Aspects of molecular medicine最新文献

{"title":"BCL-2 and BAX expression and germ cell apoptosis following the intervention of 1-isothiocyanato-4-methylsulfinylbutane in cisplatin-induced testicular toxicity and sperm DNA fragmentation in Sprague-Dawley rat","authors":"Sunday Aderemi Adelakun ,&nbsp;Olalekan Wasiu Akintunde ,&nbsp;Babatunde Ogunlade ,&nbsp;Akwu Bala Peter ,&nbsp;Jacob Adewale Siyanbade","doi":"10.1016/j.amolm.2024.100055","DOIUrl":"10.1016/j.amolm.2024.100055","url":null,"abstract":"<div><div>Cisplatin (CP) has been used in clinical oncology but causes spermatogenesis damage. Isothiocyanato-4-methylsulfonylbutane (SFN) is a potent dietary bioactive agent that has been extensively studied for its effects on disease prevention. This study focused on the intervention of SFN on Germ cell apoptosis in CP-induced testicular toxicity and sperm DNA fragmentation (SDF). A total of ninety (90) male and ninety (90) female rats (weighing, 150–200 g, 12–14 weeks old) were assigned randomly into nine groups of ten (n = 10) rats each. Group A received normal saline, group B received a single dose of 10 mg/kg CP (i.p.), group C received 50 mg/kg bwt of SFN, group D received 100 mg/kg bwt of SFN, group E received 10 mg/kg bwt CP and 50 mg/kg bwt of SFN, group F received 10 mg/kg bwt CP and 100 mg/kg bwt of SFN, group G received 10 mg/kg bwt CP and 50 mg/kg bwt vitamin C, group H received 50 mg/kg bwt of SFN and 10 mg/kg bwt CP, Group I received 100 mg/kg bwt of SFN and 10 mg/kg bwt CP. The procedure lasted for 56 days. At the end of each treatment, the 90 male rats were introduced to the 90 female rats on the proestrus at a ratio of 1:1 for fertility tests. Testicular histopathological, apoptotic marker, immunoreactivity, sperm parameters, and SDF were investigated.</div><div>Cisplatin significantly decreases chromatin condensation/de-condensation levels, haploid germ cells, the number of fetuses, and BCL-2 expression. Also, CP increases SDF and BAX expression relative to control. Treatment with SFN increased BCL-2 expression, haploid germ cells, protected sperm chromatin condensation, improved microarchitecture of testes, and decreased SDF and BAX expression.</div><div>Therefore, SFN protects against CP-induced apoptosis by controlling BCL-2 and BAX expression and ameliorates SDF.</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"4 ","pages":"Article 100055"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142527731","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":"Age and gender related changes on total antioxidant/oxidant status and electrolyte composition of saliva","authors":"Erdal Ergünol ,&nbsp;Rabia Şemsi ,&nbsp;Aylin Sepici Dinçel","doi":"10.1016/j.amolm.2024.100054","DOIUrl":"10.1016/j.amolm.2024.100054","url":null,"abstract":"<div><h3>Background</h3><div>Saliva is used as an important biological material in the diagnosis and treatment of various diseases to collect easily, to be cheap, to have a minimal risk of infection. Here in that study we aimed to evaluate age and gender-related changes on total antioxidant/oxidant status and electrolyte composition of saliva levels in individuals.</div></div><div><h3>Methods</h3><div>A total of 30 young adult (21.2 ± 2.47 years) and 14 adult (51.6 ± 9.35 years) subjects were included in the study. Stimulated saliva samples were collected. Cortisol, amylase, oxidative stress biomarkers (total antioxidant status and total oxidant status) were measured by ELISA and spectrophotometric manual methods and electrolyte level of saliva samples were determined by autoanalyzer.</div></div><div><h3>Results</h3><div>Salivary concentrations of biomarkers of young adults were compared to adult subjects, there was a statistically significant difference between cortisol (μg/dL) (p = 0.003), Ca⁺²(mg/dL) (p = 0.004), TAS (mmol Trolox Equiv/L) (p = 0.001), BUN (mg/dL) (p = 0.02), Mg⁺² (mg/dL) (p = 0.02), and K⁺ (mmol/L) (p = 0.05) levels, but there was no significant difference was found between uric acid (mg/dL) (p = 0.44), Cl^- (mmol/L) (p = 0.07), amylase (ng/mL) (p = 0.47), phosphate (mg/dL) (p = 0.63), Na⁺(mmol/L)(p = 0.21), and TOS (μmol H₂O₂ Equiv/L) (p = 0.70) levels. We evaluated <strong>s</strong>alivary cortisol, amylase, and electrolyte levels of groups that we commented on their relationship between oxidant-antioxidant defense systems of the saliva and their correlations with age and gender.</div></div><div><h3>Conclusions</h3><div>This study could suggest the use of saliva samples to correlate with age and representing the levels of the most common biological parameters for routine use and antioxidant-oxidant enzymes for clinical trials.</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"4 ","pages":"Article 100054"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142656093","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":"Current insights and future perspectives of In silico molecular docking in dengue virus proteins inhibition: A review","authors":"K. Dass ,&nbsp;N. Prakash ,&nbsp;P. Manogar ,&nbsp;R. Murugesan","doi":"10.1016/j.amolm.2024.100050","DOIUrl":"10.1016/j.amolm.2024.100050","url":null,"abstract":"<div><p>Mosquito-borne diseases such as dengue, yellow fever, chikungunya, Zika, malaria, Japanese encephalitis, West Nile fever, and elephantiasis pose significant public health threats globally. Dengue virus (DENV), transmitted primarily by <em>Aedes</em> mosquitoes, infects millions annually, particularly in tropical and subtropical regions. The virus, belonging to the Flaviviridae family, comprises four serotypes (DENV-I to DENV-IV) with distinct structural and non-structural proteins. Transmission occurs through mosquito bites, predominantly by <em>Aedes aegypti</em> and <em>Aedes albopictus</em>. In 2022, India reported 223,251 dengue cases with 308 fatalities, underscoring the urgent need for effective control strategies beyond synthetic drugs due to their costs and adverse effects. Plant-derived compounds have emerged as promising alternatives due to their biological origin, safety profile, and diverse pharmacological activities, including antiviral properties. This review focuses on the application of molecular docking techniques to evaluate the interaction between plant-derived phytochemicals and key dengue viral proteins, particularly NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. Phytochemicals such as apigenin, hesperidin, kaempferol, and myricetin demonstrated significant binding affinity and potential inhibition of crucial viral enzymes, highlighting their therapeutic promise. Studies on compounds from medicinal plants like <em>Tanacetum parthenium, Silybum marianum, Cyamopsis tetragonoloba</em>, and Astragalus spp. further support the efficacy of plant-based therapies against dengue. The findings underscore the potential of phytochemicals to inhibit viral replication and protein activity, offering a novel avenue for developing antiviral treatments. Molecular docking simulations provided insights into the molecular interactions between phytochemicals and viral proteins, guiding future research and drug development efforts. This comprehensive review consolidates current knowledge on plant-based antivirals against dengue, emphasizing their role in integrated vector management and public health strategies.</p></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"4 ","pages":"Article 100050"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949688824000170/pdfft?md5=ba3f6ced92e2c1cd057a52d85e015ae9&pid=1-s2.0-S2949688824000170-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731942","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":"The role of gut microbiota, immune system, and autophagy in the pathogenesis of inflammatory bowel disease: Molecular mechanisms and therapeutic approaches","authors":"Beatrice Garavaglia ,&nbsp;Letizia Vallino ,&nbsp;Angela Amoruso ,&nbsp;Marco Pane ,&nbsp;Alessandra Ferraresi ,&nbsp;Ciro Isidoro","doi":"10.1016/j.amolm.2024.100056","DOIUrl":"10.1016/j.amolm.2024.100056","url":null,"abstract":"<div><div>The crosstalk between gut microbiota, intestinal epithelial cells, and innate and adaptive immune system governs the maintenance of the intestinal homeostasis. Any interference in this tight dialogue and in the processes preserving cellular homeostasis (e.g., autophagy) may dysregulate the immune response and impair the clearance of harmful bacteria favoring the dysbiotic alteration of the microbial flora that leads to chronic inflammation. Gut dysbiosis is strongly associated with gastrointestinal inflammatory disorders, among them the inflammatory bowel disease (IBD). This review discusses the current knowledge on IBD, from the genetic background of high-risk patients to the molecular mechanisms underlying the disease, the contribution of the microbial flora, and the role of autophagy in intestinal epithelia homeostasis. Further, we illustrate the state of art regarding the targeted-nutritional approaches aimed to restore the beneficial crosstalk between an “anti-inflammatory” microbiota and the host. Analysis of the molecular pathogenesis of IBD will help identify genetic and diet-associated risk factors and thus suggest personalized strategies to prevent and manage the disease to improve quality of life with long-term maintenance of the remission phase.</div></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"4 ","pages":"Article 100056"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142527730","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":"In silico approach for identification of potential tetracyclic triterpenoids from mushroom as HMG-CoA reductase inhibitor","authors":"Rishav Mazumder ,&nbsp;Deijy Choudhury ,&nbsp;Alekhya Sarkar ,&nbsp;Ashmita Ghosh ,&nbsp;Sudhan Debnath ,&nbsp;Bimal Debnath ,&nbsp;Rajat Ghosh","doi":"10.1016/j.amolm.2024.100053","DOIUrl":"10.1016/j.amolm.2024.100053","url":null,"abstract":"<div><p>Cardiovascular disease is estimated to be responsible for one-third of all global deaths annually. It occurs mostly due to hyperlipidemia, a condition where excessive cholesterol deposits in blood vessels. A favorable target for treating hyperlipidemia involves the crucial role of inhibition of a specific enzyme known as 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). The primary goal of this present study is to identify potential HMG-CoA reductase inhibitors containing tetracyclic triterpene nucleus derived from mushrooms. A library of 86 myco-constituents bearing a tetracyclic triterpene scaffold was prepared and screened to identify potential HMG-CoA reductase inhibitors targeting proteins 1HW8 and 1HW9. For this purpose, molecular docking, ADME prediction, and molecular dynamics (MD) simulation studies were performed on this in-house prepared database. The virtual screening results exhibited <strong>M_02(c)</strong> as the best hit with promising SP Glide scores compared to standard statin drugs. In order to assess the stability and interactions, a 100 ns MD simulation was performed. Further, <strong>M_02(c)</strong> was also analysed for MMGBSA binding energy to access and validate the thermodynamic stability of the protein-ligand complex. The results of this study revealed that M_02(c) is a promising hit molecule and may emerge as a potent HMG-CoA reductase inhibitor in preventing and treating hyperlipidemia.</p></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"4 ","pages":"Article 100053"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949688824000200/pdfft?md5=e13cad54ef710dd34a40f2e2e52e3824&pid=1-s2.0-S2949688824000200-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168005","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":"Effects of gut microbiota-derived short-chain fatty acids on cognitive impairment: An in-silico study","authors":"Hai Duc Nguyen ,&nbsp;Giang Huong Vu ,&nbsp;Woong-Ki Kim","doi":"10.1016/j.amolm.2024.100047","DOIUrl":"https://doi.org/10.1016/j.amolm.2024.100047","url":null,"abstract":"<div><p>Increasing evidence suggests that gut microbiota-derived metabolites affect cognitive function, but the underlying molecular mechanisms remain unclear. In this study, mechanisms of cognitive dysfunction that can be targeted by acetic acid and butyric acid were analyzed using literature review, Metascape, Mienturnent, Passonline, and WissADME. We found that acetic acid and butyric acid may regulate important genes (PPARG, CASP3, IL1B, SOD2, and TNF) that protect against cognitive decline. We also found microRNAs (hsa-miR-17-5p and hsa-miR-20a-5p) and transcription factors (RELA and NFKB1) that play a critical role in this protective mechanism. The AGE-RAGE signaling pathway and apoptosis pathways also emerged as crucial to understanding the underlying pathophysiological mechanisms. Our findings are further supported by the physicochemical properties and pharmacokinetic profiles of acetic acid and butyric acid, which demonstrate remarkable intestinal absorption, ability to penetrate the blood-brain barrier, and non-inhibition of CYP450 enzymes. Our study provides further evidence of the therapeutic potential of butyric acid in managing cognitive impairment, including its anti-inflammatory properties, stimulation of insulin synthesis, and regulation of lipid metabolism. We also identified several promising treatments for cognitive impairment, including miRNA sponges, mesalazine, omega-3 fatty acids, pomalidomide, and andrographolide. Focused investigations into the apoptosis and AGE-RAGE signaling pathways, miRNA sponges, promising drugs, and the role of gut microbiota in cognitive function are warranted.</p></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"4 ","pages":"Article 100047"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949688824000145/pdfft?md5=5b35f55c4d1009f510c099fad39e9099&pid=1-s2.0-S2949688824000145-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141326201","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":"Expression of hTERT and Lp-PLA(2) genes is increased in primary hypothyroidism.","authors":"Seema Garg ,&nbsp;Parul Gupta ,&nbsp;Satyam Wahi ,&nbsp;Mohit Mehndiratta ,&nbsp;S.V. Madhu ,&nbsp;Edelbert Almeida ,&nbsp;Rajarshi Kar","doi":"10.1016/j.amolm.2024.100040","DOIUrl":"https://doi.org/10.1016/j.amolm.2024.100040","url":null,"abstract":"<div><h3>Objective</h3><p>Sightly low serum free T4 levels are associated with longer life expectancy. However, hypothyroidism is associated with increased risk of inflammation and vascular complications. Therefore, relation of thyroid hormones (THs) with life expectancy seems to be complex. This study was carried out in an effort to understand the contribution of THs in inflammation and aging.</p></div><div><h3>Methodology</h3><p>15 cases of treatment naïve primary hypothyroidism and 15 age and sex matched euthyroid controls were recruited. mRNA expression of Telomerase (<em>hTERT</em>), leucocyte telomere length (LTL) and Lipoprotein associated phospholipase A2 (<em>Lp-PLA2</em>), a marker of vascular inflammation and risk predictor of cardiovascular events were measured by qPCR in whole blood.</p></div><div><h3>Result</h3><p>Expression of <em>hTERT</em> was found to be 6.95 times higher in the cases as compared to the controls. mRNA expression of <em>Lp-PLA(2)</em> was also 3.3 times higher in cases. LTL in euthyroid was approximately 81% of the length in hypothyroid patients.</p></div><div><h3>Conclusion</h3><p>A higher expression of <em>hTERT</em> indicates that hypothyroidism confers better cell survival in peripheral leucocytes inspite of the presence of vascular inflammation. However causal relationship cannot be ascertained with these results.</p></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"3 ","pages":"Article 100040"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949688824000078/pdfft?md5=3fa9276642811680b0150755334a89ee&pid=1-s2.0-S2949688824000078-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140328049","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":"Higher oxidative stress and inflammation in obese compared to lean patients with type 2 diabetes mellitus","authors":"Mohit Mehndiratta ,&nbsp;Edelbert Anthonio Almeida ,&nbsp;Diwesh Chawla ,&nbsp;S.V. Madhu ,&nbsp;Seema Garg ,&nbsp;Rajarshi Kar","doi":"10.1016/j.amolm.2024.100042","DOIUrl":"https://doi.org/10.1016/j.amolm.2024.100042","url":null,"abstract":"<div><h3>Aim</h3><p>To compare mRNA [messenger RNA] expression of <em>RELA, NFκB1</em>, <em>TNF-α, IL-6 and MCP-1</em> in whole blood &amp; serum Total Antioxidant status [TAS] in newly diagnosed lean and obese patients with T2DM.</p></div><div><h3>Methods</h3><p>Newly diagnosed treatment naïve patients of T2DM were enrolled in this study. The patients were divided into two groups of 30 patients each, lean (BMI&lt; 18.5 kg/m²) and obese (BMI &gt;25 kg/m²) groups. mRNA expression of <em>RELA, NFκB1, TNF-α, IL-6 and MCP-1</em> was measured by real time PCR. Serum TAS was measured using a commercially available kit.</p></div><div><h3>Results</h3><p>There was a 2.7-fold increase in mRNA expression of <em>RELA</em> in obese group compared to the lean group. There was a 1.3-fold increase in mRNA expression of <em>NFκB1</em>, a 3.24-fold increase in mRNA expression of <em>TNF-α,</em> a 4.7-fold increase in mRNA expression of <em>IL 6</em> and a 3.8-fold increase in mRNA expression of <em>MCP-1</em> in obese group compared to the lean group. Mean fasting serum insulin levels were 16.07 ± 8.39 μIU/mL in the lean group and 27.11 ± 4.91μIU/mL in the obese group (p = 0.001). Mean TAS level was 5.39 ± 2.28 μM Trolox Equivalents in the obese group and 3.85 ± 3.33 μM Trolox Equivalents in the lean group (p = 0.001).</p></div><div><h3>Conclusion</h3><p>Inflammation and OS is higher in obese patients of T2DM compared to lean patients of T2DM. This could be the result of excess adipokines production or resistance to the anti-inflammatory effects of insulin with multiple explanations. Our study suggests a difference in the pathogenic mechanism in lean patients when compared with obese T2DM patients.</p></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"3 ","pages":"Article 100042"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949688824000091/pdfft?md5=2e3946877a417680f5fe6aa05f36b5b2&pid=1-s2.0-S2949688824000091-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140816625","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":"Identification of biomarkers and molecular mechanisms implicated in genetic variations underlying Alzheimer's disease pathogenesis","authors":"Hai Duc Nguyen ,&nbsp;Giang Huong Vu ,&nbsp;Woong-Ki Kim","doi":"10.1016/j.amolm.2024.100045","DOIUrl":"10.1016/j.amolm.2024.100045","url":null,"abstract":"<div><p>We analyzed data from human genome-wide association studies (GWASs) to identify genetic variants and biological pathways linked to Alzheimer's disease (AD). Ten AD biomarkers (APOE, NECTIN2, APOC1, APOC1P1, TOMM40, RNU4-67P, KRAS, Y_RNA, THORLNC, LINC01956) were found across studies, including six central genetic variants (MAPT (rs242557-A), GRIN2B (rs74442473-G), APOE (rs438811-T), ANK3 (rs438811-T), BIN1 (rs744373-G), and BDNF (rs7481773-A)). ANK3 (rs438811-T) and GRIN2B (rs74442473-G) were essential hub biomarkers for amyloid plaques, while MAPT (rs242557-A) and BIN1 (rs744373-G) were crucial for neurofibrillary tangles (NFTs). Higher-risk AD biomarkers were associated with increased protein-lipid complex formation, while lower-risk AD biomarkers were correlated with improved synaptic function. Six essential miRNAs (hsa-miR-124–3p, 15a-5p, 16–5p, 204–5p, 520g-3p, 520h) and three transcription factors (ZMAT4, ZBED6, FOXG1) emerged as possible candidates to reveal the genetic differences that lead to amyloid plaques, NFTs, and ultimately AD. These findings serve as a basis for potential AD treatments and offer new avenues for therapeutic approaches to directly target the genetic variations and processes associated with the disease.</p></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"3 ","pages":"Article 100045"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949688824000121/pdfft?md5=162a70149a1664b1e8e571f8fab0e3a7&pid=1-s2.0-S2949688824000121-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141141702","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":"A canine mastocytoma with oncogenic c-kit activation by intra-exonic alternative splicing","authors":"Mengrui Li ,&nbsp;Stephanie Vanegas ,&nbsp;Mia R. Gonzalgo ,&nbsp;Joseph A. Lacret ,&nbsp;Wensi Tao ,&nbsp;Sapna Deo ,&nbsp;Sylvia Daunert ,&nbsp;Jean-Marc Zingg","doi":"10.1016/j.amolm.2024.100039","DOIUrl":"10.1016/j.amolm.2024.100039","url":null,"abstract":"<div><p>We report a subcutaneous mastocytoma in a mid-aged Italian greyhound dog with a small 41 bp genomic deletion of the c-kit gene leading to skipping of the authentic 3′-splice junction of intron 10. The shift to an alternative splice junction in exon 11 leads to a mis-spliced in-frame mRNA transcript with a 27 bp deletion of exon 11 coding for 9 amino acids in the juxtamembrane negative regulatory domain of c-kit tyrosine kinase. In the tumor, c-kit was activated as revealed by more pronounced c-kit-regulated signaling by the PI3K/Akt and G-coupled receptor pathways. The same 9 amino acids deletion was reported in several human gastrointestinal stromal tumors (GIST) pointing to a remarkable similarity of c-kit activation by small deletions and aberrant splicing in humans and dogs, independent of exact sequence context, tumor type and location. Interestingly, the alternative splice junction in exon 11 has been conserved in <em>Primates</em> but less in other <em>Orders</em> with increased body temperature such as ruminants. We hypothesize that elevated body temperature has acted as evolutionary pressure to eliminate the alternative splice site at this hotspot. At a molecular level, hyperthermia may increase the frequency of small deletions in the c-kit gene by facilitating base slipping or hindering repair. An RT-qPCR assay was developed to detect c-kit alternative splicing in tumors and cell lines exposed to hyperthermia. The molecular mechanisms of tumorigenesis are discussed.</p></div>","PeriodicalId":72320,"journal":{"name":"Aspects of molecular medicine","volume":"3 ","pages":"Article 100039"},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949688824000066/pdfft?md5=157b42b40eb4a5bfe28ab4284d909c1f&pid=1-s2.0-S2949688824000066-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140403654","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}