ABSTRACT
The novel isosteric ribavirin analogues were synthesized by two different ways. Some of them showed significant antiviral action against hepatitis C virus (HCV), herpes simplex (HCV-1) and influenza A virus comparable to that of ribavirin itself. The data obtained confirm the proposed theory of the ribavirin possible antiviral activity mechanism related with bioisosterism.
Subject(s)
Antiviral Agents/chemical synthesis , Ribavirin/analogs & derivatives , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Survival/drug effects , Chlorocebus aethiops , Hepacivirus/drug effects , Herpesvirus 1, Human/drug effects , Humans , Influenza A virus/drug effects , Ribavirin/chemical synthesis , Ribavirin/pharmacology , Vero CellsABSTRACT
Acute pyelonephritis is a potentially life-threatening infection of the upper urinary tract. Inflammatory response and the accompanying oxidative stress can contribute to kidney tissue damage, resulting in infection-induced intoxication that can become fatal in the absence of antibiotic therapy. Here, we show that pyelonephritis was associated with oxidative stress and renal cell death. Oxidative stress observed in pyelonephritic kidney was accompanied by a reduced level of mitochondrial B-cell lymphoma 2 (Bcl-2). Importantly, renal cell death and animal mortality were both alleviated by mitochondria-targeted antioxidant 10(6'-plastoquinonyl) decylrhodamine 19 (SkQR1). These findings suggest that pyelonephritis can be treated by reducing mitochondrial reactive oxygen species and thus by protecting mitochondrial integrity and lowering kidney damage.
Subject(s)
Antioxidants/pharmacology , Mitochondria/drug effects , Oxidative Stress/physiology , Plastoquinone/analogs & derivatives , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyelonephritis/drug therapy , Reactive Oxygen Species/metabolism , Rhodamines/pharmacology , Animals , Antioxidants/therapeutic use , Blotting, Western , Cells, Cultured , Drug Delivery Systems/methods , Escherichia coli , Immunohistochemistry , Microscopy, Electron, Scanning , Mitochondria/metabolism , Peroxidase/metabolism , Plastoquinone/pharmacology , Plastoquinone/therapeutic use , Pyelonephritis/pathology , Rats , Rhodamines/therapeutic useABSTRACT
BACKGROUND AIMS: Acute pyelonephritis is one of the most frequent infectious diseases of the urinary tract and a leading cause of kidney failure worldwide. One strategy for modulating excessive inflammatory responses in pyelonephritis is administration of mesenchymal multipotent stromal cells (MMSCs). METHODS: The putative protective effect of injection of MMSCs against experimental acute pyelonephritis was examined. We used in vivo experimental model of APN where bacteria are introduced in the bladder of rat. Three days after, intravenous injection of MMSCs was done. On the 7th day blood samples and kidneys were taken for further analysis. RESULTS: We found obvious signs of oxidative stress and inflammation in the kidney in acute pyelonephritis in rats. Particularly, pro-inflammatory cytokine tumor necrosis factor-α levels, malondialdehyde, nitrite and myeloperoxidase activity were significantly increased. Histologic evaluation revealed numerous attributes of inflammation and tissue damage in the kidney. Treatment with MMSCs caused a remarkable decrease of all of these pathologic signs in renal tissue. Also, activated leukocytes induced pre-conditioning-like signaling in MMSCs. We showed alterations of expression or activity of inducible nitric oxide synthase, transforming growth factor-ß, matrix metalloproteinase-2 and glycogen synthase kinase-3ß, which could mediate immunomodulation and protective effects of MMSCs. This signaling could be characterized as inflammatory pre-conditioning. CONCLUSIONS: The beneficial capacity of MMSCs to alleviate renal inflammation was more pronounced when pre-conditioned MMSCs were used. This approach could be used to prime MMSCs with different inflammatory modulators to enhance their engraftment and function in an immunoprotected fashion.
