scholarly journals Spironolactone and XPB: An Old Drug with a New Molecular Target

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 756 ◽  
Author(s):  
Ryan D. Gabbard ◽  
Robert R. Hoopes ◽  
Michael G. Kemp
Keyword(s):  
Dna Repair ◽  
Drug Repurposing ◽  
Carcinogenic Risk ◽  
Immune Recognition ◽  
Pharmacological Effects ◽  
Negative Consequences ◽  
Factor Ii ◽  
Initiation Of Transcription ◽  
Complications Of Cirrhosis ◽  
Group B

Spironolactone (SP) is commonly used for the treatment of heart failure, hypertension, and complications of cirrhosis by antagonizing the mineralocorticoid receptor. However, SP also antagonizes the androgen receptor, and thus SP has also been shown to be effective in the treatment of acne, hair loss, and hirsutism in women. Interestingly, recent drug repurposing screens have identified new and diverse functions for SP as a simulator of tumor immunosurveillance and as an inhibitor of DNA repair and viral infection. These novel pharmacological effects of SP have all been linked to the ability of SP to induce the rapid proteolytic degradation of the xeroderma pigmentosum group B (XPB) protein. XPB is a critical enzymatic component of the multi-subunit complex known as transcription factor II-H (TFIIH), which plays essential roles in both DNA repair and the initiation of transcription. Given the critical functions for XPB and TFIIH in these processes, the loss of XPB by SP could lead to mutagenesis. However, the ability of SP to promote cancer stem cell death and facilitate immune recognition may counteract the negative consequences of SP to mitigate carcinogenic risk. Thus, SP appears to have new and interesting pharmacological effects that may extend its potential uses.

A Study of Three Cases of Familial Congenital Hypoprothrombinaemia (Factor II Deficiency)

1964 ◽  
Vol 11 (02) ◽  
pp. 497-505 ◽  
Author(s):  
O de Bastos ◽  
R. S Reno ◽  
O. T Correa
Keyword(s):  
Clotting Factors ◽  
Factor Ii ◽  
Group B ◽  
Haemorrhagic Disease ◽  
Rule Out

SummaryThree cases of true congenital hypoprothrombinaemia are presented.Studies were made to prove the deficiency of prothrombin in the patient’s plasma and to rule out deficiency of other clotting factors or the presence of abnormal anti-thrombin substances.All the patients were of group B.The results obtained confirm that the patients have a real prothrombin deficiency as the cause of a severe haemorrhagic disease.

Factor II Related Antigen and Antithrombin III Levels as Indicators of Liver Failure in Consumption Coagulopathy

1982 ◽  
Vol 47 (03) ◽  
pp. 218-220 ◽  
Author(s):  
P Sié ◽  
E Letrenne ◽  
C Caranobe ◽  
M Genestal ◽  
B Cathala ◽  
...  
Keyword(s):  
Liver Failure ◽  
Antithrombin Iii ◽  
Coagulation Factors ◽  
Consumption Coagulopathy ◽  
Blood Coagulation Factors ◽  
Factor Ii ◽  
At Iii ◽  
Group A ◽  
Group B

SummaryIn order to detect impaired synthesis of blood coagulation factors associated to consumption coagulopathy, a simultaneous evaluation of factor II-related antigen (II rAg) and of antithrombin III (AT III) was carried out in 16 patients affected with severe defibrination. An in vitro preliminary study on plasma and serum demonstrated that the levels of II rAg and of AT III, assessed by the Laurell technique with Behring antisera, were not reduced by the coagulation process. The patients were, a posteriori, classified into two groups according to the absence (group A) or the presence (group B) of factors predisposing to liver failure such as metastasis, cirrhosis, and prolonged shock. II rAg and AT III levels are significantly correlated; they are in the normal range in group A but reduced in group B. Thus II rAg or AT III level determinations are useful markers in the detection of liver failure associated to the consumption phenomenon. These results also suggest that part of the decreased AT III levels reported in severe cases of disseminated intravascular coagulation may be the consequence of an associated liver failure.

scholarly journals DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease

2021 ◽  
Vol 22 (13) ◽  
pp. 6748
Author(s):  
Heling Wang ◽  
Sofie Lautrup ◽  
Domenica Caponio ◽  
Jianying Zhang ◽  
Evandro F. Fang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Repair ◽  
Werner Syndrome ◽  
Accelerated Ageing ◽  
Genes Encoding ◽  
Group A ◽  
Group B ◽  
Novel Therapeutic Strategies ◽  
Energy Deprivation

DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA), Cockayne syndrome group A and group B (CSA, CSB, and are caused by mutations of CSA and CSB, respectively), ataxia-telangiectasia (A-T, caused by mutation of ATM), and Werner syndrome (WS, with most cases caused by mutations in WRN). Except for WS, a common trait of the aforementioned progerias is neurodegeneration. Evidence from studies using animal models and patient tissues suggests that the associated DNA repair deficiencies lead to depletion of cellular nicotinamide adenine dinucleotide (NAD+), resulting in impaired mitophagy, accumulation of damaged mitochondria, metabolic derailment, energy deprivation, and finally leading to neuronal dysfunction and loss. Intriguingly, these features are also observed in Alzheimer’s disease (AD), the most common type of dementia affecting more than 50 million individuals worldwide. Further studies on the mechanisms of the DNA repair deficient premature ageing diseases will help to unveil the mystery of ageing and may provide novel therapeutic strategies for AD.

scholarly journals RAD25 (SSL2), the yeast homolog of the human xeroderma pigmentosum group B DNA repair gene, is essential for viability.

1992 ◽  
Vol 89 (23) ◽  
pp. 11416-11420 ◽  
Author(s):  
E. Park ◽  
S. N. Guzder ◽  
M. H. Koken ◽  
I. Jaspers-Dekker ◽  
G. Weeda ◽  
...  
Keyword(s):  
Dna Repair ◽  
Xeroderma Pigmentosum ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Group B ◽  
Yeast Homolog

scholarly journals Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane

2010 ◽  
Vol 24 (7) ◽  
pp. 2334-2346 ◽  
Author(s):  
Maria D. Aamann ◽  
Martin M. Sorensen ◽  
Christina Hvitby ◽  
Brian R. Berquist ◽  
Meltem Muftuoglu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Mitochondrial Dna ◽  
Mitochondrial Membrane ◽  
Cockayne Syndrome ◽  
Dna Stability ◽  
Group B ◽  
Mitochondrial Dna Stability

Prognostic impact of DNA repair germline variants in hormone sensitive prostate cancer stage.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 262-262
Author(s):  
Manish Kohli ◽  
Steven Hart ◽  
Jenna Lilyquist ◽  
Chunling Hu ◽  
David W. Hillman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Median Time ◽  
P Value ◽  
Prognostic Impact ◽  
Time To Progression ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Group A ◽  
Group B

262 Background: Inherited and somatic aberrations in DNA repair genes in castrate resistant prostate cancer (CRPC) are associated with poor prognosis, but respond well to poly ADP ribose polymerase (PARP) inhibitors. We evaluated the prevalence and prognostic impact of harboring germline DNA repair variants in hormone sensitive prostate cancer (HSPC). Methods: Germline DNA from buffy coat was sequenced on HiSeq4000 with a median coverage of 200X for DNA repair variants in 20 genes in HSPC and CRPC patients (pts) enrolled in a hospital registry. Pts were divided into two groups; Group A: pts enrolled at the time of CRPC stage; Group B: treatment naïve HSPC stage pts. The primary endpoints were to determine any impact of harboring DNA repair variants on time to progression from HSPC to CRPC and, from CRPC to death. Group A pts were retrospectively analyzed for time to progression from HSPC to CRPC while Group B patients were followed prospectively for outcomes. Statistical analysis included Cox proportional hazard models and Wilcoxon Rank sum test with significance at p≤0.05. Results: In Group A, 51/562 CRPC pts (9.07%) had variants in the 20 genes (most frequently in BRCA2; n = 15). 44/51 pts with variants and 399/511 without variants had died. Median time of progression from HSPC to CRPC with/without variants was 22.1 vs. 25.1 months (mths); p-value = 0.679. Median time from CRPC to death with/without variants was 32.2 Vs. 27.7 mths (p = 0.6). In HSPC Group B, 14/100 pts were identified with germline variants in ATM (n = 5), CHEK2 (n = 3), BRCA1 (n = 2), BRCA2 (n = 2), RAD50 (n = 1), and MSH2 (n = 1). 31/100 have died and median time to progression from HSPC to CRPC with/without variants was 15.6 vs.11.8 mths, p-value = 0.76. Conclusions: Pts with germline DNA repair variants detected in HSPC stage were not associated with poor prognosis. Presence of additional somatic DNA repair gene aberrations in cell-free DNA, not investigated in this cohort may add to the prevalence of DNA repair gene variations in HSPC and together impact prognosis adversely so as to provide a rationale for PARP inhibitor therapy in select HSPC stage pts.

The Cockayne syndrome group B DNA repair protein as an anti-cancer target

2001 ◽  
Author(s):  
Y. Lu ◽  
Sridhar Mani ◽  
Ekambar Kandimalla ◽  
Dong Yu ◽  
Sudhir Agrawal ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cockayne Syndrome ◽  
Repair Protein ◽  
Anti Cancer ◽  
Dna Repair Protein ◽  
Group B

scholarly journals Human AP Endonuclease 1: A Potential Marker for the Prediction of Environmental Carcinogenesis Risk

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Jae Sung Park ◽  
Hye Lim Kim ◽  
Yeo Jin Kim ◽  
Jong-Il Weon ◽  
Mi-Kyung Sung ◽  
...  
Keyword(s):  
Dna Repair ◽  
Redox Regulation ◽  
Carcinogenic Risk ◽  
Human Diseases ◽  
Environment Interaction ◽  
Environmental Toxicants ◽  
Environmental Chemical ◽  
Potential Marker ◽  
Gene Environment ◽  
Environmental Carcinogenesis

Human apurinic/apyrimidinic endonuclease 1 (APE1) functions mainly in DNA repair as an enzyme removing AP sites and in redox signaling as a coactivator of various transcription factors. Based on these multifunctions of APE1 within cells, numerous studies have reported that the alteration of APE1 could be a crucial factor in development of human diseases such as cancer and neurodegeneration. In fact, the study on the combination of an individual’s genetic make-up with environmental factors (gene-environment interaction) is of great importance to understand the development of diseases, especially lethal diseases including cancer. Recent reports have suggested that the human carcinogenic risk following exposure to environmental toxicants is affected by APE1 alterations in terms of gene-environment interactions. In this review, we initially outline the critical APE1 functions in the various intracellular mechanisms including DNA repair and redox regulation and its roles in human diseases. Several findings demonstrate that the change in expression and activity as well as genetic variability of APE1 caused by environmental chemical (e.g., heavy metals and cigarette smoke) and physical carcinogens (ultraviolet and ionizing radiation) is likely associated with various cancers. These enable us to ultimately suggest APE1 as a vital marker for the prediction of environmental carcinogenesis risk.

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