Experimental and molecular pathology最新文献

{"title":"Role of A₁ adenosine receptor in cardiovascular diseases: Bridging molecular mechanisms with therapeutic opportunities.","authors":"Warisara Parichatikanond, Ratchanee Duangrat, Narawat Nuamnaichati, Supachoke Mangmool","doi":"10.1016/j.yexmp.2025.104952","DOIUrl":"https://doi.org/10.1016/j.yexmp.2025.104952","url":null,"abstract":"<p><p>Adenosine serves as a critical homeostatic regulator, exerting influence over physiological and pathological conditions in the cardiovascular system. During cellular stress, increased extracellular adenosine levels have been implicated in conferring cardioprotective effects through the activation of adenosine receptors with the A₁ adenosine receptor subtype showing the highest expression in the heart. A₁ adenosine receptor stimulation inhibits adenylyl cyclase activity via heterotrimeric G_i proteins, leading to the activation of distinct downstream effectors involved in cardiovascular homeostasis. While the comprehensive characterization of the pharmacological functions and intracellular signaling pathways associated with the A₁ adenosine receptor subtype is still ongoing, this receptor is widely recognized as a crucial pharmacological target for the treatment of various states of cardiovascular diseases (CVDs). In this review, we focus on elucidating signal transduction of A₁ adenosine receptor, particularly G_i protein-dependent and -independent pathways, and their relevance to cardiovascular protective effects as well as pathological consequences during cellular and tissue stresses in the cardiovascular system. Additionally, we provide comprehensive updates and detailed insights into a range of A₁ adenosine receptor agonists and antagonists, detailing their development and evaluation through preclinical and clinical studies with a specific focus on their potential for the management of CVDs, especially heart diseases.</p>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"141 ","pages":"104952"},"PeriodicalIF":2.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of IL-6 receptor/STAT3 downstream signaling in rheumatoid arthritis patients.","authors":"Fabio Cacciapaglia, Simone Perniola, Stefano Stano, Vincenzo Venerito, Dorotea Natuzzi, Rita Bizzoca, Florenzo Iannone","doi":"10.1016/j.yexmp.2024.104951","DOIUrl":"https://doi.org/10.1016/j.yexmp.2024.104951","url":null,"abstract":"<p><p>Interleukin-6 (IL-6) is a relevant cytokine in rheumatoid arthritis (RA) pathogenesis, potentially activating Janus kinases (JAK)-1, -2, and tyrosine kinase 2 (TYK2), and thus, three signal transducer and activator of transcription (STAT)-1, -3 or - 5 pathways. This pilot study aims to explore differences in phosphorylated (p)STAT3 levels among patients with RA, those not classified as RA (nRA), and healthy donors (HD), providing some clues on the relative contribution of each JAK protein to the downstream of the IL-6-induced STAT3 pathway. Clinical data and blood samples from 80 subjects (41 RA, 14 nRA, and 25 HD) were collected. The activity of the JAK-STAT3 pathway was assessed by Western Blot and Real Time-PCR analysis for the quantification of STAT3 in peripheral blood mononuclear cells (PBMC). Furthermore, the impact of JAK-1, -2, and TYK2 inhibitors on pSTAT3 was assessed in vitro by FACS, with and without IL-6 stimulation in RA patients naïve to treatment with DMARD and steroids. The pSTAT3 (%) was significantly higher in PBMC from RA compared to nRA patients and HD. Furthermore, pSTAT3 (%) was significantly associated with inflammation and disease activity (ESR, CRP, and DAS28). The JAK-1 inhibitor was more effective in reducing pSTAT3 expression in CD14^pos cells of RA patients, while the JAK-2 selective compound was more effective in CD4^pos cells of RA patients. On the contrary, the TYK2 selective agent showed no significant effects. This study highlights the importance of the JAK/STAT3 pathway in RA. Some differences among various JAK proteins have been pointed out, with JAK1 and JAK2 standing as the most relevant mediators of the STAT3 pathway in this in-vitro model after IL-6R activation.</p>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"141 ","pages":"104951"},"PeriodicalIF":2.8,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic analysis of the HPT axis in a model of oligoasthenozoospermia induced by Adenine in rats.","authors":"Nan Yang, Xiao-Ge Wei, Kaiying Li, Fei Wang, Fei Song, Wenjing Sun, Yan Wang, Zhenning Zhao, Jing Mu, Huisheng Ma","doi":"10.1016/j.yexmp.2024.104948","DOIUrl":"https://doi.org/10.1016/j.yexmp.2024.104948","url":null,"abstract":"<p><p>Male infertility is most commonly caused by oligozoospermia, and its pathogenesis is still poorly understood at the molecular level. This study used RNA sequencing (RNA-Seq) technology to identify candidate genes and regulatory pathways that regulate semen quality in the hypothalamic, pituitary, and testicular tissues of healthy rats and Adenine-induced oligozoospermia model rats. Semen quality testing and histological analysis of testicular tissues were performed on both groups of rats. We identified 627, 692, and 437 differentially expressed genes in the hypothalamus, pituitary gland, and testes, respectively. Functional analysis indicates that \"neuronal projections,\" \"positive regulation of hormone biosynthetic process,\" and \"neuroactive ligand-receptor interaction pathways\" are closely related to the hypothalamic-pituitary-testicular (HPT) axis hormone regulation and sperm production. Seven genes (Pomc, Rxfp1, Tac1, Npy, Insl3, Hsd3b3, Lhcgr) have been identified as key candidate genes responsible for regulating sperm quality within the HPT axis, potentially affecting rat reproductive function by influencing testicular development and testosterone secretion. These data provide a theoretical basis for further understanding the molecular mechanisms of reproductive performance in a rat model of oligoasthenozoospermia.</p>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"141 ","pages":"104948"},"PeriodicalIF":2.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms","authors":"Chi-Ying Lee ,&nbsp;Zih-Yin Lai ,&nbsp;Yung-Jen Chuang","doi":"10.1016/j.yexmp.2024.104946","DOIUrl":"10.1016/j.yexmp.2024.104946","url":null,"abstract":"<div><h3>Background</h3><div>During the COVID-19 pandemic, the viral illness caused by SARS-CoV-2 spread through respiratory droplets, resulting in a global pandemic with a range of symptoms from mild to severe. Pathological inflammation posed a critical issue, yet the genetic mechanisms behind the excessive activation of inflammatory responses remained unclear. To uncover the genetic and regulatory basis of the pathogenesis, we first explored possible genetic mechanisms from phenome-wide association studies (PWAS) with different severity levels of COVID-19. PWAS is a genetic research approach that identifies pleiotropic risk variants that contribute to elucidating potential physiological mechanisms from different traits.</div></div><div><h3>Methods</h3><div>We used the PWAS approach to link the multiple clinical symptoms to the variants. We discovered a common variant, rs2109069, in dipeptidyl peptidase 9 (<em>DPP9</em>), which relates to the elevated odds ratio of developing severe illness from COVID-19. Interestingly, the proxy of rs2109069 has been identified as the susceptible locus of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). We thus examined the <em>DPP9</em> expression patterns in selected organs, including the lungs, blood vessels, and skin.</div></div><div><h3>Results</h3><div><em>In silico</em> analysis revealed conserved driver activation between COVID-19-induced inflammation and the association with ILD and IPF. Multi-omics analysis further verified the association of DPP9 with abnormal inflammatory responses in COVID-19. Lastly, gene homology analysis inferred a potential regulatory role of DPP9 in inhibiting inflammasome activation, which suggests that DPP9 deficiency may exacerbate inflammation observed in some COVID-19 patients.</div></div><div><h3>Conclusions</h3><div>Our <em>in silico</em> findings reveal that severe COVID-19 inflammatory responses and inflammatory lung diseases share the same genetic risk loci, helping to elucidate the underlying physiological mechanisms of severe COVID-19 inflammation. Additionally, the individual differences in immune sensitivity may contribute to the varying multi-organ inflammatory effects among patients. The rs2109069 of DPP9 could be a genetic marker to predict the risk of specific COVID-19 symptoms and severity.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104946"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Irisin and neuroinflammation: Challenges and opportunities\" [Experimental and Molecular Pathology 140 (2024) 104941].","authors":"Erika Yolanda Hernández Sandoval, Zulma Dueñas","doi":"10.1016/j.yexmp.2024.104943","DOIUrl":"10.1016/j.yexmp.2024.104943","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":" ","pages":"104943"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of diet and exercise on leukocyte telomere length, markers of oxidative stress and inflammation in rats","authors":"Mehmet Mustafa Tilekli ,&nbsp;Ali Kerim Yılmaz ,&nbsp;Yavuz Yasul ,&nbsp;Nurhan Çon ,&nbsp;Sevcan Mercan ,&nbsp;Nilüfer Tek","doi":"10.1016/j.yexmp.2024.104947","DOIUrl":"10.1016/j.yexmp.2024.104947","url":null,"abstract":"<div><div>Telomere length is an important biomarker of biological aging and is affected by nutrition and physical activity. This study investigated the effects of diets with different fat content<del>s</del> and increased physical activity on certain pro/anti-inflammatory and oxidative stress markers and aging. The study is performed in a randomized, experimental, and controlled design with 48 rats, 8 weeks old, divided into 6 different groups (Control (C), exercise (E), unsaturated fat diet (USF), saturated fat diet (SF), unsaturated fat diet + exercise (USF + E), and saturated fat diet + exercise (SF + E)). The rats performed aerobic swimming exercise for 50 days and were fed a diet with different fat content. TAS, TOS, and MDA levels were determined by colorimetric analysis while 8-OHdG, IL-10, and TNF-α were determined by ELISA. Additionally, leukocyte telomere length is determined by the PCR method. Weight changes were also recorded. Plasma TOS, OSI, and TNF-α were lowest in the USF group and highest in the SF and SF + E groups. MDA, 8-OHdG and TG levels were highest in the SF group. The lowest IL-10 level was detected in group C. TL level was the highest in the USF group. There was also a moderate, negative, and significant correlation between telomeres and TOS, OSI, and TNF-α. The groups with the highest body weight gain were C, SF, and SF + E. Diets low in saturated fat or high in unsaturated fat, and physical activity were associated with leukocyte telomere length and alteration of oxidative and pro/anti-inflammatory markers.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104947"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Anti-tumor effect of antibody-drug conjugate targeting cell adhesion molecule 1 on GIST cells representing small intestinal GIST\" [Experimental and Molecular Pathology 139 (2024) 104922].","authors":"Makoto Yoshida, Jiayin Yuan, Takako Kihara, Neinei Kimura, Takashi Yamasaki, Mizuka Ohkouchi, Yuka Hashikura, Koji Isozaki, Man Hagiyama, Akihiko Ito, Seiichi Hirota","doi":"10.1016/j.yexmp.2024.104934","DOIUrl":"10.1016/j.yexmp.2024.104934","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":" ","pages":"104934"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Suppression of miR-143-3p contributes to the anti-fibrosis effect of atorvastatin on myocardial tissues via the modulation of Smad2 activity\" [Experimental and Molecular Pathology 112 (2020) 104346].","authors":"Bo Yu, Ming Yu, Hongli Zhang, Di Xie, Wei Nie, Kaiyao Shi","doi":"10.1016/j.yexmp.2024.104945","DOIUrl":"10.1016/j.yexmp.2024.104945","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":" ","pages":"104945"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathobiology of myocardial and cardiomyocyte injury in ischemic heart disease: Perspective from seventy years of cell injury research","authors":"L. Maximilian Buja","doi":"10.1016/j.yexmp.2024.104944","DOIUrl":"10.1016/j.yexmp.2024.104944","url":null,"abstract":"<div><div>This review presents a perspective on the pathobiology of acute myocardial infarction, a major manifestation of ischemic heart disease, and related mechanisms of ischemic and toxic cardiomyocyte injury, based on advances and insights that have accrued over the last seventy years, including my sixty years of involvement in the field as a physician-scientist-pathologist. This analysis is based on integration of my research within the broader context of research in the field. A particular focus has been on direct measurements in cardiomyocytes of electrolyte content by electron probe X-ray microanalysis (EPXMA) and Ca²⁺ fluxes by fura-2 microspectrofluorometry. These studies established that increased intracellular Ca²⁺ develops at a transitional stage in the progression of cardiomyocyte injury in association with ATP depletion, other electrolyte alterations, altered cell volume regulation, and altered membrane phospholipid composition. Subsequent increase in total calcium with mitochondrial calcium accumulation can occur. These alterations are characteristic of oncosis, which is an initial pre-lethal state of cell injury with cell swelling due to cell membrane dysfunction in ATP depleted cells; oncosis rapidly progresses to necrosis/necroptosis with physical disruption of the cell membrane, unless the adverse stimulus is rapidly reversed. The observed sequential changes fit a three-stage model of membrane injury leading to irreversible cell injury. The data establish oncosis as the primary mode of cardiomyocyte injury in evolving myocardial infarcts. Oncosis also has been documented to be the typical form of non-ischemic cell injury due to toxins. Cardiomyocytes with less energy impairment have the capability of undergoing apoptosis and autophagic death as well as oncosis, as is seen in pathological remodeling in chronic heart failure. Work is ongoing to apply the insights from experimental studies to better understand and ameliorate myocardial ischemia and reperfusion injury in patients. The perspective and insights in this review are derived from basic principles of pathology, an integrative discipline focused on mechanisms of disease affecting the cell, the organizing unit of living organisms.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104944"},"PeriodicalIF":2.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic criteria and therapeutic implications of rapid-onset demyelinating polyneuropathies","authors":"Wiktoria Rałowska-Gmoch ,&nbsp;Magdalena Koszewicz ,&nbsp;Beata Łabuz-Roszak ,&nbsp;Sławomir Budrewicz ,&nbsp;Edyta Dziadkowiak","doi":"10.1016/j.yexmp.2024.104942","DOIUrl":"10.1016/j.yexmp.2024.104942","url":null,"abstract":"<div><div>Guillain-Barré syndrome (GBS) and acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) are the most common autoimmune polyneuropathies. Their aetiology is unclear. The pathomechanism includes damage mainly to the myelin sheath and, in the long-term process, secondary axonal loss. Both inflammatory polyneuropathies involve different combinations of motor, sensory and autonomic fibres in the peripheral nerves. The differential diagnosis should be based on clinical and neurophysiological features, and laboratory tests. Numerous studies aim to demonstrate the most common errors in the diagnosis of Guillain-Barré syndrome and acute-onset CIDP. Misdiagnosis can result in the wrong treatment. We still do not have reliable markers to help diagnose the disease or to monitor the effectiveness of the therapy.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104942"},"PeriodicalIF":2.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142579061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}