Cell-based therapy for management of osteoarthritis

Osteoarthritis(OA)is a most common form of degenerative joint disease,primarily characterized by the degradation of articular cartilage,subchondral sclerosis and inflammation of the synovial membrane.Mesenchymal stem cells(MSCs),a multipotent adult stem cell population,can be isolated from many connective tissue lineages,including those of the diarthrodial joint.Joint-resident MSCs or MSC-like progenitor cells contribute to the maintenance of healthy microenvironment or to the response to trauma.The onset of degenerative changes in the joint related to abnormal condition or depletion of these endogenous MSCs and native host hyaline cartilage cells,leading to limited selfrepair potential of the joint and advance of the degradation.To date,no acknowledged medical treatment strategies,including non-operative and classical surgical techniques,are efficient in restoring normal anatomy and function of hyaline cartilage in OA.This highlights an urgent need for better celled-based therapeutic strategies that supplement these functional cel s exogenously to recover the tissue homeostasis and repair in joint cavity via chondrogenic and anti-in fl ammatory functions.In this review we focus on the role of native MSCs in healthy or OA joint and recent progress in cel-based researches utilizing culture-expanded chondrocytes,pluripotent stem cel s,or MSCs from different sources for treating OA.     

Metabolic therapy: lessons from liver diseases

Fatty liver disease is one of most prevalent metabolic liver diseases, which includes alcoholic (ASH) and nonalcoholic steatohepatitis (NASH). Its initial stage is characterized by fat accumulation in the liver, that can progress to steatohepatitis, a stage of the disease in which steatosis is accompanied by inflammation, hepatocellular death, oxidative stress and fibrosis. Recent evidence in experimental models as well as in patients with steatohepatitis have uncovered a role for cholesterol and sphingolipids, particularly ceramide, in the transition from steatosis to steatohepatitis, insulin resistance and hence disease progression. Cholesterol accumulation and its trafficking to mitochondria sensitizes fatty liver to subsequent hits including inflammatory cytokines, such as TNF/Fas, in a pathway involving ceramide generation by acidic sphingomyelinase (ASMase). Thus, targeting both cholesterol and/or ASMase may represent a novel therapeutic approach of relevance in ASH and NASH, two of the most common forms of liver diseases worldwide.     

Cell-based treatments for diabetes

In Type 1 diabetes mellitus the insulin-secreting beta-cells in pancreatic islets of Langerhans are selectively destroyed by autoimmune assault. Because diabetes is caused by the loss of a single cell type it is amenable to treatment by cell replacement therapy. Advances in islet transplantation procedures have demonstrated that people with Type 1 diabetes can be cured by human islet transplantation, but the severely limited availability of donor islets has restricted the widespread application of this approach, and driven the search for substitute transplant tissues. Recent experimental studies suggest that three separate sources of tissue show therapeutic potential - xenografts from other species, tissue stem cells and embryonic stem cells. Of these, xenografts are closest to clinical application but there are still major obstacles to be overcome. Insulin-expressing cells have been derived from a number of different stem cell populations but embryonic stem cells offer the major advantage of being able, in principle, to provide the vast numbers of cells required for transplantation therapy.     

Cell-based therapies for Huntington's disease

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Beneficial drugs for liver diseases

Liver diseases are a major problem of worldwide proportions. However, the number of drugs actually used successfully in humans is very small. In this review some of the most promising/studied drugs utilized for liver diseases were chosen and analysed critically from the basic to the clinical point of view. Antiviral agents are not discussed because excellent reviews have appeared on this topic. The compounds/preparations described herein are, alphabetically: colchicine, corticosteroids, curcumin, glycyrrhizin, interferons (for their antifibrotic properties), Liv 52, nitric oxide, resveratrol, silymarin, sulfoadenosylmethionine, and thalidomide. Colchicine and corticosteroids have been studied extensively in animals and humans; most clinical studies suggest that these compounds are not useful in the treatment of liver diseases. Glycyrrhizin is an herbal medicine with several components that has interesting hepatoprotective properties in patients with subacute liver failure but deserves more prospective controlled trials. Interferon has shown interesting antifibrotic properties in animals and humans; prospective studies on their antifibrotic/fibrolytic activity are required. Curcumin, resveratrol and thalidomide are very attractive newly discovered protective and curative compounds on experimental hepatic diseases. Their mechanism of action is associated with the ability to down-regulate NF-kappaB and to decrease pronecrotic and profibrotic cytokines. Unfortunately, clinical studies are lacking. Sulfoadenosylmethionine and silymarin are also promising drugs utilized mainly in cholestasis but the benefits can be expanded if more controlled trials are performed. The future is to carry out controlled prospective double-blind multicenter studies with the newly discovered drugs with proven beneficial effects on animals. Fundamental hepatobiology should also be encouraged.     

Anti-chemokine therapy for inflammatory diseases

Chemokines are inflammatory proteins acting via G-protein coupled chemokine receptors that trigger different signaling pathways. Monocyte chemoattractant protein-1 (CCL2/MCP-1) and regulated on activation, normal T expressed and secreted (CCL5/RANTES) are the two major members of the CC chemokine beta subfamily. The roles of RANTES and MCP-1 are emerging in regulating the recruitment of inflammatory cells into tissue during inflammation. The inhibition of MCP-1 and RANTES with corresponding antibodies or other inhibitors may provide benefits in different clinical scenarios including cancer, inflammation, CNS disorders, parasitic disease, autoimmune and heart diseases. RANTES and MCP-1 may represent targets for diagnostic procedures and therapeutic intervention, and may be useful as a prognostic factor in the above diseases.     

Gene therapy for cardiovascular diseases

Few disciplines in medicine will have as great an impact as molecular biology. Since the introduction of these techniques in cardiology multiple pathophysiologic pathways of cardiac diseases have been better elucidated. We have been very successful in prolonging life and providing better care for cardiac patients in the last 50 years. We could even consider that conventional therapy has reached its peak; but the new developments in molecular biology have sparked an increase in the knowledge of basic mechanisms of cardiac disease, which is likely to markedly improve diagnostic and therapeutic approaches. Nevertheless, it may be some time before we achieve a significant breakthrough in the therapy of these diseases, despite the progress in molecular and computational techniques. Gene therapy has not shown enthusiastic results, but we must be reminded that the application of these techniques to medicine is only the beginning.     

Glucocorticoid therapy for gastrointestinal diseases

Introduction: Glucocorticoids are widely used as anti-inflammatory and immunosuppressive agents in many immune-mediated gastrointestinal diseases. However, a number of undesirable side effects may occur and dictate continuous surveillance and monitoring to prevent complications.

Areas covered: This review of the English language literature identified on PubMed focuses on key aspects of glucocorticoid therapy in patients with gastrointestinal diseases, highlighting specific aspects of recognition and management of its secondary effects.

Expert opinion: Long-term cohort studies as well as placebo- and sham-controlled trials have evaluated the clinical efficacy, safety and tolerability of glucocorticoid therapy in many gastrointestinal diseases. Other immunosuppressive and biological therapies have made glucocorticoid therapy part of a broader arsenal of therapies. Newer compounds that carry less systemic toxicity and improved tolerability are increasingly used. For several gastrointestinal diseases, the role of the mucosal immunity is currently being explored and microscopic inflammation of the intestinal mucosa may have an important pathogenetic role. Glucocorticoid therapy, particularly with newer, safer compounds, may play an important new role in patients with altered motility and visceral hypersensitivity. The interplay of the gut microbiota and the host that contributes to the development of gut-associated lymphoid tissues and gut-specific immune responses will also undoubtedly be explored.     

Gene therapy for cardiovascular diseases

Gene therapy is a rapidly evolving field of medicine, which potentially offers new treatments for cardiovascular diseases. With the use of gene transfer methods it is possible to modify somatic cells in blood vessels and myocardium to overexpress or inhibit pathologically important proteins and achieve therapeutic effects. Prevention of restenosis after vascular interventions such as percutanous coronary angioplasty (PTCA), percutanous peripheral angioplasty (PTA) or stent implantation, prevention of venous graft failures and therapeutic angiogenesis are the major aims of experimental studies and clinical gene therapy. The promise of gene therapy in the treatment of cardiovascular diseases remains high. Experimental studies have established the proof of principle that gene transfer to cardiovascular system can achieve therapeutic effects. First human clinical trials provided initial evidence of the feasibility and safety of the novel therapy. There are also first successful reports on the prevention of neointimal hyperplasia and promotion of therapeutic angiogenesis in clinical trials. However, there are still important questions regarding utility, efficiency and safety of gene therapy in the treatment of cardiovascular diseases. In this review we discuss the rapid progress in cardiovascular gene therapy, the development of delivery systems and vectors, most promising therapeutic genes and results of the recent human clinical trials.     

Gene therapy for cardiovascular diseases

The advent of gene therapy techniques has made it possible to intervene in cardiovascular diseases by transferring an appropriate therapeutic gene to the relevant cells in humans. A number of preclinical efforts have begun to culminate in clinical studies for life threatening conditions like hypercholesterolaemia and ischaemic vascular disease. Other cardiovascular indications are under investigation, with late stage preclinical studies focusing on restenosis, transplant atherosclerosis and rejection, and various lipoprotein abnormalities. Several recent reviews have outlined the issues surrounding gene therapy in general [1,2]. This review will discuss gene transfer approaches designed specifically to treat diseases of the cardiovascular system, and relevant patents and patent applications.     

Cell-based therapy to promote angiogenesis in the brain following ischemic damage

Cell-based therapies are a novel approach for regeneration of microvasculature. We have shown that administration of CD34-positive cells, the rich cell fraction of endothelial progenitor cells, after stroke induces angiogenesis that results in enhanced endogenous neurogenesis and functional recovery in a murine model. Moreover, injury-induced neurogenesis occurs in the human brain following a stroke during the acute to sub-acute period. Based on these observations, clinical trials of cell therapies that aim to regenerate micro-circulation in the brain following a stroke are ongoing worldwide. This review summarizes the current basic research findings about the link between angiogenesis and neurogenesis in the post-stroke brain and introduces the ongoing clinical trials of cell-based therapies for patients that have suffered a stroke.     

Cell-based drug delivery

Drug delivery has been greatly improved over the years by means of chemical and physical agents that increase bioavailability, improve pharmacokinetic and reduce toxicities. At the same time, cell based delivery systems have also been developed. These possesses a number of advantages including prolonged delivery times, targeting of drugs to specialized cell compartments and biocompatibility. Here we'll focus on erythrocyte-based drug delivery. These systems are especially efficient in releasing drugs in circulations for weeks, have a large capacity, can be easily processed and could accommodate traditional and biologic drugs. These carriers have also been used for delivering antigens and/or contrasting agents. Carrier erythrocytes have been evaluated in thousands of drug administration in humans proving safety and efficacy of the treatments. Erythrocyte-based delivery of new and conventional drugs is thus experiencing increasing interests in drug delivery and in managing complex pathologies especially when side effects could become serious issues.