International journal of translational medicine (Basel, Switzerland)最新文献

{"title":"Comparison of the Differing Impacts of Lowered N-Acetylglucosaminyltransferase-Ia/b Activity on Motor and Sensory Function in Zebrafish.","authors":"M Kristen Hall, Cody J Hatchett, Haris A Khan, Hannah Lewis, Ruth A Schwalbe","doi":"10.3390/ijtm5030036","DOIUrl":"10.3390/ijtm5030036","url":null,"abstract":"<p><strong>Background/objectives: </strong>Perturbation in terminal N-glycan processing is a feature of congenital disorders of glycosylation and neurological disorders. Since treatment options are limited, N-glycans are plausible therapeutic targets. Here, we investigated the consequences of substituting complex/hybrid with oligomannose types of N-glycans on nervous and musculature systems, employing <i>mgat1a</i> and <i>mgat1b</i> mutant zebrafish models.</p><p><strong>Methods: </strong>CRISPR Cas9 technology was employed to engineer the <i>mgat1a</i> zebrafish model. The N-glycan populations in Wt AB, <i>mgat1a</i>-/- and <i>mgat1b</i>-/- zebrafish were characterized via lectin blotting. Motor and sensory functions were measured by tail-coiling and touch-evoked response assays in embryos and larvae. Swimming locomotion and anxiety-like behavior were characterized in adult Wt AB, and mutant zebrafish using motility and novel tank dive assays.</p><p><strong>Results: </strong>The <i>mgat1a</i>-/- model had increased oligomannosylated proteins compared to Wt AB in embryos and dissected brain, spinal cord, skeletal muscle, heart, swim bladder, and skin from adults, supporting a global knockdown of GnT-I activity. Higher levels were also observed in <i>mgat1a</i>-/- relative to <i>mgat1b</i>-/-, except in the brain. Band patterns for oligomannosylated proteins were different between all three zebrafish lines. The <i>mgat1</i>-/- embryos and larvae had deficient motor and sensory functions which persisted into adulthood, with a higher deficiency in <i>mgat1b</i>-/-. Anxiety-like behavior was decreased and increased in adult <i>mgat1a</i>-/- and <i>mgat1b</i>-/-, respectively, compared to Wt AB.</p><p><strong>Conclusions: </strong>Taken together, this study revealed that aberrant terminal N-glycan processing impacts brain, spinal and muscle control, and hence will enhance our understanding of the vital role of complex/hybrid N-glycans in nervous system health.</p>","PeriodicalId":520354,"journal":{"name":"International journal of translational medicine (Basel, Switzerland)","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12573715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433516","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":"Exploiting Synthetic Lethality of PRMT5 for Precision Treatment of MTAP-Deficient Glioblastoma.","authors":"Trang T T Nguyen, Eunhee Yi, Christian E Badr","doi":"10.3390/ijtm5030027","DOIUrl":"10.3390/ijtm5030027","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by a dismal prognosis and limited therapeutic options. Its highly invasive nature and pronounced intratumoral heterogeneity underscores the urgent need for innovative and targeted therapeutic strategies. One promising approach is synthetic lethality, which exploits cancer-specific genetic vulnerabilities to selectively eliminate tumor cells. A well-characterized example involves the deletion of methylthioadenosine phosphorylase (MTAP), commonly observed in GBM and other malignancies. This review focuses on synthetic lethality targeting protein arginine methyltransferase 5 (PRMT5) in MTAP-deleted GBM. Loss of MTAP leads to the accumulation of methylthioadenosine (MTA), a metabolite that partially inhibits PRMT5, thereby creating a selective vulnerability to PRMT5 inhibition which is used to inhibit the residual function of PRMT5. We critically evaluate preclinical and clinical data on both first- and second-generation PRMT5 inhibitors, with particular emphasis on MTA-cooperative compounds that selectively exploit MTAP deficiency. Despite promising anti-tumor activity in vitro, the clinical efficacy of PRMT5 inhibitors is often limited by the tumor microenvironment, particularly the impact of non-malignant cells that attenuate drug activity. Finally, we explore rational combination strategies that integrate PRMT5 inhibition with existing therapies to enhance clinical outcomes in GBM.</p>","PeriodicalId":520354,"journal":{"name":"International journal of translational medicine (Basel, Switzerland)","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13099004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147794668","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":"Evaluating Leucine, Isoleucine, and Valine Ratios in Mixed Cortical Cell Cultures Following Cortical Trauma: An In Vitro Assessment.","authors":"Ezek Mathew, Nathan Jones, Katherine Hernandez, Sterling B Ortega, Rob Dickerman","doi":"10.3390/ijtm5030042","DOIUrl":"10.3390/ijtm5030042","url":null,"abstract":"<p><strong>Background/objectives: </strong>Traumatic brain injury (TBI) remains the most common cause of morbidity and mortality in adolescents and adults. Although numerous animal and human studies have demonstrated the beneficial effects of branched-chain amino acids (BCAA) treatment on various models of brain injury, the optimal concentration and mechanism of action have not been elucidated.</p><p><strong>Methods: </strong>Based on our prior work, we hypothesized that a 2:1:1 ratio of BCAAs promotes neuronal regrowth and repair. Using in vitro mixed cortical cultures (composed of CNS cells, including neuronal and glial cells), we recapitulated the mechanical damage induced by TBI using the scratch assay model. We evaluated various concentrations of BCAA to promote the regrowth of CNS cells after mechanical damage.</p><p><strong>Results: </strong>A 2:1:1 ratio of leucine: isoleucine: valine was observed to yield superior regrowth rates at the 48 h time point across various concentrations when compared to a 1:1:1 ratio and even a 4:1:1 ratio. In addition, both 2:1:1 and 4:1:1 ratios offered multiple instances of accelerated regrowth, where less than 5% of the wound remained unhealed.</p><p><strong>Conclusions: </strong>The importance of leucine ratios in the context of BCAA treatment for TBI was demonstrated by the superior CNS cell regrowth offered by the 2:1:1 ratio.</p>","PeriodicalId":520354,"journal":{"name":"International journal of translational medicine (Basel, Switzerland)","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12674610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679965","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":"Therapeutic Strategies for MASH: An Update on Drug Candidates Under Investigation in Late-Phase Clinical Trials.","authors":"Samuel Dinerman, Yan Shu","doi":"10.3390/ijtm5010007","DOIUrl":"10.3390/ijtm5010007","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) is rapidly becoming a leading cause of hepatocellular carcinoma and end-stage liver transplantation. Characterized by hepatic steatosis, lobular inflammation, and hepatocyte ballooning, there is a dire need to develop therapeutic strategies to mitigate MASH alongside the subsequent fibrosis and cirrhosis. For years, therapeutic development for the treatment of MASH had been considered a graveyard, with various pharmacotherapies failing to achieve clinical efficacy. However, the recent Food and Drug Administration (FDA) approval of Madrigal Pharmaceuticals' Resmetirom in the United States provides a positive step in the collective effort to eradicate MASH. Granted, with much about Resmetirom's long-term efficacy and safety still to be determined and with the multi-factorial nature of MASH pathogenesis, continuing to evaluate alternative therapeutic options remains in the best interest of the field. Currently, therapeutics previously approved for other ailments, alongside novel therapeutics developed specifically for the treatment of MASH, are being evaluated in late-phase clinical trials. However, considering the complex nature of the disease and varying clinical outcomes to assess treatment efficacy, achieving regulatory approval as a MASH therapeutic continues to be a rigorous endeavor. In this review, we summarize notable therapeutics of various mechanistic backgrounds having achieved, or actively undergoing, late-phase clinical trials for the treatment of MASH and offer our perspectives on anti-MASH therapeutic development.</p>","PeriodicalId":520354,"journal":{"name":"International journal of translational medicine (Basel, Switzerland)","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12830047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146055883","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 Practical Format to Organize Cancer Constellations Using Innate Immune System Biomarkers: Implications for Early Diagnosis and Prognostication.","authors":"Martin Tobi, Harvinder Talwar, Noreen F Rossi, Warren Lockette, Benita McVicker","doi":"10.3390/ijtm4040050","DOIUrl":"10.3390/ijtm4040050","url":null,"abstract":"<p><p>Cancer discovery is directed at the identification of a specific cancer type which allows for specific therapeutic interventions.</p><p><strong>Background/objectives: </strong>Recently, similar immune checkpoint therapeutics have been applied with success across several cancer types, opening the field for other immune disruptive interventions that have practical applications.</p><p><strong>Methods: </strong>We have discovered an innate immune system (InImS) biomarker that allows for the characterization of allied cancer subtypes and outliers that might aid with diagnosis, treatment, and prognostication.</p><p><strong>Results: </strong>These InImS biomarkers are related to PD-L1 treatment outcomes and can be potentially manipulated by dietary means.</p><p><strong>Conclusions: </strong>The FERAD (ferritin-fecal p87) and absolute neutrophil/lymphocyte (aNLR) ratios are two such InImS biomarkers and we show herein, that they allow for the discovery of diagnosis and prognostication patterns, as demonstrated by this study.</p>","PeriodicalId":520354,"journal":{"name":"International journal of translational medicine (Basel, Switzerland)","volume":"4 4","pages":"726-739"},"PeriodicalIF":0.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702210","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":"Contribution of Sex Differences to the Development of Cardiovascular Disease in Metabolic-Associated Steatotic Liver Disease (MASLD).","authors":"Lucy C Taylor, Gertrude Arthur, Marcella de Carvalho Cruz, David E Stec, Olufunto O Badmus","doi":"10.3390/ijtm4040052","DOIUrl":"10.3390/ijtm4040052","url":null,"abstract":"<p><p>Sex differences are a complex and crucial variable in developing and progressing metabolic and cardiovascular disease pathophysiology and clinical outcomes. The female sex, compared to the male sex, is protected from metabolic disturbances and their resulting cardiovascular events. However, the peculiar life phases associated with females, such as puberty, pregnancy, premenopausal, and menopausal stages, are all associated with different risks for the development of cardiovascular disease (CVD). Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition of hepatic steatosis, and at least one feature of metabolic syndrome is associated with an increased risk of cardiovascular events. The risk of MASLD and its progression to the development of CVD differs between men and women. Differences in several factors, including formyl peptide receptor (FPR) 2, adipose tissue distribution, liver pyruvate kinase (LPK), and ketone body production, may underlie the sex differences in the risk of development of MASLD-induced CVD. Understanding the specific risk factors involved in the development and progression of MASLD between the sexes is crucial. This knowledge will provide important insights into the mechanisms responsible for its cardiovascular complications and can potentially lead to therapeutics targeted explicitly for each sex, offering new hope in the fight against MASLD-induced CVD.</p>","PeriodicalId":520354,"journal":{"name":"International journal of translational medicine (Basel, Switzerland)","volume":"4 4","pages":"782-809"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133193","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":"Reduction of N-Acetylglucosaminyltransferase-I Activity Promotes Neuroblastoma Invasiveness and EGF-Stimulated Proliferation In Vitro.","authors":"Adam P Burch, M Kristen Hall, Debra Wease, Ruth A Schwalbe","doi":"10.3390/ijtm4030035","DOIUrl":"10.3390/ijtm4030035","url":null,"abstract":"<p><p>Aberrant N-glycosylation has been associated with progression of the pediatric cancer neuroblastoma (NB) but remains understudied. Here we investigated oligomannose N-glycans in NB by genetic editing of <i>MGAT1</i> in a human NB cell line, BE(2)-C, called BE(2)-C(MGAT1^-/-). Lectin binding studies confirmed that BE(2)-C(MGAT1^-/-) had decreased complex and increased oligomannose N-glycans. The relevance of 2D and 3D cell cultures was demonstrated for cell morphology, cell proliferation, and cell invasion, thereby highlighting the necessity for 3D cell culture in investigating cancerous properties. Western blotting revealed that oligomannosylated EGFR had increased autophosphorylation. Proliferation was decreased in BE(2)-C(MGAT1^-/-) using 2D and 3D cultures, but both cell lines had similar proliferation rates using 3D cultures without serum. Upon EGF treatment, BE(2)-C(MGAT1^-/-), but not BE(2)-C, showed increased proliferation, and furthermore, the mutant proliferated much faster than BE(2)-C under 3D conditions. Cell spheroid invasiveness was greatly increased in BE(2)-C(MGAT1^-/-) compared with BE(2)-C. Moreover, invasiveness was reduced in both cell lines with either EGF or RhoA activator treatment, regardless of the N-glycan population. Thus, this study further extends our earlier findings that oligomannose N-glycans enhance NB cell invasiveness, and that EGF stimulation of oligomannosylated EGFR greatly enhances cell proliferation rates, underlining the role of oligomannose N-glycans in the promotion of NB.</p>","PeriodicalId":520354,"journal":{"name":"International journal of translational medicine (Basel, Switzerland)","volume":"4 3","pages":"519-538"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916531","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}