Enzyme inhibitor

Disruption of DNA damage repair via impaired homologous recombination is characteristic of Ewing sarcoma (EWS) cells. We hypothesize that this disruption results in increased reliance on non-homologous end joining (NHEJ) to repair DNA damage. In this study, we investigated if pharmacological inhibition of the enzyme responsible for NHEJ, the DNA-PK holoenzyme, alters the response of EWS cells to genotoxic standard of care chemotherapy. We used analyses of cell viability and proliferation to investigate the effects of clinical DNA-PK inhibitors (DNA-PKi) in combination with six therapeutic or experimental agents for EWS...

In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells...

BACKGROUND: Hypervolemia is thought to be a major contributor to higher left ventricular mass (LVM), a potent predictor for cardiovascular mortality among patients on maintenance hemodialysis. We hypothesized that a decrease in vector length (a bioimpedance proxy of hypervolemia) would be associated with an increase in LVM. METHODS: Using data from the Frequent Hemodialysis Network Daily Trial (n=160) we used linear regression to assess the association of changes in vector length from baseline to month 12 with changes in magnetic resonance imaging (MRI) measures of LVM and other cardiac parameters...

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. FGFR4 has been implicated in HCC progression, making it a promising therapeutic target. We introduce an approach for identifying novel FGFR4 inhibitors by sequentially adding fragments to a common warhead unit. This strategy resulted in the discovery of a potent inhibitor, 4c , with an IC50 of 33 nM and high selectivity among members of the FGFR family. Although further optimisation is required, our approach demonstrated the potential for discovering potent FGFR4 inhibitors for HCC treatment, and provides a useful method for obtaining hit compounds from small fragments...

BACKGROUND: The utilization of amorphous silica nanoparticles (SiNPs) is gaining popularity in various applications, but it poses a potential risk to human and environmental health. However, the underlying causes and mechanisms of SiNPs-induced kidney damage are still largely unknown. OBJECTIVES: This study aimed to investigate the SiNPs-induced damage in the kidney and further explore the possible mechanisms of SiNPs-induced nephrotoxicity. METHODS: Thirty adult male rats were divided into 3 different groups...

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BACKGROUND AND OBJECTIVES: Myocardial ischemia-reperfusion injury (MIRI) refers to the damage of cardiac function caused by restoration of blood flow perfusion in ischemic myocardium. However, long non-coding RNA prostate androgen regulated transcript 1 (PART1)'s role in MIRI remain unclear. METHODS: Immunofluorescence detected LC3 expression. Intermolecular relationships were verified by dual luciferase reporter assay. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry and transferase-mediated dUTP nick-end labeling (TUNEL) assays analyzed cell viability and apoptosis...

The escalating drug resistance among microorganisms underscores the urgent need for innovative therapeutic strategies and a comprehensive understanding of bacteria's defense mechanisms against oxidative stress and antibiotics. Among the recently discovered barriers, the endogenous production of hydrogen sulfide (H2 S) via the reverse transsulfuration pathway, emerges as a noteworthy factor. In this study, we have explored the catalytic capabilities and crystal structure of cystathionine γ-lyase from Pseudomonas aeruginosa (PaCGL), a multidrug-opportunistic pathogen chiefly responsible for nosocomial infections...

Huntington's disease (HD) is an inherited, autosomal, neurodegenerative ailment that affects the striatum of the brain. Despite its debilitating effect on its patients, there is no proven cure for HD management as of yet. Neuroinflammation, excitotoxicity, and environmental factors have been reported to influence the regulation of gene expression by modifying epigenetic mechanisms. Aside focusing on the etiology, changes in epigenetic mechanisms have become a crucial factor influencing the interaction between HTT protein and epigenetically transcribed genes involved in neuroinflammation and HD...

Discovering effective anti-cancer agents poses a formidable challenge given the limited efficacy of current therapeutic modalities against various cancer types due to intrinsic resistance mechanisms. Cancer immunochemotherapy is an alternative strategy for breast cancer treatment and overcoming cancer resistance. Human Indoleamine 2,3-dioxygenase (hIDO1) and human Tryptophan 2,3-dioxygenase 2 (hTDO2) play pivotal roles in tryptophan metabolism, leading to the generation of kynurenine and other bioactive metabolites...

Elevated blood pressure (BP) is the largest contributor to the incident cardiovascular disease worldwide. Despite explicit guideline recommendations for the diagnosis and management of hypertension, a large proportion of patients remain undiagnosed, untreated, or treated but uncontrolled. Inadequate BP control is associated with many complex factors including patient preference, physician's inertia, health systems disparities, and poor adherence to prescribed antihypertensive drug treatment. The primary driver for reduced cardiovascular morbidity and mortality is lowering of BP ''per se'' and not class effects of specific pharmacotherapies...

Gliomas with Isocitrate dehydrogenase (IDH) mutation represent a discrete category of primary brain tumors with distinct and unique characteristics, behaviors, and clinical disease outcomes. IDH mutations lead to aberrant high-level production of the oncometabolite D-2-hydroxyglutarate (D-2HG), which act as a competitive inhibitor of enzymes regulating epigenetics, signaling pathways, metabolism, and various other processes. This review summarizes the significance of IDH mutations, resulting upregulation of D-2HG and the associated molecular pathways in gliomagenesis...

Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied...

Melanin is the major pigment responsible for the coloring of mammalian skin, hair, and eyes to defend against ultraviolet radiation. However, excessive melanin production has resulted in numerous types of hyperpigmentation disorders. Tyrosinase-related protein 1 (TYRP1) is a transmembrane glycoprotein enzyme found in many organisms, including humans, that plays an important role in melanogenesis. Thus, controlling the enzyme activity of TYRP1 with tyrosinase inhibitors is a vital step in the treatment of hyperpigmentation problems in humans...

The acetylation of α-tubulin on lysine 40 is a well-studied post-translational modification which has been associated with the presence of long-lived stable microtubules that are more resistant to mechanical breakdown. The discovery of α-tubulin acetyltransferase 1 (ATAT1), the enzyme responsible for lysine 40 acetylation on α-tubulin in a wide range of species, including protists, nematodes, and mammals, dates to about a decade ago. However, the role of ATAT1 in different cellular activities and molecular pathways has been only recently disclosed...

The clinical usage of doxorubicin (DOX) is hampered due to cardiomyopathy. Studies reveal that estrogen (E2) modulates DOX-induced cardiotoxicity. Yet, the exact mechanism is unclear. The objective of the current study is to evaluate the influence of E2 and more specifically its metabolite 2-methoxyestradiol (2ME) on cardiac remodeling and the reprogramming of cardiac metabolism in rats subjected to DOX cardiotoxicity. Seventy-two female rats were divided into groups. Cardiotoxicity was induced by administering DOX (2...

BI 187004, a selective small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β-HSD1 inhibition (50%) was detected in a very low-dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose-dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target-mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high-affinity and low-capacity target 11β-HSD1...

Antimicrobial resistance (AMR) is a pressing global issue exacerbated by the abuse of antibiotics and the formation of bacterial biofilms, which cause up to 80% of human bacterial infections. This study presents a computational strategy to address AMR by developing three novel quantitative structure-activity relationship (QSAR) models based on molecular topology to identify potential anti-biofilm and antibacterial agents. The models aim to determine the chemo-topological pattern of Gram (+) antibacterial, Gram (-) antibacterial, and biofilm formation inhibition activity...

Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by Plasmodium falciparum and Plasmodium vivax , Trypanosoma brucei , Mycobacterium tuberculosis , and Helicobacter pylori . Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have K i values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme...

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome is a newly described hemato-inflammatory acquired monogenic entity that presents in adulthood. One of the main features of VEXAS syndrome is a high venous thromboembolism (VTE) burden, with approximately 30-40% experiencing lower extremity deep vein thrombosis and a lower incidence of pulmonary embolism at approximately 10%. To date, VEXAS syndrome has not been associated with rarer forms of VTE such as cerebral sinus vein thrombosis (CSVT) and Budd-Chiari syndrome, which are well-recognized vascular manifestations in Behcet's disease, another autoinflammatory vasculitic disease...