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Pharmacology & Therapeutics Oct 2023The pharmacological treatment of dyslipidemia, a major modifiable risk factor for developing atherosclerotic cardiovascular disease (ASCVD), remains a debated and... (Review)
Review
The pharmacological treatment of dyslipidemia, a major modifiable risk factor for developing atherosclerotic cardiovascular disease (ASCVD), remains a debated and controversial issue, not only in terms of the most appropriate therapeutic range for lipid levels, but also with regard to the optimal strategy and sequence approach (stepwise vs upstream therapy). Current treatment guidelines for the management of dyslipidemia focus on the intensity of low-density lipoprotein cholesterol (LDL-C) reduction, stratified according to risk for developing ASCVD. Beyond statins and ezetimibe, different medications targeting LDL-C have been recently approved by regulatory agencies with potential innovative mechanisms of action, including proprotein convertase subtilisin/kexin type 9 modulators (monoclonal antibodies such as evolocumab and alirocumab; small interfering RNA molecules such as inclisiran), ATP-citrate lyase inhibitors (bempedoic acid), angiopoietin-like 3 inhibitors (evinacumab), and microsomal triglyceride transfer protein inhibitors (lomitapide). An understanding of their pharmacological aspects, benefit-risk profile, including impact on hard cardiovascular endpoints beyond LDL-C reduction, and potential advantages from the patient perspective (e.g., adherence) - the focus of this evidence-based review - is crucial for practitioners across medical specialties to minimize therapeutic inertia and support clinical practice.
PubMed: 37567512
DOI: 10.1016/j.pharmthera.2023.108507 -
The Canadian Journal of Cardiology Dec 2023Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a... (Review)
Review
Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a monogenic etiology, caused by pathogenic loss of function variants in the PCSK9, ANGPTL3, MTTP, or APOB genes. In this focused review, we discuss development and clinical use of several new therapeutics that inhibit these gene products to target elevated levels of low-density lipoprotein cholesterol. In particular, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) have notably affected clinical practice, followed recently by inhibition of angiopoietin-like 3 (ANGPTL3). Currently used in the clinic are alirocumab and evolocumab, two anti-PCSK9 monoclonal antibodies, inclisiran, a small interfering RNA that prevents PCSK9 translation, evinacumab, an anti-ANGPTL3 monoclonal antibody, and lomitapide, a small-molecule inhibitor of microsomal triglyceride transfer protein. Additional therapies are in preclinical or clinical trial stages of development. These consist of other monoclonal antibodies, antisense oligonucleotides, small-molecule inhibitors, mimetic peptides, adnectins, vaccines, and gene-editing therapies. Vaccines and gene-editing therapies in particular hold great potential to confer active long-term attenuation or provide single-treatment life-long knock-down of PCSK9 or ANGPTL3 activity. Biologic therapies inspired by monogenic hypocholesterolemia states are becoming valuable tools to help protect against atherosclerotic cardiovascular disease.
Topics: Humans; Cholesterol, LDL; Proprotein Convertase 9; PCSK9 Inhibitors; Cardiovascular Diseases; Antibodies, Monoclonal; Atherosclerosis; Biological Therapy; Vaccines; Anticholesteremic Agents; Angiopoietin-Like Protein 3
PubMed: 37562541
DOI: 10.1016/j.cjca.2023.08.003 -
Journal of Microbiological Methods Dec 2023Bacterial-based genotoxicity test systems play a significant role in the detection and evaluation of genotoxicity in vitro and have gained importance due to attributes... (Review)
Review
Bacterial-based genotoxicity test systems play a significant role in the detection and evaluation of genotoxicity in vitro and have gained importance due to attributes like wide applicability, speed, high sensitivity, good reproducibility, and simplicity. The Salmonella microsomal mutagenicity assay was created by Ames and colleagues at the beginning of the 1970s, and it was based on the fundamental notion that in auxotrophic bacterial strains with inhibited growth, a mutant gene would revert to its original state on exposure to genotoxicants. This is the most successful and widely used in vitro genotoxicity test. Later, a number of additional test systems that incorporated DNA repair mechanisms including the bacterial SOS response were created. Genetic engineering has further provided significant advancement in these test systems with the development of highly sophisticated bacterial tester strains with significantly increased sensitivity to evaluate the chemical nature of hazardous substances and pollutants. These bacterial bioassays render an opportunity to detect the defined effects of compounds at the molecular level. In this review, all the aspects related to the bacterial system in genotoxicity assessment have been summarized and their role is elaborated concerning real-time requirements and future perspectives.
Topics: Reproducibility of Results; DNA Damage; Mutagenicity Tests; Bacteria; Mutagenesis
PubMed: 38008307
DOI: 10.1016/j.mimet.2023.106860 -
European Heart Journal May 2024The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2...
BACKGROUND AND AIMS
The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI.
METHODS
The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study.
RESULTS
Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients.
CONCLUSIONS
ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.
Topics: Animals; Female; Humans; Male; Mice; Middle Aged; Aldehyde Dehydrogenase, Mitochondrial; Benzamides; Benzodioxoles; Disease Models, Animal; Extracellular Traps; Leukotriene Antagonists; Leukotriene C4; Mice, Knockout; Myocardial Reperfusion Injury; Neutrophils; Protein-Arginine Deiminase Type 4; ST Elevation Myocardial Infarction
PubMed: 38666340
DOI: 10.1093/eurheartj/ehae205 -
Pharmacological Research Oct 2023While recent targeted and immunotherapies in malignant melanoma are encouraging, most patients acquire resistance, implicating a need to identify additional drug targets...
While recent targeted and immunotherapies in malignant melanoma are encouraging, most patients acquire resistance, implicating a need to identify additional drug targets to improve outcomes. Recently, attention has been given to pathways that regulate redox homeostasis, especially the lipid peroxidase pathway that protects cells against ferroptosis. Here we identify microsomal glutathione S-transferase 1 (MGST1), a non-selenium-dependent glutathione peroxidase, as highly expressed in malignant and drug resistant melanomas and as a specific determinant of metastatic spread and therapeutic sensitivity. Loss of MGST1 in mouse and human melanoma enhanced cellular oxidative stress, and diminished glycolysis, oxidative phosphorylation, and pentose phosphate pathway. Gp100 activated pmel-1 T cells killed more Mgst1 KD than control melanoma cells and KD cells were more sensitive to cytotoxic anticancer drugs and ferroptotic cell death. When compared to control, mice bearing Mgst1 KD B16 tumors had more CD8 T cell infiltration with reduced expression of inhibitory receptors and increased cytokine response, large reduction of lung metastases and enhanced survival. Targeting MGST1 alters the redox balance and limits metastases in melanoma, enhancing the therapeutic index for chemo- and immunotherapies.
Topics: Humans; Mice; Animals; Glutathione Transferase; Antineoplastic Agents; Oxidative Stress; Lung Neoplasms; Melanoma; Glutathione
PubMed: 37648102
DOI: 10.1016/j.phrs.2023.106899 -
Journal of Medicinal Chemistry Aug 2023Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors...
Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-β-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 () and . This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-β-induced pulmonary fibrosis.
Topics: Mice; Animals; Humans; Histone Deacetylase Inhibitors; Transforming Growth Factor beta; Histone Deacetylases; Drug Evaluation, Preclinical; Caco-2 Cells; Idiopathic Pulmonary Fibrosis; Histone Deacetylase 6; Repressor Proteins
PubMed: 37463500
DOI: 10.1021/acs.jmedchem.3c00644 -
ACS Infectious Diseases Oct 2023We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5-dibenzo[,]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic...
We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5-dibenzo[,]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 μg/mL at pH 6.5). The more polar compounds in the series (LogD values of <2) had the best metabolic stability (CL values of <50 μL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC values >30 μM, and there was no correlation between antiplasmodial activity and cytotoxicity. The four most potent compounds had IC values of 4.2 to 9.4 nM and selectivity indices of 670 to >12,000. They were more than 4 orders-of-magnitude less potent against three other protozoal pathogens (, , and ) but did have relatively high potency against , with IC values ranging from 80 to 200 nM. These keto lactams are converted into their poorly soluble 4(1)-quinolone transannular condensation products in culture medium and in mouse blood. The similar antiplasmodial potencies of three keto lactam-quinolone pairs suggest that the quinolones likely contribute to the antimalarial activity of the lactams.
Topics: Mice; Animals; Humans; Antimalarials; Lactams; Trypanosoma brucei rhodesiense; Trypanosoma cruzi; Quinolones
PubMed: 37695781
DOI: 10.1021/acsinfecdis.3c00245 -
Frontiers in Pharmacology 2023Lipid-lowering therapy is an important tool for the treatment of lipid metabolic diseases, which are increasing in prevalence. However, the failure of conventional... (Review)
Review
Lipid-lowering therapy is an important tool for the treatment of lipid metabolic diseases, which are increasing in prevalence. However, the failure of conventional lipid-lowering drugs to achieve the desired efficacy in some patients, and the side-effects of these drug regimens, highlight the urgent need for novel lipid-lowering drugs. The liver and intestine are important in the production and removal of endogenous and exogenous lipids, respectively, and have an important impact on circulating lipid levels. Elevated circulating lipids predisposes an individual to lipid deposition in the vascular wall, affecting vascular function. Berberine (BBR) modulates liver lipid production and clearance by regulating cellular targets such as cluster of differentiation 36 (CD36), acetyl-CoA carboxylase (ACC), microsomal triglyceride transfer protein (MTTP), scavenger receptor class B type 1 (SR-BI), low-density lipoprotein receptor (LDLR), and ATP-binding cassette transporter A1 (ABCA1). It influences intestinal lipid synthesis and metabolism by modulating gut microbiota composition and metabolism. Finally, BBR maintains vascular function by targeting proteins such as endothelial nitric oxide synthase (eNOS) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). This paper elucidates and summarizes the pharmacological mechanisms of berberine in lipid metabolic diseases from a multi-organ (liver, intestine, and vascular system) and multi-target perspective.
PubMed: 38034996
DOI: 10.3389/fphar.2023.1283784