Genetic signature related to heme-hemoglobin metabolism pathway in sepsis secondary to pneumonia

Leishmaniasis is one of the six entities on the list of most important diseases of the World Health Organization/Tropical Disease Research (WHO/TDR). After Malaria, it is one of the most prevalent and lethal parasitic diseases. VL is the fatal form of this disease, especially if left untreated. The drugs that are currently available for the treatment of VL are expensive, toxic, or no longer effective, especially in endemic regions. Currently, no vaccine has been developed to immunize humans against VL. The major problems with the current drugs are the development of resistance and their adverse effects. Therefore, there is a strong urge to research and design drugs that have better efficacies and low toxicities as compared to current chemotherapeutic drugs. Leishmania has various enzymes involved in its metabolic pathways, which are unique to either the same genus or trypanosomatids, making them a very suitable, attractive and novel target sites for drug development. One of the significant pathways unique to trypanosomatids is the thiol metabolism pathway, which is involved in the maintenance of redox homeostasis as well as protection of the parasite in the macrophage from oxidative stress-induced damage. In this review the several pathways, their essential enzymes as well as the proposed changes in the parasites due to drug resistance have been discussed to help to understand the most suitable drug target. The thiol metabolism pathway is discussed in detail, providing evidence of this pathway being the most favorable choice for drug targeting in VL.

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Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites

Journal of Personalized Medicine ◽

10.3390/jpm11060507 ◽

2021 ◽

Vol 11 (6) ◽

pp. 507

Author(s):

Yuanhuang Chen ◽

Lauren A. Marcath ◽

Finn Magnus Eliassen ◽

Tone Hoel Lende ◽

Havard Soiland ◽

...

Keyword(s):

Metabolic Activity ◽

Active Metabolite ◽

Estrogenic Activity ◽

Metabolic Activation ◽

Active Metabolites ◽

Serum Samples ◽

Concentration Data ◽

Metabolism Pathway ◽

Tamoxifen Metabolism ◽

Tamoxifen Efficacy

Background: Tamoxifen, as a treatment of estrogen receptor positive (ER+) breast cancer, is a weak anti-estrogen that requires metabolic activation to form metabolites with higher anti-estrogenic activity. Endoxifen is the most-studied active tamoxifen metabolite, and endoxifen concentrations are highly associated with CYP2D6 activity. Associations of tamoxifen efficacy with measured or CYP2D6-predicted endoxifen concentrations have been inconclusive. Another active metabolite, 4-OHtam, and other, less active metabolites, Z-4′-endoxifen and Z-4′-OHtam, have also been reported to be associated with tamoxifen efficacy. Method: Genotype for 20 pharmacogenes was determined by VeriDose® Core Panel and VeriDose®CYP2D6 CNV Panel, followed by translation to metabolic activity phenotype following standard activity scoring. Concentrations of tamoxifen and seven metabolites were measured by UPLC-MS/MS in serum samples collected from patients receiving 20 mg tamoxifen per day. Metabolic activity was tested for association with tamoxifen and its metabolites using linear regression with adjustment for upstream metabolites to identify genes associated with each step in the tamoxifen metabolism pathway. Results: A total of 187 patients with genetic and tamoxifen concentration data were included in the analysis. CYP2D6 was the primary gene associated with the tamoxifen metabolism pathway, especially the conversion of tamoxifen to endoxifen. CYP3A4 and CYP2C9 were also responsible for the metabolism of tamoxifen. CYP2C9 especially impacted the hydroxylation to 4-OHtam, and this involved the OATP1B1 (SLCO1B1) transporter. Conclusion: Multiple genes are involved in tamoxifen metabolism and multi-gene panels could be useful to predict active metabolite concentrations and guide tamoxifen dosing.

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Population structure of Dothistroma septosporum in Poland: revealing the genetic signature of a recently established pathogen

Plant Pathology ◽

10.1111/ppa.13383 ◽

2021 ◽

Author(s):

Piotr Boroń ◽

Anna Lenart‐Boroń ◽

Martin Mullett ◽

Bartłomiej Grad ◽

Katarzyna Nawrot‐Chorabik

Keyword(s):

Population Structure ◽

Genetic Signature ◽

Dothistroma Septosporum

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Metformin Attenuates the Metabolic Disturbance and Depression-like Behaviors Induced by Corticosterone and Mediates the Glucose Metabolism Pathway

Pharmacopsychiatry ◽

10.1055/a-1351-0566 ◽

2021 ◽

Author(s):

Yong Hao ◽

Yingpeng Tong ◽

Yanhong Guo ◽

Xiaoe Lang ◽

Xinxin Huang ◽

...

Keyword(s):

Glucose Metabolism ◽

Tricarboxylic Acid Cycle ◽

Antidepressant Activity ◽

Tricarboxylic Acid ◽

Serum Glucose ◽

Metabolomic Analysis ◽

Chain Reaction ◽

Qrt Pcr ◽

Metabolism Pathway ◽

Polymerase Chain

Abstract Background Metabolism disturbances are common in patients with depression. The drug metformin has been reported to exhibit antidepressant activity. The purpose of this study was to investigate metabolism disturbances induced by corticosterone (CORT) and determine if metformin can reverse these effects and their accompanying depression-like behaviors. Methods Rats were exposed to corticosterone with or without metformin administration. Depression-like behaviors were tested. Gene expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. In addition, the metabolites were quantified by LC-MS/MS analysis. Results Metformin attenuated the depression-like behaviors induced by CORT. Furthermore, metformin reversed disturbances in body weight, serum glucose, and triglyceride levels, as well as hepatic TG levels induced by CORT. Metformin normalized the alterations in the expression of glucose metabolism-related genes (PGC-1α, G6pc, Pepck, Gck, PYGL, Gys2, PKLR, GLUT4) and insulin resistance-related genes (AdipoR1, AdipoR2) in the muscles and livers of rats induced by CORT. Metabolomic analysis showed that metformin reversed the effects of CORT on 11 metabolites involved in the pathways of the tricarboxylic acid cycle, glycolysis, and gluconeogenesis (3-phospho-D-glycerate, β-D-fructose 6-phosphate, D-glucose 6-phosphate, and pyruvate). Conclusion Our findings suggest that metformin can attenuate metabolism disturbances and depression-like behaviors induced by CORT mediating the glucose metabolism pathway.

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