Experimental biology and medicine (Maywood, N.J.)最新文献

{"title":"Exploring epigenetic and microRNA approaches for γ-globin gene regulation.","authors":"Athena Starlard-Davenport, Ashley Fitzgerald, Betty S Pace","doi":"10.1177/15353702211028195","DOIUrl":"https://doi.org/10.1177/15353702211028195","url":null,"abstract":"Therapeutic interventions aimed at inducing fetal hemoglobin and reducing the concentration of sickle hemoglobin is an effective approach to ameliorating acute and chronic complications of sickle cell disease, exemplified by the long-term use of hydroxyurea. However, there remains an unmet need for the development of additional safe and effective drugs for single agent or combination therapy for individuals with β-hemoglobinopathies. Regulation of the γ-globin to β-globin switch is achieved by chromatin remodeling at the HBB locus on chromosome 11 and interactions of major DNA binding proteins, such as KLF1 and BCL11A in the proximal promoters of the globin genes. Experimental evidence also supports a role of epigenetic modifications including DNA methylation, histone acetylation/methylation, and microRNA expression in γ-globin gene silencing during development. In this review, we will critically evaluate the role of epigenetic mechanisms in γ-globin gene regulation and discuss data generated in tissue culture, pre-clinical animal models, and clinical trials to support drug development to date. The question remains whether modulation of epigenetic pathways will produce sufficient efficacy and specificity for fetal hemoglobin induction and to what extent targeting these pathways form the basis of prospects for clinical therapy.","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"2347-2357"},"PeriodicalIF":3.2,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/15353702211028195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39207778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric oxide modulation in neuroinflammation and the role of mesenchymal stem cells.","authors":"Pan M Liy,&nbsp;Nur Nabilah A Puzi,&nbsp;Shinsmon Jose,&nbsp;Sharmili Vidyadaran","doi":"10.1177/1535370221997052","DOIUrl":"https://doi.org/10.1177/1535370221997052","url":null,"abstract":"<p><p>Nitric oxide is a versatile mediator formed by enzymes called nitric oxide synthases. It has numerous homeostatic functions and important roles in inflammation. Within the inflamed brain, microglia and astrocytes produce large amounts of nitric oxide during inflammation. Excessive nitric oxide causes neuronal toxicity and death and mesenchymal stem cells can be used as an approach to limit the neuronal damage caused by neuroinflammation. Mesenchymal stem cell therapy ameliorates inflammation and neuronal damage in disease models of Alzheimer's disease, Parkinson's disease, and other neuroinflammatory disorders. Interestingly, we have reported that <i>in vitro</i>, mesenchymal stem cells themselves contribute to a rise in nitric oxide levels through microglial cues. This may be an undesirable effect and highlights a possible need to explore acellular approaches for mesenchymal stem cell therapy in the central nervous system.</p>","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"2399-2406"},"PeriodicalIF":3.2,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1535370221997052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25485219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal cystic disease in tuberous sclerosis complex.","authors":"Prashant Kumar,&nbsp;Fahad Zadjali,&nbsp;Ying Yao,&nbsp;John J Bissler","doi":"10.1177/15353702211038378","DOIUrl":"https://doi.org/10.1177/15353702211038378","url":null,"abstract":"<p><p>Tuberous sclerosis complex (TSC) is associated with <i>TSC1</i> or <i>TSC2</i> gene mutations resulting in hyperactivation of the mTORC1 pathway. This mTORC1 activation is associated with abnormal tissue development and proliferation such that in the kidney there are both solid tumors and cystic lesions. This review summarizes recent advances in tuberous sclerosis complex nephrology and focuses on the genetics and cell biology of tuberous sclerosis complex renal disease, highlighting a role of extracellular vesicles and the innate immune system in disease pathogenesis.</p>","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"2111-2117"},"PeriodicalIF":3.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524767/pdf/10.1177_15353702211038378.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39392023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutically leveraging GABA_A receptors in cancer.","authors":"Debanjan Bhattacharya,&nbsp;Vaibhavkumar S Gawali,&nbsp;Laura Kallay,&nbsp;Donatien K Toukam,&nbsp;Abigail Koehler,&nbsp;Peter Stambrook,&nbsp;Daniel Pomeranz Krummel,&nbsp;Soma Sengupta","doi":"10.1177/15353702211032549","DOIUrl":"https://doi.org/10.1177/15353702211032549","url":null,"abstract":"<p><p>γ-aminobutyric acid or GABA is an amino acid that functionally acts as a neurotransmitter and is critical to neurotransmission. GABA is also a metabolite in the Krebs cycle. It is therefore unsurprising that GABA and its receptors are also present outside of the central nervous system, including in immune cells. This observation suggests that GABAergic signaling impacts events beyond brain function and possibly human health beyond neurological disorders. Indeed, GABA receptor subunits are expressed in pathological disease states, including in disparate cancers. The role that GABA and its receptors may play in cancer development and progression remains unclear. If, however, those cancers have functional GABA receptors that participate in GABAergic signaling, it raises an important question whether these signaling pathways might be targetable for therapeutic benefit. Herein we summarize the effects of modulating Type-A GABA receptor signaling in various cancers and highlight how Type-A GABA receptors could emerge as a novel therapeutic target in cancer.</p>","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"2128-2135"},"PeriodicalIF":3.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524771/pdf/10.1177_15353702211032549.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39521180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"12 Survival-related differentially expressed genes based on the TARGET-osteosarcoma database.","authors":"Emel Rothzerg,&nbsp;Jiake Xu,&nbsp;David Wood,&nbsp;Sulev Kõks","doi":"10.1177/15353702211007410","DOIUrl":"https://doi.org/10.1177/15353702211007410","url":null,"abstract":"<p><p>The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project aims to determine molecular changes that drive childhood cancers, including osteosarcoma. The main purpose of the program is to use the open-source database to develop novel, effective, and less toxic therapies. We downloaded TARGET-OS RNA-Sequencing data through R studio and merged the mRNA expression of genes with clinical information (vital status, survival time and gender). Further, we analyzed differential gene expressions between dead and alive patients based on TARGET-OS project. By this study, we found 5758 differentially expressed genes between deceased and alive patients with a false discovery rate below 0.05; 4469 genes were upregulated in deceased patients compared to alive, whereas 1289 genes were downregulated. The survival-related genes were obtained using Kaplan-Meier survival analysis and Cox univariate regression (KM < 0.05 and Cox <i>P</i>-value < 0.05). Out of 5758 differentially expressed genes, only 217 have been associated with overall survival. Eight survival-related downregulated genes (<i>ERCC4</i>, <i>CLUAP1</i>, <i>CTNNBIP1</i>, <i>GCA</i>, <i>RAB40C</i>, <i>SIRPA</i>, <i>USP11</i>, and <i>TCN2</i>) and four survival-related upregulated genes (<i>MUC1</i>, <i>COL13A1</i>, <i>JAG2</i> and <i>KAZALD1</i>) were selected for further analysis as potential independent prognostic candidate genes. This study may help to discover novel prognostic markers and potential therapeutic targets for osteosarcoma.</p>","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"2072-2081"},"PeriodicalIF":3.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/15353702211007410","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38932108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of lymphangiogenesis by extracellular vesicles in cancer metastasis.","authors":"Chu-An Wang,&nbsp;Shaw-Jenq Tsai","doi":"10.1177/15353702211021022","DOIUrl":"https://doi.org/10.1177/15353702211021022","url":null,"abstract":"<p><p>Metastasis is not only one of the hallmarks of cancer but, unfortunately, it also is the most accurate biomarker for poor prognosis. Cancer cells metastasize through two different but eventually merged routes, the vasculature and lymphatic systems. The processes of cancer metastasis through blood vessel have been extensively studied and are well documented in the literature. In contrast, metastasis through the lymphatic system is less studied. Most people believe that cancer cells metastasize through lymphatic vessel are passive because the lymphatic system is thought to be a sewage draining system that collects whatever appears in the tissue fluid. It was recently found that cancer cells disseminated from lymphatic vessels are protected from being destroyed by our body's defense system. Furthermore, some cancer cells or cancer-associated immune cells secrete lymphangiogenic factors to recruit lymphatic vessel infiltration to the tumor region, a process known as lymphangiogenesis. To ensure the efficiency of lymphangiogenesis, the lymphangiogenic mediators are carried or packed by nanometer-sized particles named extracellular vesicles. Extracellular vesicles are lipid bilayer particles released from eventually every single cell, including bacterium, with diameters ranging from 30 nm (exosome) to several micrometers (apoptotic body). Components carried by extracellular vesicles include but are not limited to DNA, RNA, protein, fatty acid, and other metabolites. Recent studies suggest that cancer cells not only secrete more extracellular vesicles but also upload critical mediators required for lymphatic metastasis onto extracellular vesicles. This review will summarize recent advances in cancer lymphatic metastasis and how cancer cells regulate this process via extracellular vesicle-dependent lymphangiogenesis.</p>","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"2048-2056"},"PeriodicalIF":3.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/15353702211021022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39241151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dedicated to Dr. Peter Stambrook.","authors":"Steven R Goodman","doi":"10.1177/15353702211036636","DOIUrl":"https://doi.org/10.1177/15353702211036636","url":null,"abstract":"","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"2047"},"PeriodicalIF":3.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524773/pdf/10.1177_15353702211036636.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39521178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of myokines and osteokines in cancer cachexia.","authors":"Fabrizio Pin,&nbsp;Lynda F Bonewald,&nbsp;Andrea Bonetto","doi":"10.1177/15353702211009213","DOIUrl":"https://doi.org/10.1177/15353702211009213","url":null,"abstract":"<p><p>Cancer-induced muscle wasting, i.e. cachexia, is associated with different types of cancer such as pancreatic, colorectal, lung, liver, gastric and esophageal. Cachexia affects prognosis and survival in cancer, and it is estimated that it will be the ultimate cause of death for up to 30% of cancer patients. Musculoskeletal alterations are known hallmarks of cancer cachexia, with skeletal muscle atrophy and weakness as the most studied. Recent evidence has shed light on the presence of bone loss in cachectic patients, even in the absence of bone-metastatic disease. In particular, we and others have shown that muscle and bone communicate by exchanging paracrine and endocrine factors, known as myokines and osteokines. This review will focus on describing the role of the most studied myokines, such as myostatin, irisin, the muscle metabolite β-aminoisobutyric acid, BAIBA, and IL-6, and osteokines, including TGF-β, osteocalcin, sclerostin, RANKL, PTHrP, FGF23, and the lipid mediator, PGE₂ during cancer-induced cachexia. The interplay of muscle and bone factors, together with tumor-derived soluble factors, characterizes a complex clinical scenario in which musculoskeletal alterations are amongst the most debilitating features. Understanding and targeting the \"secretome\" of cachectic patients will likely represent a promising strategy to preserve bone and muscle during cancer cachexia thereby enhancing recovery.</p>","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"2118-2127"},"PeriodicalIF":3.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/15353702211009213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38841888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic analysis of molecular characterization and clinical relevance of m6A regulators in digestive system pan-cancers.","authors":"Tiankuo Kou,&nbsp;Ruizhi Chai,&nbsp;Lan Jin,&nbsp;Zhigang Bai,&nbsp;Yun Yang,&nbsp;Yongtian Zhao,&nbsp;Dongfang Wu,&nbsp;Zhongtao Zhang,&nbsp;Yingchi Yang","doi":"10.1177/15353702211019681","DOIUrl":"https://doi.org/10.1177/15353702211019681","url":null,"abstract":"<p><p>Digestive system tumors, which mainly include esophagus, stomach, colorectum, liver, pancreas, bile duct, and some other tumors, often have a poor prognosis. N6-methyladenosine (m6A) has critical functions in development and tumorigenesis and may help improve the molecular mechanisms of digestive system tumors. However, current understanding of the reconstitution of m6A in digestive system tumors is far from comprehensive. Herein, this study systematically analyzed multi-layered genomic characteristics and clinical relevance of m6A regulators in 1906 patients involving seven digestive system tumor types. We discovered that m6A regulators showed extensive genetic changes and highly consistent expression regulation. The m6A expression was closely related to the activity of cancer pathways. At the same time, we also identified m6A regulators significantly related to the common cancer pathways of digestive system tumors and specific cancer pathways of digestive tract and digestive glands. These cancer pathways may explain the prognostic differences of patients with digestive tract tumors. In addition, m6A regulators demonstrated strong potential in prognostic stratification and drug development, especially in multiple research cohorts on pancreatic cancer, pointing to a strong prognostic stratification capability of m6A regulators. Finally, a m6A scoring model significantly related to highly active ubiquitin-mediated proteolysis, mismatch repair, cell cycle, ebasal transcription factors was constructed and had a strong prognostic stratification ability in digestive gland tumors. The score showed a significant negative correlation with the tumor immune microenvironment. This study demonstrated that the similarities and difference of the action mechanism m6A regulators in the digestive tract and digestive gland tumor progression could guide potential drug development.</p>","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"2007-2018"},"PeriodicalIF":3.2,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/15353702211019681","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39074985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential expression and alternative splicing of transcripts in orbital adipose/connective tissue of thyroid-associated ophthalmopathy.","authors":"Lianqun Wu,&nbsp;Yu Liang,&nbsp;Nan Song,&nbsp;Xiying Wang,&nbsp;Chao Jiang,&nbsp;Xinxin Chen,&nbsp;Bing Qin,&nbsp;Xiantao Sun,&nbsp;Guohua Liu,&nbsp;Chen Zhao","doi":"10.1177/15353702211017292","DOIUrl":"https://doi.org/10.1177/15353702211017292","url":null,"abstract":"<p><p>Thyroid-associated ophthalmopathy is a typical autoimmune disease of orbital tissues. Alternative splicing significantly influences many diseases progression, including cancer, age-related macular degeneration, and multiple sclerosis, by modulating the expression of transcripts. However, its role in thyroid-associated ophthalmopathy is still unclear. In this study, differential expression transcripts and differential alternative splicing genes in orbital adipose/connective tissues of thyroid-associated ophthalmopathy patients were detected using RNA sequencing, Cuffdiff, and replicate multivariate analysis of transcript splicing. Three thousand ninety six differential expression transcripts and 2355 differential alternative splicing genes were screened out, while functional enrichment analysis indicated that differential expression transcript and differential alternative splicing genes were associated with immune modulation, extracellular matrix remodeling, and adipogenesis. The expression of the <i>SORBS1</i>, <i>SEPT2</i>, <i>COL12A1</i>, and <i>VCAN</i> gene transcripts was verified by qRT-PCR. In conclusion, prevalent alternative splicing is involved in the disease development in thyroid-associated ophthalmopathy. More attention should be paid to the mechanism of alternative splicing to explore more potential therapeutic targets in thyroid-associated ophthalmopathy.</p>","PeriodicalId":520623,"journal":{"name":"Experimental biology and medicine (Maywood, N.J.)","volume":" ","pages":"1990-2006"},"PeriodicalIF":3.2,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/15353702211017292","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38970285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}