The epidemic of heart failure has stimulated interest in understanding cardiac regeneration. Evidence has been reported supporting regeneration via transplantation of multiple cell types, as well as replication of postmitotic cardiomyocytes. In addition, the adult myocardium harbors endogenous c-kit(pos) cardiac stem cells (eCSCs), whose relevance for regeneration is controversial. Here, using different rodent models of diffuse myocardial damage causing acute heart failure, we show that eCSCs restore cardiac function by regenerating lost cardiomyocytes. Ablation of the eCSC abolishes regeneration and functional recovery. The regenerative process is completely restored by replacing the ablated eCSCs with the progeny of one eCSC. eCSCs recovered from the host and recloned retain their regenerative potential in vivo and in vitro. After regeneration, selective suicide of these exogenous CSCs and their progeny abolishes regeneration, severely impairing ventricular performance. These data show that c-kit(pos) eCSCs are necessary and sufficient for the regeneration and repair of myocardial damage.
Key Words: vascular smooth muscle cells Ⅲ microRNA Ⅲ miR-133 Ⅲ smooth muscle differentiation Ⅲ vascular remodeling V ascular smooth muscle cells (VSMCs) within adult blood vessels proliferate at a very low rate, exhibit very low synthetic activity, and express a unique repertoire of contractile proteins, ion channels, and signaling molecules. 1 Unlike skeletal muscle and cardiac muscle, which consist of terminally differentiated cells, adult VSMCs retain remarkable plasticity and can undergo rather profound and reversible changes in phenotype and growth properties in response to changes in local environmental cues. Salient examples of VSMC plasticity can be seen in response to vascular injury when VSMCs dramatically increase their proliferation, migration, and synthetic capacity, playing a critical role in vascular repair. 1,2 A detrimental consequence of the high degree of plasticity exhibited by adult VSMCs is that it can lead to an adverse phenotypic switch and acquisition of characteristics that can contribute to development or progression of vascular disease in humans, including atherosclerosis, restenosis, cancer, and hypertension. [1][2][3] VSMC phenotypic modulation is characterized by significant changes in gene expression patterns, matrix and cytokine production, contractility, and growth state, ultimately leading to their switch from a synthetic to a proliferative phenotype.Original received January 3, 2011; revision received August 8, 2011; accepted August 9, 2011. In July 2011, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.5 days.From Thus, understanding the regulatory mechanisms underlying the VSMC phenotypic switch is of paramount importance. [1][2][3] One of the key breakthroughs for the study of gene expression regulation has recently been the discovery of microRNAs (miRNAs or miRs) and their role in gene silencing through mRNA degradation or translational inhibition. 4,5 Increasing evidence indicates that miRNAs regulate key genetic programs in cardiovascular biology, physiology, and disease. 4,5 In particular, miR-21, -143, -145, -221, -222 have all been implicated to play a role in VSMC function and phenotypic plasticity. 6 -11 More recently, 2 articles demonstrated that miR-1 is induced by myocardin overexpression in human SMCs, contributing to myocardin-dependent reduction of human SMC growth in vitro. 12,13 miR-133a-1/miR-1-2 and miR133a-2/miR-1-1 are 2 bicistronic miRNA clusters reported to be specifically expressed in cardiac and skeletal muscle. 4,5 A third bicistronic miRNA cluster, comprising miR-206 and miR-133b, is expressed specifically in skeletal muscle but not in the heart. 4,5 miR-1 (miR-1-1/miR-1-2) and miR-133 (miR133a-1/miR-133a-2) play essential roles in cardiac and skeletal muscle development, physiology, and disease 4,5 ; however, their functions in VSMCs and vascular disease are largely unknown. Thus, the aim of the present study was to evaluate the role, if any, of miR-1 and miR-133 in V...
Multiple cornerstones have shaped the history of vaccines, which may contain live-attenuated viruses, inactivated organisms/viruses, inactivated toxins, or merely segments of the pathogen that could elicit an immune response. The story began with Hippocrates 400 B.C. with his description of mumps and diphtheria. No further discoveries were recorded until 1100 A.D. when the smallpox vaccine was described. During the eighteenth century, vaccines for cholera and yellow fever were reported and Edward Jenner, the father of vaccination and immunology, published his work on smallpox. The nineteenth century was a major landmark, with the “Germ Theory of disease” of Louis Pasteur, the discovery of the germ tubercle bacillus for tuberculosis by Robert Koch, and the isolation of pneumococcus organism by George Miller Sternberg. Another landmark was the discovery of diphtheria toxin by Emile Roux and its serological treatment by Emil Von Behring and Paul Ehrlih. In addition, Pasteur was able to generate the first live-attenuated viral vaccine against rabies. Typhoid vaccines were then developed, followed by the plague vaccine of Yersin. At the beginning of World War I, the tetanus toxoid was introduced, followed in 1915 by the pertussis vaccine. In 1974, The Expanded Program of Immunization was established within the WHO for bacille Calmette–Guerin, Polio, DTP, measles, yellow fever, and hepatitis B. The year 1996 witnessed the launching of the International AIDS Vaccine Initiative. In 1988, the WHO passed a resolution to eradicate polio by the year 2000 and in 2006; the first vaccine to prevent cervical cancer was developed. In 2010, “The Decade of vaccines” was launched, and on April 1st 2012, the United Nations launched the “shot@Life” campaign. In brief, the armamentarium of vaccines continues to grow with more emphasis on safety, availability, and accessibility. This mini review highlights the major historical events and pioneers in the course of development of vaccines, which have eradicated so many life-threatening diseases, despite the vaccination attitudes and waves appearing through history.
The co-occurrence of the three disease entities, inflammatory bowel disease (IBD), colorectal cancer (CRC), type 2diabetes mellitus (T2DM) along with inflammation and dismicrobism has been frequently reported. Some authors have even suggested that dysbiosis could be the link through a molecular crosstalk of multiple inflammatory loops including TGFβ, NFKB, TNFα and ROS among others.This review focuses on the inflammatory process along with the role of microbiota in the pathophysiology of the three diseases.The etiology of IBD is multifactorial, and like CRC and T2DM, it is associated with a widespread and sustained GI inflammation and dismicrobism, whereby an array of pro-inflammatory mediators and other related biomolecules are up-regulated, both locally and systematically. Such a persistent or an inadequately resolved chronic inflammation may be a causative agent, in the presence other factors, leading to several pathologies such as IBD, CRC and T2DM.TGFβ plays a crucial role in pancreatic β cell malfunctioning as glucotoxicity stimulates its signaling cascade through smad 3, IL-6 and epithelial to mesenchymal transition. Such a cascade could lead to macrophages and other cells recruitment, inflammation, then IBD and CRC.NFkB is also another key regulator in the crosstalk among the pathways leading to the three disease entities. It plays a major role in linking inflammation to cancer development through its ability to up regulate several inflammatory and tumor promoting cytokines like: IL-6, IL-1 α and TNF α, as well as genes like BCL2 and BCLXL. It activates JAK/STAT signaling network via STAT3 transcription factors and promotes epithelial to mesenchymal transition. It also increases the risk for T2DM in obese people. In brief, NFKB is a matchmaker between inflammation, IBD, cancer and diabetes.In addition, TNFα plays a pivotal role in systemic inflammation. It is increased in the mucosa of IBD patients and has a central role in its pathogenesis. It also activates other signaling pathways like NFKB and MAPK leading to CRC. It is also overexpressed in the adipose tissues of obese patients thus linking it to T2DM, chronic inflammation and consequently CRC.On the other hand, increasing evidence suggests that dysbiosis plays a role in initiating, maintaining and determining the severity of IBD. Actually, among its functions, it modulates genotoxic metabolites which are able to induce CRC, a fact proven to be sustained by stool transfer from patients with CRC. Probiotics, however, may actively prevent CRC as well as IBD and results in a significant decrease in fasting glycemia in T2DM patients.In conclusion, IBD, CRC and T2DM are commonly occurring interrelated clinical problems. They share a common basis influenced by an inflammatory process, an imbalance in intestinal microbiota, and a crosstalk between various signaling pathways. Would probiotics interrupt the crosstalk or orient it in the physiological direction?
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