

Gout and hyperlipidaemia. Effect of overweight on the levels of circulating lipids

A study of the serum lipids in 90 patients with gout and 90 controls matched for age and weight index demonstrated that in gout there was a significant elevation of the mean serum levels of cholesterol (282 +/- 55 mg/100 ml), triglycerides (183 +/- 161 mg/100 ml) and phospholipids (270 +/- 61 mg/100 ml) compared with the controls whose mean values were respectively 243 +/- 41 mg, 95 +/- 53 mg and 245 +/- 36 mg. Hyperlipidaemia of mixed type was the most common lipid defect in the patients with gout; there was no difference in the frequency of pure hypercholesterolaemia (without hypertriglyceridaemia) between gout and the controls. The frequency of anomalies of blood lipid levels in gout does not result from (or not solely from) obesity since patients with gout and controls were matched for their weight and height. There was a correlation between the serum lipid levels and obesity in the controls but this was not demonstrable in the patients with gout.     

Multiple adaptive mechanisms to chronic liver disease revealed at early stages of liver carcinogenesis in the Mdr2-knockout mice

Molecular events preceding the development of hepatocellular carcinoma were studied in the Mdr2-knockout (Mdr2-KO) mice. These mice lack the liver-specific P-glycoprotein responsible for phosphatidylcholine transport across the canalicular membrane. Portal inflammation ensues at an early age followed by hepatocellular carcinoma development after the age of 1 year. Liver tissue samples of Mdr2-KO mice in the early and late precancerous stages of liver disease were subjected to histologic, biochemical, and gene expression profiling analysis. In an early stage, multiple protective mechanisms were found, including induction of many anti-inflammatory and antioxidant genes and increase of total antioxidant capacity of liver tissue. Despite stimulation of hepatocyte DNA replication, their mitotic activity was blocked at this stage. In the late stage of the disease, although the total antioxidant capacity of liver tissue of Mdr2-KO mice was normal, and inflammation was less prominent, many protective genes remained overexpressed. Increased mitotic activity of hepatocytes resulted in multiple dysplastic nodules, some of them being steatotic. Expression of many genes regulating lipid and phospholipid metabolism was distorted, including up-regulation of choline kinase A, a known oncogene. Many other oncogenes, including cyclin D1, Jun, and some Ras homologues, were up-regulated in Mdr2-KO mice at both stages of liver disease. However, we found no increase of Ras activation. Our data suggest that some of the adaptive mechanisms induced in the early stages of hepatic disease, which protect the liver from injury, could have an effect in hepatocarcinogenesis at later stages of the disease in this hepatocellular carcinoma model.     

The psychological profile and affective response of women diagnosed with unexplained infertility undergoing in vitro fertilization

It has been hypothesized that unexplained infertility may be related to specific personality and coping styles. We studied two groups of women with explained infertility (EIF, n?=?63) and unexplained infertility (UIF, n?=?42) undergoing an in vitro fertilization (IVF) cycle. Women completed personality and coping style questionnaires prior to the onset of the cycle, and state depression and anxiety scales before and at two additional time points during the cycle. Almost no in-between group differences were found at any of the measured time points in regards to the Minnesota Multiphasic Personality Inventory-2 validity and clinical scales, Illness Cognitions and Life Orientation Test, or for the situational measures. The few differences found suggest a more adaptive, better coping, and functioning defensive system in women with EIF. In conclusion, we did not find any clinically significant personality differences or differences in depression or anxiety levels between women with EIF and UIF during an IVF cycle. Minor differences found are probably a reaction to the ambiguous medical situation with its uncertain prognosis, amplifying certain traits which are not specific to one psychological structure but rather to the common experience shared by the group. The results of this study do not support the possibility that personality traits are involved in the pathophysiology of unexplained infertility.     

Modulation of hepatitis C virus release by the interferon-induced protein BST-2/tetherin

Hepatitis C virus is a leading cause of chronic hepatitis and liver cancer. Little information exists on the interplay between innate defense mechanisms and viral antagonists that promote viral egress. Herein, the effects of Tetherin/BST-2 on HCV release were investigated. In Huh-7.5 hepatocytes, low expression levels of BST-2 were detected. Treatment of Huh-7.5 cells with IFNα, elevated BST-2 expression levels. However, HCV could not alter the expression of IFNα-induced BST-2, nor of stably over-expressed BST-2. Significantly, over expressed BST-2 moderately blocked HCV production and release from Huh-7.5 cells. Functional analysis of BST-2, confirmed its ability to inhibit the release of HIV delta-Vpu from Huh-7.5-BST-2 cells. HIV-Vpu antagonized BST-2 activity and rescued HIV delta-Vpu release from Huh-7.5-BST-2 cells. However, vpu slightly rescued HCV release and production from Huh-7.5-BST-2. We conclude that BST-2 moderately restricts HCV production and release from Huh-7.5 hepatocytes, while the virus lacks mechanisms to counteract this restriction.     

Evaluating the effects of oseltamivir phosphate on platelet counts: a retrospective review

Abstract

Desialylation of platelets results in platelet clearance by the Ashwell-Morrell Receptors (AMR) found on hepatocytes. Studies suggest that oseltamivir phosphate inhibits human sialidases, enzymes responsible for desialylation, extending the lifespan of circulating platelets. We thus evaluated, the effects of oseltamivir on platelet count (PC) following treatment. Of the 385 patients evaluated for influenza, 283 (73.5%) were influenza-infected. Of the 283 infected patients, 241 (85.2%) received oseltamivir (I + O+) while 42 patients did not (I + O-). One hundred two non-infected patients received oseltamivir (I-O+). The two groups receiving oseltamivir (I + O+, I-O+), demonstrated a statistically greater increase in the PC (57.53 ± 93.81, p = .013 and 50.79 ± 70.59, p = .023, respectively) relative to the group that did not (18.45 ± 89.33 × 10⁹/L). The observed increase in PC was statistically similar (p = .61) in both groups receiving oseltamivir (I + O+, I-O+), suggesting that this effect is independent of influenza. Comparing clinical characteristics between responders and non-responders to oseltamivir treatment showed that only duration of oseltamivir treatment (AOR = 1.30, 95% CI 1.05–1.61, p = .015) was associated with a positive PC response. Our findings suggest a correlation between oseltamivir treatment and an increase in PCs. Future studies assessing the possible uses of oseltamivir in medical conditions characterized by diminished or defective thrombopoiesis are warranted.