Current Molecular Medicine (v.11, #5)

The Effects of Weightlessness on the Human Organism and Mammalian Cells by J. Pietsch, J. Bauer, M. Egli, M. Infanger, P. Wise, C. Ulbrich, D. Grimm (350-364).
It has always been a desire of mankind to conquest Space. A major step in realizing this dream wasthe completion of the International Space Station (ISS). Living there for several months confirmed earlyobservations of short-term spaceflights that a loss of gravity affects the health of astronauts. Space medicinetries to understand the mechanism of microgravity-induced health problems and to conceive potentcountermeasures. There are four different aspects which make space medicine appealing: i) finding betterstrategies for adapting astronauts to weightlessness; ii) identification of microgravity-induced diseases (e.g.osteoporosis, muscle atrophy, cardiac problems and others); iii) defining new therapies to conquer thesediseases which will benefit astronauts as well as people on Earth in the end; and iv) on top of that, unveilingthe mechanisms of weightlessness-dependent molecular and cellular changes is a requirement for improvingspace medicine. In mammalian cells, microgravity induces apoptosis and alters the cytoskeleton and affectssignal transduction pathways, cell differentiation, growth, proliferation, migration and adhesion.This review focused on gravi-sensitive signal transduction elements and pathways as well as molecularmechanisms in human cells, aiming to understand the cellular changes in altered gravity. Moreover, the latestinformation on how these changes lead to clinically relevant health problems and current strategies ofcountermeasures are reviewed.

Accumulating evidence suggests that the success of some anticancer therapies not only relies ontheir direct cytotoxicity on tumor cells but also on their ability to promote anticancer immune responses.However, immunosuppressive cells such as Myeloid Derived Suppressor Cells (MDSC) that are generatedduring tumor progression blunt antitumor immune responses and thus represent a major obstacle to the clinicalimplementation of immunotherapy protocols. We have recently identified 5-Fluorouracil (5-FU) as ananticancer agent that selectively induced MDSC apoptotic cell death in vitro and in vivo. The elimination ofMDSC by 5-FU increased IFN.. secretion by tumor specific CD8+ T cells infiltrating the tumor and promoted Tcelldependent antitumor responses in vivo, suggesting that some anticancer therapies can reverse tumormediatedimmunosuppression. Here, we review the molecular pathways leading to the induction of MDSC incancer and discuss how different anticancer agents successfully target these cells in vivo, thereby restoringpotent anticancer immunity.

Hepatitis C Virus, Oxidative Stress and Steatosis: Current Status and Perspectives by J. Gonzalez-Gallego, M.V. Garcia-Mediavilla, S. Sanchez-Campos (373-390).
Reactive oxygen and nitrogen species (ROS/RNS), whether produced endogenously as aconsequence of normal cell functions or derived from external sources, pose a constant threat to cells living inan aerobic environment. When the production of ROS/RNS overrides the antioxidant capability of the targetcells, oxidative damage may occur as a consequence of the interaction with DNA, protein, and lipids. HepatitisC virus (HCV) is a major cause of viral hepatitis. Although the molecular mechanisms of HCV pathogenesisremain unclear, oxidative stress is emerging as a key step and a major initiator in the development and theprogression of liver damage, and the evaluation of oxidative stress may be useful for a better understanding ofthe pathogenesis of hepatitis C. Liver steatosis is one of the most important histopathological features inpatients with chronic hepatitis C. Both viral and host factors contribute to the development of steatosis, andputative defects caused by ROS/RNS may be involved through abnormalities in lipid metabolism. This reviewis aimed to offer an updated overview of the relationship between oxidative stress and HCV infection, focusingon the significance of ROS/RNS in the pathogenesis of liver disease. The potential role played by oxidativestress in the pathogenic mechanisms of HCV-related steatosis is also discussed.

Atherosclerotic vascular disease, diabetes mellitus (DM) and dementia are major global healthproblems. Both endogenous and exogenous factors activate genes functioning in biological processes. Thisreview article focuses on gene-activation mechanisms that regress atherosclerosis, eliminate DM type 2(DM2), and prevent cognitive decline and dementia.Gene-activating compounds upregulating functions of liver endoplasmic reticulum (ER) and affecting lipid andprotein metabolism, increase ER size through membrane synthesis, and produce an antiatherogenic plasmalipoprotein profile. Numerous gene-activators regress atherosclerosis and reduce the occurrence ofatherosclerotic disease. The gene-activators increase glucose disposal rate and insulin sensitivity and, byrestoring normal glucose and insulin levels, remove metabolic syndrome and DM2. Patients with DM2 show animprovement of plasma lipoprotein profile and glucose tolerance together with increase in liver phospholipid(PL) and cytochrome (CYP) P450. The gene-activating compounds induce hepatic protein and PL synthesis,and upregulate enzymes including CYPs and glucokinase, nuclear receptors, apolipoproteins and ABC (ATPbindingcassette) transporters. They induce reparation of ER structures and eliminate consequences of ERstress. Healthy living habits activate mechanisms that maintain high levels of HDL and apolipoprotein AI,promote health, and prevent cognitive decline and dementia. Agonists of liver X receptor (LXR) reduce amyloidin brain plaques and improve cognitive performance in mouse models of Alzheimer`s disease.The gene activation increases the capacity to withstand cellular stress and to repair cellular damage andincreases life span. Life free of major health problems and in good cognitive health promotes well-being andliving a long and active life.

Osteoprotegerin and Diabetes-Associated Pathologies by A.M. Blazquez-Medela, J.M. Lopez-Novoa, C. Martinez-Salgado (401-416).
Osteoprotegerin (OPG) is a member of the tumour necrosis factor receptor superfamily of cytokineswhich, in spite of being initially described as a strong anti-resorptive factor, has lately been considered as apossible link between bone and vascular disease. In the last few years, several studies have evidenced itsclose relationship with the development of diabetes. In this review, we analyse the role of OPG in diabeticpatients and its links with the most relevant associated diseases such as atherosclerosis, hypertension,endothelial dysfunction and diabetic nephropathy, as well as its connection with related pathologies as fibrosis,obesity and metabolic syndrome.

Bitter gourd (Momordica charantia, BG) is both a nutritious and healthy food with a distinctive bitterflavor, and it is also widely exploited in folklore medicine. This review focuses on the efficacies and molecularmechanisms of BG-induced anti-diabetic, anti-HIV, and antitumor activities contributed by over twenty activecomponents. The intent of this review is to provide comprehensive and valuable information for medicinalresearchers, drug investigators, clinicians, and even patients with an interest in BG. In conclusion, BG is acornucopia of health and it deserves in-depth investigations for clinical application in the future.