Expert Reviews in Molecular Medicine最新文献

{"title":"Inflammasomes in breast cancer: the ignition spark of progression and resistance?","authors":"Sawsan Elgohary,&nbsp;Hend M El Tayebi","doi":"10.1017/erm.2023.14","DOIUrl":"https://doi.org/10.1017/erm.2023.14","url":null,"abstract":"<p><p>Inflammation and immune evasion are major key players in breast cancer (BC) progression. Recently, the FDA approved the use of anti-programmed death-ligand 1 antibody (anti-PD-L1) and phosphoinositide 3-kinase (PI3K) inhibitors against aggressive BC. Despite the paradigm shift in BC treatments, patients still suffer from resistance, recurrence and serious immune-related adverse events. These obstacles require unravelling of the hidden molecular contributors for such therapy failure hence yielding therapeutics that are at least as efficient yet safer. Inflammasome pathway is activated when the pattern recognition receptor senses danger signals (danger-associated molecular patterns) from damagedRdying cells or pathogen-associated molecular patterns found in microbes, leading to secretion of the active pro-inflammatory cytokines interleukin-1<i>β</i> (IL-1<i>β</i>) and interleukin-18 (IL-18). It has been shown throughout numerous studies that inflammasome pathway enhanced invasion, metastasis, provoked BC progression and therapy resistance. Additionally, inflammasomes upregulated the proliferative index ki67 and enhanced PD-L1 expression leading to immunotherapy resistance. IL-1<i>β</i> contributed to significant decrease in oestrogen receptor levels and promoted BC chemo-resistance. High levels of IL-18 in sera of BC patients were associated with worst prognosis. Stimulation of purinergic receptors and modulation of adipokines in obese subjects activated inflammasomes that evoked radiotherapy resistance and BC progression. The micro RNA miR-223-3p attenuated the inflammasome over-expression leading to lowered tumour volume and lessened angiogenesis in BC. This review sheds the light on the molecular pathways of inflammasomes and their impacts in distinct BC subtypes. In addition, it highlights novel strategies in treatment and prevention of BC.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e22"},"PeriodicalIF":6.2,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9741280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt/<i>β</i>-catenin signalling pathway in breast cancer cells and its effect on reversing tumour drug resistance by alkaloids extracted from traditional Chinese medicine.","authors":"Xin-Lei Wu,&nbsp;Shen-Guo Lin,&nbsp;Yi-Wen Mao,&nbsp;Jun-Xian Wu,&nbsp;Chen-Da Hu,&nbsp;Rui Lv,&nbsp;Hong-Dou Zeng,&nbsp;Ming-Hao Zhang,&nbsp;Li-Zi Lin,&nbsp;Shan-Shan Ouyang,&nbsp;Ya-Xin Zhao","doi":"10.1017/erm.2023.16","DOIUrl":"https://doi.org/10.1017/erm.2023.16","url":null,"abstract":"<p><p>Breast cancer is a high-risk disease with a high mortality rate among women. Chemotherapy plays an important role in the treatment of breast cancer. However, chemotherapy eventually results in tumours that are resistant to drugs. In recent years, many studies have revealed that the activation of Wnt/<i>β</i>-catenin signalling is crucial for the emergence and growth of breast tumours as well as the development of drug resistance. Additionally, drugs that target this pathway can reverse drug resistance in breast cancer therapy. Traditional Chinese medicine has the properties of multi-target and tenderness. Therefore, integrating traditional Chinese medicine and modern medicine into chemotherapy provides a new strategy for reversing the drug resistance of breast tumours. This paper mainly reviews the possible mechanism of Wnt/<i>β</i>-catenin in promoting the process of breast tumour drug resistance, and the progress of alkaloids extracted from traditional Chinese medicine in the targeting of this pathway in order to reverse the drug resistance of breast cancer.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e21"},"PeriodicalIF":6.2,"publicationDate":"2023-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10109177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated phosphate metabolism in autism spectrum disorder: associations and insights for future research.","authors":"Ronald B Brown","doi":"10.1017/erm.2023.15","DOIUrl":"https://doi.org/10.1017/erm.2023.15","url":null,"abstract":"<p><p>Studies of autism spectrum disorder (ASD) related to exposure to toxic levels of dietary phosphate are lacking. Phosphate toxicity from dysregulated phosphate metabolism can negatively impact almost every major organ system of the body, including the central nervous system. The present paper used a grounded theory-literature review method to synthesise associations of dysregulated phosphate metabolism with the aetiology of ASD. Cell signalling in autism has been linked to an altered balance between phosphoinositide kinases, which phosphorylate proteins, and the counteracting effect of phosphatases in neuronal membranes. Glial cell overgrowth in the developing ASD brain can lead to disturbances in neuro-circuitry, neuroinflammation and immune responses which are potentially related to excessive inorganic phosphate. The rise in ASD prevalence has been suggested to originate in changes to the gut microbiome from increasing consumption of additives in processed food, including phosphate additives. Ketogenic diets and dietary patterns that eliminate casein also reduce phosphate intake, which may account for many of the suggested benefits of these diets in children with ASD. Dysregulated phosphate metabolism is causatively linked to comorbid conditions associated with ASD such as cancer, tuberous sclerosis, mitochondrial dysfunction, diabetes, epilepsy, obesity, chronic kidney disease, tauopathy, cardiovascular disease and bone mineral disorders. Associations and proposals presented in this paper offer novel insights and directions for future research linking the aetiology of ASD with dysregulated phosphate metabolism and phosphate toxicity from excessive dietary phosphorus intake.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e20"},"PeriodicalIF":6.2,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9965953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Helicobacter pylori</i> virulence factors: subversion of host immune system and development of various clinical outcomes.","authors":"Roghayeh Mohammadzadeh,&nbsp;Shaho Menbari,&nbsp;Abbas Pishdadian,&nbsp;Hadi Farsiani","doi":"10.1017/erm.2023.17","DOIUrl":"https://doi.org/10.1017/erm.2023.17","url":null,"abstract":"<p><p><i>Helicobacter pylori</i> (<i>H. pylori</i>) is a worldwide spread bacterium, co-evolving with humans for at least 100 000 years. Despite the uncertainty about the mode of <i>H. pylori</i> transmission, the development of intra-gastric and extra-gastric diseases is attributed to this bacterium. The morphological transformation and production of heterogenic virulence factors enable <i>H. pylori</i> to overcome the harsh stomach environment. Using numerous potent disease-associated virulence factors makes <i>H. pylori</i> a prominent pathogenic bacterium. These bacterial determinants are adhesins (e.g., blood group antigen-binding adhesin (BabA)/sialic acid-binding adhesin (SabA)), enzymes (e.g., urease), toxins (e.g., vacuolating cytotoxin A (VacA)), and effector proteins (e.g., cytotoxin-associated gene A (CagA)) involved in colonisation, immune evasion, and disease induction. <i>H. pylori</i> not only cleverly evades the immune system but also robustly induces immune responses. This insidious bacterium employs various strategies to evade human innate and adaptive immune responses, leading to a life-long infection. Owing to the alteration of surface molecules, innate immune receptors couldn't recognise this bacterium; moreover, modulation of effector T cells subverts adaptive immune response. Most of the infected humans are asymptomatic and only a few of them present severe clinical outcomes. Therefore, the identification of virulence factors will pave the way for the prediction of infection severity and the development of an effective vaccine. <i>H. pylori</i> virulence factors are hereby comprehensively reviewed and the bacterium evasion from the immune response is properly discussed.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e23"},"PeriodicalIF":6.2,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9834572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual role of glycans and binding receptors in pathogenesis of enveloped viruses (by mainly focusing on two recent pandemics).","authors":"Fatemeh Pourrajab,&nbsp;Mohamad Reza Zare-Khormizi","doi":"10.1017/erm.2023.12","DOIUrl":"https://doi.org/10.1017/erm.2023.12","url":null,"abstract":"<p><p>A period of about a decade has been estimated to pass for the emergence of a new infectious strain of a virus that may lead to the occurrence of a pandemic one. It is now suggested that the variants of the 1918 H1N1 and coronavirus disease-19 pandemics could have existed in humans after the initial cross-species introduction to humans and underwent multiple low-level seasonal epidemics before the occurrence of their outbreaks. They share similarities in the continuation, widespreadness due to high transmissibility, high fatality rate and clinical symptoms. They are assumed to share a similar principle of a zoonotic source and a cross-species pathway for transmission. They show some similarities in their pathogenesis with other enveloped viruses: Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), human immunodeficiency virus, Ebola, Lassa and measles viruses. The highly pathogenic nature of these viruses and their genetic variants may depend on their binding affinity for host cell receptors, whereby they efficiently circumvent or block host cell immune responses triggered by cytokines (interferon). High transmission rates and viral pathogenicity are attributed to glycan moieties that facilitate virus binding to host multiple receptors and cell entry, thereby helping viruses to evade immune recognition and response. Also, mucosa glycotopes are a matter of concern that play as primary sites for virus attachment and body entry. Finding general lectins or ligands that block the viral-host receptors interaction or identifying individual glycotopes is the therapeutic and prognosis topic that demands the main focus.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e19"},"PeriodicalIF":6.2,"publicationDate":"2023-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10002811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New perspective on DNA response pathway (DDR) in glioblastoma, focus on classic biomarkers and emerging roles of ncRNAs.","authors":"Bianca Oana Pirlog,&nbsp;Silvina Ilut,&nbsp;Radu Pirlog,&nbsp;Paul Chiroi,&nbsp;Andreea Nutu,&nbsp;Delia Ioana Radutiu,&nbsp;George Daniel Cuc,&nbsp;Ioana Berindan-Neagoe,&nbsp;Seyed Fazel Nabavi,&nbsp;Rosanna Filosa,&nbsp;Seyed Mohammad Nabavi","doi":"10.1017/erm.2023.10","DOIUrl":"https://doi.org/10.1017/erm.2023.10","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) is the most frequent type of primary brain cancer, having a median survival of only 15 months. The current standard of care includes a combination of surgery, radiotherapy (RT) and chemotherapy with temozolomide, but with limited results. Moreover, multiple studies have shown that tumour relapse and resistance to classic therapeutic approaches are common events that occur in the majority of patients, and eventually leading to death. New approaches to better understand the intricated tumour biology involved in GBM are needed in order to develop personalised treatment approaches. Advances in cancer biology have widen our understanding over the GBM genome and allowing a better classification of these tumours based on their molecular profile.</p><p><strong>Methods: </strong>A new targeted therapeutic approach that is currently investigated in multiple clinical trials in GBM is represented by molecules that target various defects in the DNA damage repair (DDR) pathway, a mechanism activated by endogenous and exogenous factors that induce alteration of DNA, and is involved for the development of chemotherapy and RT resistance. This intricate pathway is regulated by p53, two important kinases ATR and ATM and non-coding RNAs including microRNAs, long-non-coding RNAs and circular RNAs that regulate the expression of all the proteins involved in the pathway.</p><p><strong>Results: </strong>Currently, the most studied DDR inhibitors are represented by PARP inhibitors (PARPi) with important results in ovarian and breast cancer. PARPi are a class of tumour agnostic drugs that showed their efficacy also in other localisations such as colon and prostate tumours that have a molecular signature associated with genomic instability. These inhibitors induce the accumulation of intracellular DNA damage, cell cycle arrest, mitotic catastrophe and apoptosis.</p><p><strong>Conclusions: </strong>This study aims to provide an integrated image of the DDR pathway in glioblastoma under physiological and treatment pressure with a focus of the regulatory roles of ncRNAs. The DDR inhibitors are emerging as an important new therapeutic approach for tumours with genomic instability and alterations in DDR pathways. The first clinical trials with PARPi in GBM are currently ongoing and will be presented in the article. Moreover, we consider that by incorporating the regulatory network in the DDR pathway in GBM we can fill the missing gaps that limited previous attempts to effectively target it in brain tumours. An overview of the importance of ncRNAs in GBM and DDR physiology and how they are interconnected is presented.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e18"},"PeriodicalIF":6.2,"publicationDate":"2023-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9629598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current updates on arrhythmia within Timothy syndrome: genetics, mechanisms and therapeutics.","authors":"Congshan Jiang,&nbsp;Yanmin Zhang","doi":"10.1017/erm.2023.11","DOIUrl":"https://doi.org/10.1017/erm.2023.11","url":null,"abstract":"<p><p>Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative gene <i>CACNA1C</i> encoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function of <i>CACNA1C</i> gene encoding Ca_v1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation-transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e17"},"PeriodicalIF":6.2,"publicationDate":"2023-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10334464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting N-cadherin (CDH2) and the malignant bone marrow microenvironment in acute leukaemia.","authors":"Jessica Parker,&nbsp;Sean Hockney,&nbsp;Orest W Blaschuk,&nbsp;Deepali Pal","doi":"10.1017/erm.2023.13","DOIUrl":"https://doi.org/10.1017/erm.2023.13","url":null,"abstract":"<p><p>This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia-niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e16"},"PeriodicalIF":6.2,"publicationDate":"2023-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10317925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"25 years of <i>ERMM</i>.","authors":"Nicola Curtin","doi":"10.1017/erm.2023.8","DOIUrl":"https://doi.org/10.1017/erm.2023.8","url":null,"abstract":"","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e12"},"PeriodicalIF":6.2,"publicationDate":"2023-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10317905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Fusobacterium nucleatum</i>: a novel immune modulator in breast cancer?","authors":"Alexa Little,&nbsp;Mark Tangney,&nbsp;Michael M Tunney,&nbsp;Niamh E Buckley","doi":"10.1017/erm.2023.9","DOIUrl":"https://doi.org/10.1017/erm.2023.9","url":null,"abstract":"<p><p>Breast cancer was the most commonly diagnosed cancer worldwide in 2020. Greater understanding of the factors which promote tumour progression, metastatic development and therapeutic resistance is needed. In recent years, a distinct microbiome has been detected in the breast, a site previously thought to be sterile. Here, we review the clinical and molecular relevance of the oral anaerobic bacterium <i>Fusobacterium nucleatum</i> in breast cancer. <i>F. nucleatum</i> is enriched in breast tumour tissue compared with matched healthy tissue and has been shown to promote mammary tumour growth and metastatic progression in mouse models. Current literature suggests that <i>F. nucleatum</i> modulates immune escape and inflammation within the tissue microenvironment, two well-defined hallmarks of cancer. Furthermore, the microbiome, and <i>F. nucleatum</i> specifically, has been shown to affect patient response to therapy including immune checkpoint inhibitors. These findings highlight areas of future research needed to better understand the influence of <i>F. nucleatum</i> in the development and treatment of breast cancer.</p>","PeriodicalId":50462,"journal":{"name":"Expert Reviews in Molecular Medicine","volume":"25 ","pages":"e15"},"PeriodicalIF":6.2,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10016299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}