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British Journal of Haematology Jun 2013Gaucher disease is an autosomal, recessively inherited, lysosomal storage disease, which has been associated with gammopathies and malignancies. This report represents... (Meta-Analysis)
Meta-Analysis Review
Gaucher disease is an autosomal, recessively inherited, lysosomal storage disease, which has been associated with gammopathies and malignancies. This report represents the results of a systematic review of the literature on the prevalence of monoclonal gammopathies and malignancies in Gaucher disease. A PubMed search identified 365 studies, of which 80 reported on concomitant Gaucher disease and malignancies and/or gammopathies (15 cohort/cross sectional studies, and 65 case reports/series). Based on these studies, we conclude that compared to the general population, Gaucher patients have an increased risk of cancer in general [pooled relative risk of 1·70 (95% confidence interval 1·27-2·31)], and multiple myeloma and haematological malignancies in particular (estimated risk between 25·0 and 51·1 and 3·5 and 12·7, respectively). In addition, an increased risk has been reported for hepatocellular carcinoma and renal cell carcinoma. Several factors have been hypothesized to play a role in the pathophysiology. These include: splenectomy, immune dysregulation, endoplasmic reticulum stress, genetic modifiers, altered iron metabolism and insulin resistance.
Topics: Gaucher Disease; Humans; Neoplasms; Paraproteinemias; Prevalence; Risk
PubMed: 23594419
DOI: 10.1111/bjh.12335 -
American Journal of Nephrology 2013Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is an important cause of chronic renal dysfunction with no effective clinical intervention. To further elucidate the... (Review)
Review
BACKGROUND/AIMS
Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is an important cause of chronic renal dysfunction with no effective clinical intervention. To further elucidate the mechanisms of renal cell apoptosis in CCN, all relevant in vivo studies on this subject were analyzed.
METHODS
We searched for in vivo studies on the mechanisms of CsA-induced renal cell apoptosis in Medline (1966-July 2010), Embase (1980-July 2010) and ISI (1986-July 2010). The studies were evaluated for their quality according to a set of in vivo standards, data extracted according to PICOS, and then synthesized.
RESULTS
Renal cell apoptosis was an important feature of CCN and an important factor of renal dysfunction. First, CsA could upregulate Fas/Fas ligand, downregulate Bcl-2/Bcl-XL, and increase caspase-1 and caspase-3. Second, it could induce oxidative stress and damage the antioxidant defense system. Third, it could increase endoplasmic reticulum stress protein in a dose- and time-dependent manner. Fourth, CsA could impair the urine concentration and decrease the expression of hypertonicity-induced genes. Fifth, CsA-induced renal cell apoptosis was significantly decreased by blocking the angiotensin II type 1 receptor using losartan.
CONCLUSIONS
The in vivo mechanisms for CCN are more complex than those found in vitro. CsA can induce renal cell apoptosis using five pathways in vivo and activated caspases might be the ultimate intersection of these pathways and the common intracellular pathway mediating apoptosis. These data provide new potential points for intervention and need to be confirmed by further studies.
Topics: Animals; Apoptosis; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Diseases
PubMed: 23295863
DOI: 10.1159/000345988 -
Experimental Diabetes Research 2012Diabetic nephropathy is a serious complication of diabetes mellitus, and its prevalence has been increasing worldwide. Therefore, there is an urgent need to identify a... (Review)
Review
Diabetic nephropathy is a serious complication of diabetes mellitus, and its prevalence has been increasing worldwide. Therefore, there is an urgent need to identify a new therapeutic target to prevent diabetic nephropathy. Autophagy is a major catabolic pathway involved in degrading and recycling macromolecules and damaged organelles to maintain intracellular homeostasis. The study of autophagy in mammalian systems is advancing rapidly and has revealed that it is involved in the pathogenesis of various metabolic or age-related diseases. The functional role of autophagy in the kidneys is also currently under intense investigation although, until recently, evidence showing the involvement of autophagy in the pathogenesis of diabetic nephropathy has been limited. We provide a systematic review of autophagy and discuss the therapeutic potential of autophagy in diabetic nephropathy to help future investigations in this field.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Diabetic Nephropathies; Endoplasmic Reticulum; Homeostasis; Humans; Hypoxia; Kidney; Mice; Microscopy, Electron; Nephrons; Oxidative Stress; Prevalence; Reactive Oxygen Species; Sirtuin 1; TOR Serine-Threonine Kinases
PubMed: 22028701
DOI: 10.1155/2012/628978 -
American Journal of Nephrology 2011Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is a major cause of chronic renal dysfunction and has no effective clinical interventions yet. (Review)
Review
BACKGROUND
Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is a major cause of chronic renal dysfunction and has no effective clinical interventions yet.
OBJECTIVE
To reveal the mechanisms of renal cell apoptosis in CCN, we analyzed all in vitro studies of such mechanisms.
METHODS
We collected all in vitro studies about the mechanisms of renal cell apoptosis induced by CsA in Medline (1966 to July 2010), Embase (1980 to July 2010) and ISI (1986 to July 2010), evaluated their quality according to in vitro standards and extracted data following the PICOS principles and synthesized the data.
RESULTS
First,CsA could upregulate Fas and Fas-L expression, increase FADD and apoptosis enzymes (caspase-2, -3, -4, -7, -8, -9 and -10) and downregulate the Bcl-2 and Bcl-xL. Second, CsA could induce oxidative stress and damage the antioxidant defense system. Third, CsA could increase the expression of HERP, GRP78 and CHOP. Fourth, CsA could induce renal cell apoptosis and increase their iNOS and p53 expression in cultured cells.
CONCLUSIONS
At least four pathways are involved in renal cell apoptosis induced by CsA in different cell species. Caspases might be their final common pathway in vitro. They might all provide potential points for interventions, but these need to be confirmed in vivo.
Topics: Animals; Apoptosis; Cyclosporine; Endoplasmic Reticulum Chaperone BiP; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases
PubMed: 21613783
DOI: 10.1159/000328584