Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8

Morla, Shravan; Desai, Umesh R.

doi:10.3390/biom10081166

Cited by 8 publications

(6 citation statements)

References 48 publications

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“…It also participates in the supportive activities of inborn immunity ( 37 ). The elevated MMP-8 activities facilitate the etiology of numerous illnesses, such as atherosis, lung fibrosis, and septic disease ( 38 ). Pedro Martínez-Paz et al.…”

Section: Discussionmentioning

confidence: 99%

Six potential biomarkers in septic shock: a deep bioinformatics and prospective observational study

et al. 2023

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BackgroundSeptic shock occurs when sepsis is related to severe hypotension and leads to a remarkable high number of deaths. The early diagnosis of septic shock is essential to reduce mortality. High-quality biomarkers can be objectively measured and evaluated as indicators to accurately predict disease diagnosis. However, single-gene prediction efficiency is inadequate; therefore, we identified a risk-score model based on gene signature to elevate predictive efficiency.MethodsThe gene expression profiles of GSE33118 and GSE26440 were downloaded from the Gene Expression Omnibus (GEO) database. These two datasets were merged, and the differentially expressed genes (DEGs) were identified using the limma package in R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of DEGs were performed. Subsequently, Lasso regression and Boruta feature selection algorithm were combined to identify the hub genes of septic shock. GSE9692 was then subjected to weighted gene co-expression network analysis (WGCNA) to identify the septic shock-related gene modules. Subsequently, the genes within such modules that matched with septic shock-related DEGs were identified as the hub genes of septic shock. To further understand the function and signaling pathways of hub genes, we performed gene set variation analysis (GSVA) and then used the CIBERSORT tool to analyze the immune cell infiltration pattern of diseases. The diagnostic value of hub genes in septic shock was determined using receiver operating characteristic (ROC) analysis and verified using quantitative PCR (qPCR) and Western blotting in our hospital patients with septic shock.ResultsA total of 975 DEGs in the GSE33118 and GSE26440 databases were obtained, of which 30 DEGs were remarkably upregulated. With the use of Lasso regression and Boruta feature selection algorithm, six hub genes (CD177, CLEC5A, CYSTM1, MCEMP1, MMP8, and RGL4) with expression differences in septic shock were screened as potential diagnostic markers for septic shock among the significant DEGs and were further validated in the GSE9692 dataset. WGCNA was used to identify the co-expression modules and module–trait correlation. Enrichment analysis showed significant enrichment in the reactive oxygen species pathway, hypoxia, phosphatidylinositol 3-kinases (PI3K)/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, nuclear factor-κβ/tumor necrosis factor alpha (NF-κβ/TNF-α), and interleukin-6 (IL-6)/Janus Kinase (JAK)/Signal Transducers and Activators of Transcription 3 (STAT3) signaling pathways. The receiver operating characteristic curve (ROC) of these signature genes was 0.938, 0.914, 0.939, 0.956, 0.932, and 0.914, respectively. In the immune cell infiltration analysis, the infiltration of M0 macrophages, activated mast cells, neutrophils, CD8 T cells, and naive B cells was more significant in the septic shock group. In addition, higher expression levels of CD177, CLEC5A, CYSTM1, MCEMP1, MMP8, and RGL4 messenger RNA (mRNA) were observed in peripheral blood mononuclear cells (PBMCs) isolated from septic shock patients than from healthy donors. Higher expression levels of CD177 and MMP8 proteins were also observed in the PBMCs isolated from septic shock patients than from control participants.ConclusionsCD177, CLEC5A, CYSTM1, MCEMP1, MMP8, and RGL4 were identified as hub genes, which were of considerable value in the early diagnosis of septic shock patients. These preliminary findings are of great significance for studying immune cell infiltration in the pathogenesis of septic shock, which should be further validated in clinical studies and basic studies.

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Section: Discussionmentioning

confidence: 99%

Six potential biomarkers in septic shock: a deep bioinformatics and prospective observational study

et al. 2023

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“…For this, we evaluated the electrostatic surface potential (ESP) of the three studied proteins, as shown in Fig. 3 66 . The presence of multiple electropositive micro-domains being close to each other could favor the binding of small molecule inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies

Rudrapal,

Eltayeb,

Rakshit

et al. 2023

Sci Rep

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Cyclooxygenase (COX) and Lipoxygenase (LOX) are essential enzymes for arachidonic acid (AA) to eicosanoids conversion. These AA-derived eicosanoids are essential for initiating immunological responses, causing inflammation, and resolving inflammation. Dual COX/5-LOX inhibitors are believed to be promising novel anti-inflammatory agents. They inhibit the synthesis of prostaglandins (PGs) and leukotrienes (LTs), but have no effect on lipoxin formation. This mechanism of combined inhibition circumvents certain limitations for selective COX-2 inhibitors and spares the gastrointestinal mucosa. Natural products, i.e. spice chemicals and herbs, offer an excellent opportunity for drug discovery. They have proven anti-inflammatory properties. However, the potential of a molecule to be a lead/ drug candidate can be much more enhanced if it has the property of inhibition in a dual mechanism. Synergistic activity is always a better option than the molecule's normal biological activity. Herein, we have explored the dual COX/5-LOX inhibition property of the three major potent phytoconsituents (curcumin, capsaicin, and gingerol) from Indian spices using in silico tools and biophysical techniques in a quest to identify their probable inhibitory role as anti-inflammatory agents. Results revealed the dual COX/5-LOX inhibitory potential of curcumin. Gingerol and capsaicin also revealed favorable results as dual COX/5-LOX inhibitors. Our results are substantiated by target similarity studies, molecular docking, molecular dynamics, energy calculations, DFT, and QSAR studies. In experimental inhibitory (in vitro) studies, curcumin exhibited the best dual inhibitory activities against COX-1/2 and 5-LOX enzymes. Capsaicin and gingerol also showed inhibitory potential against both COX and LOX enzymes. In view of the anti-inflammatory potential these spice chemicals, this research could pave the way for more scientific exploration in this area for drug discovery.

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“…Plasmatic MMP8 concentrations were linked to the presence and severity of coronary artery disease [ 193 ] and serum MMP8 levels were associated with cardiovascular outcome in patients [ 194 ]. The recent discovery of small molecule inhibitors of MMP8 such as sulfated mimetics of glycosaminoglycans (sulfated quinazolinones) looks promising to prevent atherosclerosis-mediated cardiovascular events [ 195 ].…”

Section: Mmps and Timps In Atherosclerosis And Diabetes Vascular Comp...mentioning

confidence: 99%

Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Metabolism: Insights into Health and Disease

Molière

Jaulin

Tomasetto

et al. 2023

IJMS

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Matrix metalloproteinases (MMPs) are a family of zinc-activated peptidases that can be classified into six major classes, including gelatinases, collagenases, stromelysins, matrilysins, membrane type metalloproteinases, and other unclassified MMPs. The activity of MMPs is regulated by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). MMPs are involved in a wide range of biological processes, both in normal physiological conditions and pathological states. While some of these functions occur during development, others occur in postnatal life. Although the roles of several MMPs have been extensively studied in cancer and inflammation, their function in metabolism and metabolic diseases have only recently begun to be uncovered, particularly over the last two decades. This review aims to summarize the current knowledge regarding the metabolic roles of metalloproteinases in physiology, with a strong emphasis on adipose tissue homeostasis, and to highlight the consequences of impaired or exacerbated MMP actions in the development of metabolic disorders such as obesity, fatty liver disease, and type 2 diabetes.

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Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8

Cited by 8 publications

References 48 publications

Six potential biomarkers in septic shock: a deep bioinformatics and prospective observational study

Six potential biomarkers in septic shock: a deep bioinformatics and prospective observational study

Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies

Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Metabolism: Insights into Health and Disease

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