Clinical Implication of Phosphodiesterase-4-Inhibition

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(3), P. 1209 - 1209

Published: Jan. 21, 2022

The pleiotropic function of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathways in health and disease led to the development pharmacological phosphodiesterase inhibitors (PDE-I) attenuate cAMP degradation. While there are many isotypes PDE, a predominant role PDE4 is regulate fundamental functions, including endothelial epithelial barrier stability, modulation inflammatory responses cognitive and/or mood functions. This makes use PDE4-I an interesting tool for various therapeutic approaches. However, due presence tissues, significant danger serious side effects. Based on this, aim this review provide comprehensive overview approaches effects different applications. In summary, despite obstacles approaches, current data warrant future research utilize potential 4 inhibition.

Language: Английский

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Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Feb. 25, 2022

Abstract This study investigates aberrant DNA methylations as potential diagnosis and prognosis markers for esophageal squamous-cell carcinoma (ESCC), which if diagnosed at advanced stages has <30% five-year survival rate. Comparing genome-wide methylation sites of 91 ESCC matched adjacent normal tissues, we identified 35,577 differentially methylated CpG (DMCs) characterized their distribution patterns. Integrating whole-genome RNA-sequencing data the same samples, found multiple dysregulated transcription factors ESCC-specific genomic correlates DMCs. Using featured DMCs, developed a 12-marker diagnostic panel with high accuracy in our dataset TCGA dataset, 4-marker prognostic distinguishing high-risk patients. In-vitro experiments validated functions 4 marker host genes. Together these results provide additional evidence important roles development progression. Our DMC-based panels have values clinical care ESCC, laying foundations developing targeted assays future non-invasive cancer detection methods.

Language: Английский

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Curcumin in Cancer and Inflammation: An In-Depth Exploration of Molecular Interactions, Therapeutic Potentials, and the Role in Disease Management

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2911 - 2911

Published: March 2, 2024

This paper delves into the diverse and significant roles of curcumin, a polyphenolic compound from Curcuma longa plant, in context cancer inflammatory diseases. Distinguished by its unique molecular structure, curcumin exhibits potent biological activities including anti-inflammatory, antioxidant, potential anticancer effects. The research comprehensively investigates curcumin’s interactions with key proteins involved progression response, primarily through docking studies. In cancer, effectiveness is determined examining interaction pivotal like CDK2, CK2α, GSK3β, DYRK2, EGFR, among others. These suggest role impeding cell proliferation survival. Additionally, highlights impact on inflammation influence such as COX-2, CRP, PDE4, MD-2, which are central to pathway. vitro clinical studies extensively reviewed, shedding light binding mechanisms, pharmacological impacts, therapeutic application various cancers conditions. understanding functionality agent. Conclusively, this review emphasizes promise treating wide range health issues, attributed complex chemistry broad properties. points towards growing importance multi-faceted natural medical scientific community.

Language: Английский

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The Complexity and Multiplicity of the Specific cAMP Phosphodiesterase Family: PDE4, Open New Adapted Therapeutic Approaches

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(18), P. 10616 - 10616

Published: Sept. 13, 2022

Cyclic nucleotides (cAMP, cGMP) play a major role in normal and pathologic signaling. Beyond receptors, cyclic nucleotide phosphodiesterases; (PDEs) rapidly convert the its respective 5'-nucleotide to control intracellular cAMP and/or cGMP levels maintain physiological state. However, many pathologies, dysregulations of various PDEs (PDE1-PDE11) contribute mainly organs tissue failures related uncontrolled phosphorylation cascade. Among these, PDE4 represents greatest family, since it is constituted by 4 genes with multiple variants differently distributed at tissue, cellular subcellular levels, allowing different fine-tuned regulations. Since 1980s, pharmaceutical companies have developed inhibitors (PDE4-I) overcome cardiovascular diseases. Since, they encountered undesired problems, (emesis), focused their research on other PDEs. Today, increases knowledge complex regulations tissues evolution drug design, resulted renewal PDE4-I development. The present review describes recent development targeting diseases, obesity, diabetes, ulcerative colitis, Crohn's disease, malignancies, fatty liver osteoporosis, depression, as well COVID-19. direct therapeutic approach extended developing allosteric protein/protein interactions act PDE interactome.

Language: Английский

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The regulatory role of PDE4B in the progression of inflammatory function study

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: Oct. 6, 2022

Inflammation is a response of the body to external stimuli (eg. chemical irritants, bacteria, viruses, etc.), and when are persistent, they tend trigger chronic inflammation. The presence inflammation an important component tumor microenvironment produced by variety inflammatory cells macrophages, neutrophils, leukocytes, etc.). relationship between cancer development has been widely accepted, associated with many cancers, including bronchitis lung cancer, cystitis inducing bladder cancer. Moreover, colorectitis more likely develop into colorectal Therefore, specific cellular mechanisms hot topic research. Recent studies have identified phosphodiesterase 4B (PDE4B), member (PDEs) protein family, as major cyclic AMP (cAMP) metabolizing enzyme in cells, therapeutic role PDE4B inflammation, In this review, we will present tumors potential clinical application.

Language: Английский

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GNAS mutation inhibits growth and induces phosphodiesterase 4D expression in colorectal cancer cell lines

International Journal of Cancer, Journal Year: 2024, Volume and Issue: 154(11), P. 1987 - 1998

Published: Feb. 6, 2024

Approximately 5% of colorectal cancers (CRCs) have a gain-of-function mutation in the GNAS gene, which leads to activation cAMP-dependent signaling pathways and associates with poor prognosis. We investigated effect an activating CRC cell lines on gene expression proliferation vitro, tumor growth vivo. GNAS-mutated (GNASmt) HCT116 cells showed stimulated synthesis cAMP as compared parental (Par) cells. The most upregulated GNASmt was cAMP-hydrolyzing phosphodiesterase 4D (PDE4D) detected by RNA sequencing. To further validate our finding, we analyzed PDE4D set human tumors (n = 35) demonstrated overexpression mutant wild-type tumors. proliferated more slowly than Par PDE4 inhibitor Ro 20-1724 subtype selective GEBR-7b suppressed without inhibitory these inhibitors also seen intrinsically SK-CO-1 line having high levels expression. In vivo, formed smaller nude mice. conclusion, findings demonstrate that results suppression Moreover, mutation-induced provides potential avenue impede through use inhibitors.

Language: Английский

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Whole-exome sequencing identifies somatic mutations and intratumor heterogeneity in inflammatory breast cancer

npj Breast Cancer, Journal Year: 2021, Volume and Issue: 7(1)

Published: June 1, 2021

Abstract Inflammatory breast cancer (IBC) is the most aggressive form of cancer. Although it a rare subtype, IBC responsible for roughly 10% deaths. In order to obtain better understanding genomic landscape and intratumor heterogeneity (ITH) in IBC, we conducted whole-exome sequencing 16 tissue samples (12 tumor four normal samples) from six hormone-receptor-positive patients, analyzed somatic mutations copy number aberrations, inferred subclonal structures demonstrate ITH. Our results showed that KMT2C was frequently mutated gene (42%, 5/12 samples), followed by HECTD1 , LAMA3 FLG2 UGT2B4 STK33 BRCA2 ACP4 PIK3CA DNAH8 (all nine genes tied at 33% frequency, 4/12 samples). data indicated PTEN FBXW7 may be considered driver IBC. We identified various different levels ITH between EIF4G3 IL12RB2 PDE4B potentially generate

Language: Английский

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Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Feb. 3, 2023

Abstract Background Chronic inflammation is a well-known risk factor for the development of gastric cancer (GC). Nevertheless, molecular mechanisms underlying inflammation-related GC progression are incompletely defined. Methods Bioinformatic analysis was performed based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), expression miR-26b-5p in cells tissues validated by quantitative real-time PCR (qRT-PCR). Cell proliferation examined through Counting Kit-8 (CCK8), 5-Ethynyl-2’-deoxyuridine (EdU), colony formation, flow cytometry, tumor xenografts. Correlation between Cyclin dependent kinase 8 (CDK8) or Phosphodiesterase 4B (PDE4B) analyzed dual-luciferase reporter assays, qRT-PCR, Western blot. effect Signal transducer activator transcription 3 (STAT3) pathway investigated using blot, immunofluorescence (IF), immunohistochemistry (IHC). impact STAT3 determined assays qRT-PCR. Results significantly downregulated Helicobacter Pylori (H. pylori )-infected cells. decreased also detected compared to normal epithelium (GES1) adjacent tissues. low promoted vitro vivo related poor outcome patients. In terms mechanism, directly targeted PDE4B CDK8, resulting phosphorylation nuclear translocation STAT3, which associated with regulation miR-26b-5p. Notably, transcriptionally suppressed thus forming miR-26b-5p-PDE4B/CDK8-STAT3 positive feedback loop. Conclusion newly identified loop plays an important role may serve as promising therapeutic target GC.

Language: Английский

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PDE4 Inhibitors for Disease Therapy: Advances and Future Perspective

Future Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 15(13), P. 1185 - 1207

Published: July 1, 2023

The PDE4 enzyme family is specifically responsible for hydrolyzing cAMP and plays a vital role in regulating the balance of second messengers. As crucial regulator signal transduction, has displayed promising pharmacological targets variety diseases, which its inhibitors have been used as therapeutic strategy. This review provides comprehensive summary development past few years, along with structure, clinical research progress multiple PDE4, focusing on strategies inhibitors. We hope our analysis will provide significant reference future new

Language: Английский

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Modulation of Cognitive Activity by Plant-Based Extracts (Allium cepa, Coffea robusta, and Brassica oleracea) through the Phosphodiesterase 4B inhibition: Insite from a Mice Model Study

Phytomedicine Plus, Journal Year: 2025, Volume and Issue: unknown, P. 100778 - 100778

Published: March 1, 2025

Language: Английский

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