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Biomedicine & Pharmacotherapy =... Sep 2022Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary... (Review)
Review
Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary progressive multiple sclerosis. We performed a systematic review of the pharmacogenetics of Siponimod, and we found that (430 C>T; rs1799853) and CYP2C9 * 3 (1075 A>C; rs1057910), both translated no-function alleles, have been related to a lower metabolism of siponimod by CYP2C9 enzyme. The FDA-approved drug label and EMA risk management plan for siponimod require testing patients for CYP2C9 genotype before treatment starts. The FDA drug label states that siponimod is contraindicated in patients carrying a CYP2C9 * 3/* 3 genotype, and a daily maintenance dose of 1 mg in patients with CYP2C9 * 1/* 3 and * 2/* 3 genotypes. The EMA reported the potential long-term safety implications in CYP2C9 poor metabolizer patients treated with this drug. Based on this systematic review we concluded that CYP2C9 SNPs influence on siponimod response might be stated by assessing not only CYP2C9 * 2 and CYP2C9 * 3 but other genetic variants resulting in CYP2C9 IM/PM status. CYP2C9 IM phenotype translated from the CYP2C9 * 2 genotype should be revised since it is contradictory compared to other CYP2C9 no-function alleles, and CYP2C9 * 2 might be excluded from PGx testing recommendation before treatment starts with siponimod since it is not translated into a therapeutic recommendation.
Topics: Azetidines; Benzyl Compounds; Cytochrome P-450 CYP2C9; Genotype; Pharmacogenetics
PubMed: 36076616
DOI: 10.1016/j.biopha.2022.113536 -
European Journal of Medicinal Chemistry Dec 2023Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of... (Review)
Review
Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Autophagy; Drug Discovery; Lysosomes
PubMed: 37778240
DOI: 10.1016/j.ejmech.2023.115839 -
International Journal of Medical... 2023The members of the transmembrane emp24 domain-containing protein (TMED) family are summarized in human as four subfamilies, α (TMED 4, 9), β (TMED 2), γ (TMED1, 3, 5,... (Review)
Review
The members of the transmembrane emp24 domain-containing protein (TMED) family are summarized in human as four subfamilies, α (TMED 4, 9), β (TMED 2), γ (TMED1, 3, 5, 6, 7) and δ (TMED 10), with a total of nine members, which are important regulators of intracellular protein transport and are involved in normal embryonic development, as well as in the pathogenic processes of many human diseases. Here we systematically review the composition, structure and function of TMED family members, and describe the progress of TMED family in human diseases, including malignancies (head and neck tumors, lung cancer, breast cancer, ovarian cancer, endometrial cancer, gastrointestinal tumors, urological tumors, osteosarcomas, etc.), immune responses, diabetes, neurodegenerative diseases, and nonalcoholic fatty liver disease, dilated cardiomyopathy, mucin 1 nephropathy (MKD), and desiccation syndrome (SS). Finally, we discuss and prospect the potential of TMED for disease prognosis prediction and therapeutic targeting, with a view to laying the foundation for therapeutic research based on TMED family causative genes.
Topics: Pregnancy; Female; Humans; Membrane Proteins; Protein Transport; Non-alcoholic Fatty Liver Disease; Vesicular Transport Proteins
PubMed: 37928880
DOI: 10.7150/ijms.87272 -
Cardiovascular Diabetology Dec 2022Apolipoprotein C1 (apoC1) is a small size apolipoprotein whose exact role is not totally clarified but which seems to modulate significantly the metabolism of... (Review)
Review
Apolipoprotein C1 (apoC1) is a small size apolipoprotein whose exact role is not totally clarified but which seems to modulate significantly the metabolism of lipoproteins. ApoC1 is involved in the metabolism of triglyceride-rich lipoproteins by inhibiting the binding of very low density lipoproteins (VLDL) to VLDL-receptor (VLDL-R), to low density lipoprotein receptor (LDL-R) and to LDL receptor related protein (LRP), by reducing the activity of lipoprotein lipase (LPL) and by stimulating VLDL production, all these effects leading to increase plasma triglycerides. ApoC1 takes also part in the metabolism of high density lipoproteins (HDL) by inhibiting Cholesterol Ester Transfer Protein (CETP). The functionality of apoC1 on CETP activity is impaired in diabetes that might account, at least in part, for the increased plasma CETP activity observed in patients with diabetes. Its different effects on lipoprotein metabolism with a possible role in the modulation of inflammation makes the net impact of apoC1 on cardiometabolic risk difficult to figure out and apoC1 might be considered as pro-atherogenic or anti-atherogenic depending on the overall metabolic context. Making the link between total plasma apoC1 levels and the risk of cardio-metabolic diseases is difficult due to the high exchangeability of this small protein whose biological effects might depend essentially on its association with VLDL or HDL. The role of apoC1 in humans is not entirely elucidated and further studies are needed to determine its precise role in lipid metabolism and its possible pleiotropic effects on inflammation and vascular wall biology. In this review, we will present data on apoC1 structure and distribution among lipoproteins, on the effects of apoC1 on VLDL metabolism and HDL metabolism and we will discuss the possible links between apoC1, atherosclerosis and diabetes.
Topics: Humans; Apolipoprotein C-I; Atherosclerosis; Cholesterol Ester Transfer Proteins; Diabetes Mellitus; Inflammation; Lipoproteins, HDL; Lipoproteins, VLDL; Triglycerides
PubMed: 36471375
DOI: 10.1186/s12933-022-01703-5 -
Human Cell Mar 2022The Proviral Integration of Molony murine leukemia virus (PIM)-1 protein contributes to the solid cancers and hematologic malignancies, cell growth, proliferation,... (Review)
Review
The Proviral Integration of Molony murine leukemia virus (PIM)-1 protein contributes to the solid cancers and hematologic malignancies, cell growth, proliferation, differentiation, migration, and other life activities. Many studies have related these functions to its molecular structure, subcellular localization and expression level. However, recognition of specific active sites and their effects on the activity of this constitutively active kinase is still a challenge. Based on the close relationship between its molecular structure and functional activity, this review covers the specific residues involved in the binding of ATP and different substrates in its catalytic domain. This review then elaborates on the relevant changes in protein conformation and cell functions after PIM-1 binds to different substrates. Therefore, this intensive study can improve the understanding of PIM-1-regulated signaling pathways by facilitating the discovery of its potential phosphorylation substrates.
Topics: Animals; Catalytic Domain; Cell Proliferation; Hematologic Neoplasms; Mice; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-pim-1
PubMed: 35000143
DOI: 10.1007/s13577-021-00656-3 -
Archives of Gynecology and Obstetrics Jun 2017In general, male and female are prescribed the same amount of dosage even if most of the cases female required less dosage than male. Physicians are often facing problem... (Review)
Review
PURPOSE
In general, male and female are prescribed the same amount of dosage even if most of the cases female required less dosage than male. Physicians are often facing problem on appropriate drug dosing, efficient treatment, and drug safety for a female in general. To identify and synthesize evidence about the effectiveness of gender-based therapy; provide the information to patients, providers, and health system intervention to ensure safety treatment; and minimize adverse effects.
METHODS
We performed a systematic review to evaluate the effect of gender difference on pharmacotherapy. Published articles from January 1990 to December 2015 were identified using specific term in MEDLINE (PubMed), EMBASE, and the Cochrane library according to search strategies that strengthen the reporting of observational and clinical studies.
RESULTS
Twenty-six studies fulfilled the inclusion criteria for this systematic review, yielding a total of 6309 subjects. We observed that female generally has a lower the gastric emptying time, gastric PH, lean body mass, and higher plasma volume, BMI, body fat, as well as reduce hepatic clearance, difference in activity of Cytochrome P450 enzyme, and metabolize drugs at different rate compared with male. Other significant factors such as conjugation, protein binding, absorption, and the renal elimination could not be ignored. However, these differences can lead to adverse effects in female especially for the pregnant, post-menopausal, and elderly women.
CONCLUSION
This systematic review provides an evidence for the effectiveness of dosage difference to ensure safety and efficient treatment. Future studies on the current topic are, therefore, recommended to reduce the adverse effect of therapy.
Topics: Body Weight; Drug Dosage Calculations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Gastric Emptying; Gastrointestinal Transit; Humans; Male; Pharmacokinetics; Precision Medicine; Sex Factors
PubMed: 28378180
DOI: 10.1007/s00404-017-4363-3 -
Autoimmunity Reviews Sep 2023Psoriatic arthritis (PsA) is an inflammatory complex condition. Posttranslational modifications influence almost all aspects of normal cell biology and pathogenesis. The... (Review)
Review
BACKGROUND AND AIMS
Psoriatic arthritis (PsA) is an inflammatory complex condition. Posttranslational modifications influence almost all aspects of normal cell biology and pathogenesis. The aim of this systematic review was to collect all published evidence regarding posttranslational modifications in PsA, and the main outcome was to evaluate an association between disease outcomes and specific posttranslational modifications in PsA.
METHODS
A systematic electronic search was performed in Medline, PubMed, Cochrane, Virtual Health Library, and Embase databases. A total of 587 articles were identified; 59 were evaluated after removing duplicates and scanning, of which 47 were included. A descriptive analysis was conducted, with results grouped according to the type of posttranslational modification evaluated. The protocol was registered at the PROSPERO database.
RESULTS
Seven posttranslational modifications were identified: citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress. Anti-citrullinated peptide and anti-carbamylated protein have been evaluated in rheumatoid arthritis. There is now information suggesting that these antibodies may be helpful in improving the diagnosis of PsA and that they may demonstrate a correlation with worse disease progression (erosions, polyarticular involvement, and poor treatment response). Glycosylation was associated with increased inflammation and phosphorylation products related to the expression of SIRT2 and pSTAT3 or the presence of Th17 and cytokine interleukin-22, suggesting a possible therapeutic target.
CONCLUSIONS
Posttranslational modifications often play a key role in modulating protein function in PsA and correlate with disease outcomes. Citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress were identified as associated with diagnosis and prognosis.
Topics: Humans; Arthritis, Psoriatic; Protein Processing, Post-Translational; Citrullination; Glycosylation; Arthritis, Rheumatoid
PubMed: 37487969
DOI: 10.1016/j.autrev.2023.103393 -
Scientific Reports Dec 2016We aimed to comprehensively compare two compartmented oral proteomes, the salivary and the dental pellicle proteome. Systematic review and datamining was used to obtain... (Review)
Review
We aimed to comprehensively compare two compartmented oral proteomes, the salivary and the dental pellicle proteome. Systematic review and datamining was used to obtain the physico-chemical, structural, functional and interactional properties of 1,515 salivary and 60 identified pellicle proteins. Salivary and pellicle proteins did not differ significantly in their aliphatic index, hydrophaty, instability index, or isoelectric point. Pellicle proteins were significantly more charged at low and high pH and were significantly smaller (10-20 kDa) than salivary proteins. Protein structure and solvent accessible molecular surface did not differ significantly. Proteins of the pellicle were more phosphorylated and glycosylated than salivary proteins. Ion binding and enzymatic activities also differed significantly. Protein-protein-ligand interaction networks relied on few key proteins. The identified differences between salivary and pellicle proteins could guide proteome compartmentalization and result in specialized functionality. Key proteins could be potential targets for diagnostic or therapeutic application.
Topics: Animals; Data Mining; Dental Enamel Proteins; Dental Pellicle; Humans; Proteome; Salivary Proteins and Peptides
PubMed: 27966577
DOI: 10.1038/srep38882 -
Wiley Interdisciplinary Reviews. RNA Nov 2021In the last decade, an intriguing new paradigm of regulation has emerged in which some transcripts longer than 200 nucleotides and no coding potential, long noncoding... (Review)
Review
In the last decade, an intriguing new paradigm of regulation has emerged in which some transcripts longer than 200 nucleotides and no coding potential, long noncoding RNA (lncRNAs), exhibit the capability to control posttranslational modifications of nonhistone proteins in both invertebrates and vertebrates. The extent of such a regulation is still largely unknown. We performed a systematic review to identify and evaluate the potential impact of lncRNA-dependent methylation of nonhistone proteins. Collectively, these lncRNAs primarily act as scaffolds upon which methyltransferases (MTases) and targets are brought in proximity. In this manner, the N-MTase activity of EZH2, protein arginine-MTase 1/4/5, and SMYD2 is exploited to modulate the stability or the compartmentalization of several nonhistone proteins with roles in cell signaling, gene expression, and RNA processing. Moreover, these lncRNAs can indirectly affect the methylation of nonhistone proteins by transcriptional or posttranscriptional regulation of MTases. Strikingly, the lncRNAs/MTases/nonhistone proteins networking seem to be relevant to carcinogenesis and neurological disorders. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.
Topics: Animals; Gene Expression Regulation; Methylation; Protein Processing, Post-Translational; RNA Processing, Post-Transcriptional; RNA, Long Noncoding
PubMed: 33913612
DOI: 10.1002/wrna.1661 -
Rheumatology (Oxford, England) Nov 2022Small ubiquitin-like modifier (SUMO) proteins can reversibly attach covalently or non-covalently to lysine residues of various substrates. The processes are named...
Small ubiquitin-like modifier (SUMO) proteins can reversibly attach covalently or non-covalently to lysine residues of various substrates. The processes are named SUMOylation and de-SUMOylation, which maintain a dynamic balance in the physiological state, and are regulated by SUMO components. However, the dysregulation of components disturbs the balance and alters the functions of target proteins, which causes the occurrence of diseases. To date, certain SUMO components, including SUMO-1, SUMO-2/3, SAE1/Uba2, Ubc9, PIASs (protein inhibitors of activated signal transducer and activator of transcription) and SENPs (SUMO-specific proteases), have been found to participate in the pathogenesis of RA and their potential value as therapeutic targets also have been highlighted. In addition, single nucleotide polymorphisms (SNPs) in the SUMO components have been reported to be associated with disease susceptibility. Until now, only the SNP site of SUMO-4 has been reported in RA. Here we provided a systematic overview of the general characteristics of SUMO components and highlighted a summary of their impact on RA.
Topics: Humans; Arthritis, Rheumatoid; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitin; Ubiquitin-Activating Enzymes; Ubiquitin-Conjugating Enzymes
PubMed: 35595244
DOI: 10.1093/rheumatology/keac297