Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Doxorubicin (Dox) is a chemotherapeutic agent that causes significant cardiotoxicity. We showed previously that Dox activates p53 and induces apoptosis in mouse hearts. This study was designed to elucidate the molecular events that lead to p53 stabilization, to examine the pathways involved in Dox-induced apoptosis, and to evaluate the effectiveness of pifithrin-alpha (PFT-alpha), a p53 inhibitor, in blocking apoptosis of rat H9c2 myoblasts. H9c2 cells that were exposed to 5 muM Dox had elevated levels of p53 and phosphorylated p53 at Ser15. Dox also triggered a transient activation of p38, p42/p44ERK, and p46/p54JNK MAP kinases. Caspase activity assays and Western blot analysis showed that H9c2 cells treated with Dox for 16 h had marked increase in the levels of caspases-2, -3, -8, -9, -12, Fas, and cleaved poly(ADP ribose) polymerase (PARP). There was a concomitant increase in p53 binding activity, cytochrome c release, and apoptosis. These results suggest that Dox can trigger intrinsic, extrinsic, and endoplasmic reticulum-associated apoptotic pathways. Pretreatment of cells with PFT-alpha followed by Dox administration attenuated Dox-induced increases in p53 levels and p53 binding activity and partially blocked the activation of p46/p54JNK and p42/p44ERK. PFT-alpha also led to decreased levels of caspases-2, -3, -8, -9, -12, Fas, PARP, cytochrome c release, and apoptosis. Our results suggest that p53 stabilization is a focal point of Dox-induced apoptosis and that PFT-alpha interferes with multiple steps of Dox-induced apoptosis.
 ...
PMID:Multiple actions of pifithrin-alpha on doxorubicin-induced apoptosis in rat myoblastic H9c2 cells. 1668 11

Recent studies indicated pulse pressure as a risk factor for left ventricular hypertrophy, myocardial infarction, congestive heart failure and stroke as well as chronic renal failure progression. The present study examined the effects of carvedilol and its combination with captopril on blood pressure, left ventricular hypertrophy, kidney vascular changes and kidney function in spontaneously hypertensive rats with adriamycin nephropathy. Four groups of 20 SHR each were involved: (1) control group: SHR; (2) ADR group: SHR treated with ADR (2mg/kg i.v. twice in 20 days); (3) ADR-C group: SHR treated with ADR and carvedilol (30 mg/kg/day) and (4) ADR-CC group: SHR treated with ADR and carvedilol (30 mg/kg/day) and captopril (60 mg/kg/day). Systolic-, diastolic- and mean-pressures and pulse pressure were determined at weeks 6 and 12 after the second ADR injection; and body weight, creatinine clearance and proteinuria at weeks -3, 6 and 12. The rats were sacrificed at week 6 or 12, the weights of the left and right ventricles and kidneys measured and the kidney vascular index was calculated as described by Bader and Mayer. Both carvedilol alone and combined with captopril significantly reduced systemic blood pressure but the effect of the latter was more pronounced and registered from week 4 till the end of the study. Carvedilol and its combination with captopril significantly decreased SBP, DBP and MAP. They also decreased PP, prevented the development of LVH, and renal vascular changes and slowed the progression of chronic renal failure and these effects were stronger in the ADR-CC group than in the ADR-C group. The antihypertensive drugs failed to prevent proteinuria in ADR SHR. Significant positive correlations were found between PP (but not SBP, DBP and MAP) and both proteinuria and Ccr in all groups of rats. In conclusion, carvedilol alone, but more strongly in combination with captopril, significantly reduced blood pressure, PP, LVH, renal blood vessel changes and chronic renal failure progression.
 ...
PMID:Effect of carvedilol on pulse pressure and left ventricular hypertrophy in spontaneously hypertensive rats with adriamycin nephropathy. 1901 53

Inhibition of ErbB2 (HER2) with monoclonal antibodies, an effective therapy in some forms of breast cancer, is associated with cardiotoxicity, the pathophysiology of which is poorly understood. Recent data suggest, that dual inhibition of ErbB1 (EGFR) and ErbB2 signaling is more efficient in cancer therapy, however, cardiac safety of this therapeutic approach is unknown. We therefore tested an ErbB1-(CGP059326) and an ErbB1/ErbB2-(PKI166) tyrosine kinase inhibitor in an in-vitro system of adult rat ventricular cardiomyocytes and assessed their effects on 1. cell viability, 2. myofibrillar structure, 3. contractile function, and 4. MAPK- and Akt-signaling alone or in combination with Doxorubicin. Neither CGP nor PKI induced cardiomyocyte necrosis or apoptosis. PKI but not CGP caused myofibrillar structural damage that was additive to that induced by Doxorubicin at clinically relevant doses. These changes were associated with an inhibition of excitation-contraction coupling. PKI but not CGP decreased p-Erk1/2, suggesting a role for this MAP-kinase signaling pathway in the maintenance of myofibrils. These data indicate that the ErbB2 signaling pathway is critical for the maintenance of myofibrillar structure and function. Clinical studies using ErbB2-targeted inhibitors for the treatment of cancer should be designed to include careful monitoring for cardiac dysfunction.
 ...
PMID:Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes. 1933 11

To assess the efficacy and safety of Shenfu injection for septic shock. All clinical studies of Shenfu injection for septic shock were searched from Cochrane library, Medline, EMbase, CBM, CNKI, Wanfang and VIP. Quality assessment and information extraction were done by two independent screening. The quality of the included documents was evaluated by the Cochrane Collaboration's tool for assessing risk of bias and allocation concealment. Revman 5. 1. 4 software was used for data analysis. A total of 6 randomized controlled trials were included (499 patients), in which, 6 studies did not mention allocation concealment, blind and loss-up information. Meta-analysis showed that the Shenfu injection group was better than the conventional treatment group in SBP (OR = 9.00, 95% Cl [3.89, 14.11]; OR = 20.28, 95% Cl [16.46, 24.10], respectively) and DBP (OR = 11.25, 95% Cl [7.65, 14.85]; OR = 8.17, 95% Cl [5.21, 11.13], respectively); in improving shock symptom (OR = 4.60, 95% Cl [1.88, 11.28]; OR = 0.88, 95% Cl [0.16, 4.87]; OR = 1.02, 95% Cl [0.27, 3.93]; OR = 1.65, 95% Cl [0.42, 6.42]) and reducing HR (OR = -29.71, 95% Cl [-40.51, -18.91]; OR = -18.00, 95% Cl [-27.16, -8.84]), (OR = 8.00, 95% Cl [1.96, 14.04]), there was inconsistency between the two groups; the Shenfu injection group showed no advantage in MAP (OR = -0.10, 95% Cl [-2.34, 2.14]) and CI (OR = 0.00, 95% Cl [- 1.24, 1.24]). ADR/AE information of Shenfu injection was not fully reported. This study may exist publication bias. Shenfu injection on the basis of conventional treatment can improve blood pressure of the treatment of septic shock; we can not get a positive conclusion in improving shock symptom and HR. Also, due to the sample size of included studies were small and of lower quality, conclusions above still need high-qualitied randomized, double-blind, controlled trials be confirmed.
 ...
PMID:[Systematic review of shenfu injection for septic shock]. 2447 53