Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporine A (CsA), a fungal undecapeptide, is the most common immunosuppressive drug used in organ transplantation and autoimmune diseases. However, nephrotoxicity is the major adverse effect of CsA use. The molecular mechanisms of CsA nephrotoxicity are not well characterized, but more recent studies suggest an involvement of angiotensin II (ANG II) and reactive oxygen species in the development of cyclosporine nephrotoxicity. Induction of heat shock proteins (HSPs) is one of the best-described cellular responses to heat stress, hypoxia, and exposure to oxidants. HSPs have beneficial roles in protein processing and protection against cell injury. There is emerging evidence that ANG II induces oxidative stress in vitro and in vivo. This study was thus designed to investigate the role of Angiotensin II type I (AT1) receptor antagonist, irbesartan, on CsA-induced nephrotoxicity. Five groups of rats were employed in this study: group 1 served as control, group 2 rats were treated with CsA (20 mg kg(-1), subcutaneously for 21 days), and groups 3, 4, and 5 received CsA along with irbesartan (10, 25, and 50 mg kg(-1), perorally 24 hr before and 21 days concurrently), respectively. Renal function was assessed by measuring serum creatinine, blood urea nitrogen, creatinine, and urea clearance. The renal oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels, and enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Renal morphological alterations were assessed by histopathological examination. CsA administration for 21 days resulted in a marked renal oxidative stress and significantly deranged the renal functions as well as renal morphology. All these factors were significantly improved by irbesartan (50 mg kg(-1)) treatment. HSP72, HSP47, and HSP25 were clearly induced and expressed in CsA-treated animals. The induction and expression of HSP25 was markedly protected by treatment with irbesartan, whereas the induction and expression of HSP47 and HSP72 remained unaltered with the irbesartan treatment. These results clearly demonstrate the pivotal role of ANG II-induced oxidative stress and therapeutic potential of AT, receptor antagonist in ameliorating CsA-induced nephrotoxicity.
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PMID:Amelioration of cyclosporine nephrotoxicity by irbesartan, A selective AT1 receptor antagonist. 1552 4

We tested the hypothesis that activation Jak2, which is prominently involved in the up-regulation of the renin-angiotensin system (RAS), constitutes a focal point in relaying signals triggered by a Angiotensin II (Ang II) and hypoxia/reoxygenation separately to cause an enhanced susceptibility of cardiac myocyte to apoptotic cell death. Ang II-treated adult cardiomyocytes in culture exhibited an increased level of apoptosis that accompanied activation of pro-apoptotic as well as anti-apoptotic signaling pathways. We observed increased phosphorylation of Jak2 kinase, Stat1, JNK, with increased expression of Bax protein, followed by an increase in caspase-1 and caspase-3 activity. Activation of these pro-apoptotic pathways was blocked by the Jak2 pharmacological inhibitor, Tyrphostin AG490. We also observed an increase in phosphorylation of cardioprotective pathway components, namely S6 ribosomal protein, and heat shock protein 27 (HSP27). Likewise, the oxidative stress, via the hypoxia/reoxygenation treatment of rat adult cardiomyocytes, produced apoptosis that was dependent upon activation of Jak2. The apoptotic response was not only reduced by Losartan, an inverse agonist of the AT1, receptor, but by treatment with AG490 as well. Taken together, these observations provide clear evidence in favor of Jak2 signaling as mediator of the apoptotic response in cardiomyocytes. However, there was a concomitant induction of cytoprotective signaling that presumably provides a negative feed-back to the deleterious effects of the agonist.
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PMID:Janus kinase-2 signaling mediates apoptosis in rat cardiomyocytes. 1626 69

Ataxia telangiectasia (A-T) is a progressive neurodegenerative disorder caused by disruption of the gene, ataxia telangiectasia mutated (ATM). Present study was aimed at identifying proteins that are present in abnormal levels in A-T brain that may identify alternative targets for therapeutic interventions. Proteomic and Western blot analysis have shown massive expression of the small heat shock protein 27 (Hsp27) in frontal cortices of A-T brains compared to negligible levels in controls. The expression of other stress proteins, Hsp70, alphaB-crystallin, and prohibitin remained unchanged in the A-T and control brains. Significant decreases in reactive oxygen species, protein carbonyl groups and lipid peroxidation products were observed in the A-T brains. There is no evidence of caspase 3 activation or DAXX mediated apoptosis. We propose that neurons in the frontal lobe are protected by the expression of Hsp27, which scavenges the oxidative stress molecules formed consequent to the primary loss of ATM function.
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PMID:Differential expression of small heat shock protein 27 (Hsp27) in Ataxia telangiectasia brains. 1932 56

DNA damage activates p53 and its downstream target genes, which further leads to apoptosis or survival either by the cell cycle arrest or by DNA repair. In many tumors, the heat shock protein 27 (Hsp27) is expressed at high levels to provide protection against anticancer drugs. However, the roles of Hsp27 in p53-mediated cellular responses to DNA damage are controversial. Here, we investigated the interplay between the phosphorylation status of Hsp27 and p53 in kidney 293A (HEK293A) cells and found that over-expressing phosphorylated Hsp27 mimics (Hsp27-3D) activated p53/p21 in an ATM-dependent manner. In addition, incubation with doxorubicin (Dox), an anticancer drug, induced Hsp27 phosphorylation in human adenocarcinoma cells (MCF-7). In contrast, inhibition of Hsp27 phosphorylation retarded both p53 induction and p21 accumulation, and led to cell apoptosis. Furthermore, phosphorylated Hsp27 increased p53 nuclear importing and its downstream target gene expression such as p21 and MDM2, while de-phosphorylated Hsp27 impeded this procession. Taken together, our data suggest that Hsp27, in its phosphorylated or de-phosphorylated status, plays different roles in regulating p53 pathway and cell survival.
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PMID:Phosphorylated Hsp27 activates ATM-dependent p53 signaling and mediates the resistance of MCF-7 cells to doxorubicin-induced apoptosis. 2335 34

The ongoing coronavirus disease 2019 (COVID-19) pandemic has affected millions worldwide and has been found to cause severe disease in patients with underlying comorbidities. In patients with known malignancies, in addition to constraints in routine healthcare, the risk of being susceptible to developing severe forms of the disease is of grave concern. While follow-up studies on survivors of the severe acute respiratory syndrome (SARS) 2003 outbreak revealed increased susceptibility to infections, tumours and cardiovascular abnormalities, recent studies implicating angiopoietin 2 in induction of inflammatory intussusceptive angiogenesis and diffuse alveolar damage in COVID-19 patients raises the possibility of progression of carcinogenetic processes in patients with known malignancies. Angiotensin converting enzyme-2 (ACE-2) mediated cellular entry of SARS-Cov2 leads to receptor shedding of ACE-2 and disrupts the renin angiotensin aldosterone axis (RAAS). This augments the pro-inflammatory and proliferative effects of RAAS, while attenuating the anti-inflammatory and anti-proliferative angiotensin 1-7 /Mas pathway. Angiopoietin-2, a molecule responsible for angiogenesis and cancer progression which corelates with tumour load in certain cancers, is upregulated by angiotensin 2-AT1 Receptor axis. Tumour microenvironment-comprising of various cells, blood vessels and extra cellular matrix which express the RAAS peptides-plays a key role in cancer initiation, progression and metastasis. Angiotensin 2 induces the formation of a desmoplastic environment, favouring cancer cell growth. ACE-2 downregulation causes bradykinin accumulation which may exert its proliferative action via mitogen activated protein kinase pathways which has established roles in cancers of breast and kidney. In addition to cytokine storm causing organ damage, acute inflammation in COVID-19 may also cause epithelial mesenchymal transition and heat shock protein 27 phosphorylation, both of which are key mediators in cancer signalling pathways. We hypothesise that SARS-Cov2, by impacting the RAAS and immune system, has the potential to cause tumour cell proliferation, apoptosis evasion and metastasis, thereby increasing the possibility of cancer progression in patients with known malignancies.
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PMID:Cancer progression in COVID-19: integrating the roles of renin angiotensin aldosterone system, angiopoietin-2, heat shock protein-27 and epithelial mesenchymal transition. 3308 49