International Journal of Molecular Sciences最新文献

{"title":"Opioid-Based Haptens: Development of Immunotherapy","authors":"S. Hosztafi, A. R. Galambos, István Köteles, D. Karádi, Susanna Fürst, M. Al-Khrasani","doi":"10.3390/ijms25147781","DOIUrl":"https://doi.org/10.3390/ijms25147781","url":null,"abstract":"Over the past decades, extensive preclinical research has been conducted to develop vaccinations to protect against substance use disorder caused by opioids, nicotine, cocaine, and designer drugs. Morphine or fentanyl derivatives are small molecules, and these compounds are not immunogenic, but when conjugated as haptens to a carrier protein will elicit the production of antibodies capable of reacting specifically with the unconjugated hapten or its parent compound. The position of the attachment in opioid haptens to the carrier protein will influence the specificity of the antiserum produced in immunized animals with the hapten–carrier conjugate. Immunoassays for the determination of opioid drugs are based on the ability of drugs to inhibit the reaction between drug-specific antibodies and the corresponding drug–carrier conjugate or the corresponding labelled hapten. Pharmacological studies of the hapten–carrier conjugates resulted in the development of vaccines for treating opioid use disorders (OUDs). Immunotherapy for opioid addiction includes the induction of anti-drug vaccines which are composed of a hapten, a carrier protein, and adjuvants. In this review we survey the design of opioid haptens, the development of the opioid radioimmunoassay, and the results of immunotherapy for OUDs.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Modifiable Risk Factors Influencing Coronary Artery Disease Severity","authors":"Kamila Florek, Maja Kübler, Magdalena Górka, Piotr Kübler","doi":"10.3390/ijms25147766","DOIUrl":"https://doi.org/10.3390/ijms25147766","url":null,"abstract":"Cardiovascular diseases (CVDs) remain the leading cause of death worldwide with coronary artery disease (CAD) being the first culprit in this group. In terms of CAD, not only its presence but also its severity plays a role in the patient’s treatment and prognosis. CAD complexity can be assessed with the indicator named the SYNTAX score (SS). A higher SS is associated with major adverse cardiovascular event (MACE) occurrence in short- and long-term observations. Hence, the risk factors affecting CAD severity based on SS results may help lower the risk among patients with already developed CAD to reduce their impact on coronary atherosclerosis progression. The well-established risk factors of CAD are consistent with those associated with the coronary plaque burden. However, recently, it was shown that new indicators exist, which we present in this paper, that significantly contribute to CAD complexity such as inflammatory parameters, C-reactive protein (CRP), ratios based on blood smear results, and uric acid. Moreover, microbiota alteration, vitamin D deficiency, and obstructive sleep apnea (OSA) also predicted CAD severity. However, sometimes, certain indicators were revealed as significant only in terms of chronic coronary syndromes (CCSs) or specific acute coronary syndromes (ACSs). Importantly, there is a need to apply the interdisciplinary and translational approach to the novel CAD severity risk assessment to maximize the impact of secondary prevention among patients at risk of coronary atherosclerosis progression.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Glutathione Transferase M1, T1, P1 and A1 Gene Polymorphism and Susceptibility to IgA Vasculitis","authors":"Ana Juras, Kristina Crkvenac Gornik, M. Held, M. Šestan, D. Turudic, M. Šapina, S. Srsen, Sanda Huljev Frković, M. Frković, A. Gagro, M. Jelušić","doi":"10.3390/ijms25147777","DOIUrl":"https://doi.org/10.3390/ijms25147777","url":null,"abstract":"Endothelial cell injury is a hallmark of IgA vasculitis (IgAV), possibly associated with various factors, including oxidative stress. Certain single nucleotide polymorphisms (SNPs) of glutathione S-transferases (GST) genes have been shown to increase susceptibility to oxidative stress. The objective of our study was to evaluate the gene polymorphisms of GSTM1, GSTT1, GSTP1, and GSTA1 in patients with IgAV. DNA was extracted from the blood of 124 children with IgAV and 168 age-matched healthy controls. A higher frequency of the GSTM1 null genotype was observed in patients with gastrointestinal (GI) system involvement compared to those without GI system involvement (51.5% vs. 28.6%, p = 0.011). Additionally, the GSTM1 null genotype was less prevalent (30.8% vs. 69.2%, p = 0.032), while the GSTP1 Val/Val genotype was significantly more prevalent in patients who developed urogenital complications (scrotal swelling) during the course of the disease (60% vs. 40%, p = 0.039). This study is the first to suggest an association between GSTM1 and GSTP1 polymorphisms and various phenotypes observed during the clinical course of IgAV in the pediatric population. However, it was performed on a national and likely single ethnic cohort, too small for definitive conclusions, so larger studies are needed to confirm this association.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Metabolomics and Transcriptomics Analyses of the Biosynthesis of Arbutin and 6′-O-Caffeoylarbutin in Vaccinium dunalianum Cell Suspension Cultures Fed with Hydroquinone","authors":"Churan Li, Boxiao Wu, Weihua Wang, Xiaoqin Yang, Yun Liu, Guolei Zhu, Si-da Xie, Qian Jiang, Yong Ding, Yingjun Zhang, Ping Zhao, Lihua Zou","doi":"10.3390/ijms25147760","DOIUrl":"https://doi.org/10.3390/ijms25147760","url":null,"abstract":"Arbutin and 6′-O-caffeoylarbutin (CA) from Vaccinium dunalianum Wight are known for their ability to inhibit melanin synthesis. To boost the production of arbutin and CA, precursor feeding with hydroquinone (HQ) was studied in V. dunalianum suspension cells. The effect of HQ on the biosynthesis of arbutin and CA in the suspension cells was investigated using high-performance liquid chromatography (HPLC), and possible molecular mechanisms were analyzed using metabolomics and transcriptomics analyses. HPLC analysis only showed that the addition of HQ significantly enhanced arbutin synthesis in cells, peaking at 15.52 ± 0.28 mg·g−1 after 0.5 mmol·L−1 HQ treatment for 12 h. Subsequently, metabolomics identified 78 differential expression metabolites (DEMs), of which arbutin and CA were significantly up-regulated metabolites. Moreover, transcriptomics found a total of 10,628 differential expression genes (DEGs). The integrated transcriptomics and metabolomics revealed that HQ significantly enhanced the expression of two arbutin synthase (AS) genes (Unigene0063512 and Unigene0063513), boosting arbutin synthesis. Additionally, it is speculated that CA was generated from arbutin and 3,4,5-tricaffeoylquinic acid catalyzed by caffeoyl transferase, with Unigene0044545, Unigene0043539, and Unigene0017356 as potentially associated genes with CA synthesis. These findings indicate that the precursor feeding strategy offers a promising approach for the mass production of arbutin and CA in V. dunalianum suspension cells and provides new insights for CA biosynthesis in V. dunalianum.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Necrosis Factor-Alpha: Ally and Enemy in Protean Cutaneous Sceneries","authors":"K. Pocino, Valeria Carnazzo, A. Stefanile, V. Basile, Cristina Guerriero, M. Marino, D. Rigante, Umberto Basile","doi":"10.3390/ijms25147762","DOIUrl":"https://doi.org/10.3390/ijms25147762","url":null,"abstract":"Skin is the forestage for a series of many-sided functions of tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine with staggering versatility and sizable implications for tissue homeostasis, immune responses, angiogenesis, apoptosis, local and systemic inflammation. An aberrant TNF-α-mediated crosstalk has been linked to the pathogenesis of acute and chronic skin inflammatory diseases, and indeed, TNF-α dysregulation can contribute to the development and progression of psoriasis, vitiligo, local damage following exposition to ultraviolet light radiations, cutaneous lupus erythematosus, and acne vulgaris. Therapies that target TNF-α are conspicuously used in the treatment of different skin disorders, aiming to modulate the in vivo immune functions triggered by many cutaneous cells, including keratinocytes, mast cells, or Langerhans cells, and reduce inflammation taking place within the skin. Herein, we focus on the key relationships between TNF-α and distinct skin non-neoplastic inflammatory or physiologic conditions, showing that a natural induction of TNF-α may have a protective significance but that TNF-α overproduction may be harmful or even lethal. Many questions remain unraveled in the therapeutic practice, and caution should be exercised due to eventual backlashes exerted by TNF-α in maintaining skin health or in provoking skin disease.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular and Molecular Biology of Mitochondria in Chronic Obstructive Pulmonary Disease","authors":"Chin-Ling Li, Shih-Feng Liu","doi":"10.3390/ijms25147780","DOIUrl":"https://doi.org/10.3390/ijms25147780","url":null,"abstract":"Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by enduring airflow limitation and chronic inflammation. Growing evidence highlights mitochondrial dysfunction as a critical factor in COPD development and progression. This review explores the cellular and molecular biology of mitochondria in COPD, focusing on structural and functional changes, including alterations in mitochondrial shape, behavior, and respiratory chain complexes. We discuss the impact on cellular signaling pathways, apoptosis, and cellular aging. Therapeutic strategies targeting mitochondrial dysfunction, such as antioxidants and mitochondrial biogenesis inducers, are examined for their potential to manage COPD. Additionally, we consider the role of mitochondrial biomarkers in diagnosis, evaluating disease progression, and monitoring treatment efficacy. Understanding the interplay between mitochondrial biology and COPD is crucial for developing targeted therapies to slow disease progression and improve patient outcomes. Despite advances, further research is needed to fully elucidate mitochondrial dysfunction mechanisms, discover new biomarkers, and develop targeted therapies, aiming for comprehensive disease management that preserves lung function and enhances the quality of life for COPD patients.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De Novo DNM1L Mutation in a Patient with Encephalopathy, Cardiomyopathy and Fatal Non-Epileptic Paroxysmal Refractory Vomiting","authors":"B. Berti, D. Verrigni, A. Nasca, M. Di Nottia, Daniela Leone, A. Torraco, T. Rizza, E. Bellacchio, A. Legati, C. Palermo, S. Marchet, C. Lamperti, A. Novelli, Eugenio Maria Mercuri, E. Bertini, Marika Pane, Daniele Ghezzi, R. Carrozzo","doi":"10.3390/ijms25147782","DOIUrl":"https://doi.org/10.3390/ijms25147782","url":null,"abstract":"Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic–dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet Contribution and Endothelial Activation and Stress Index-Potential Mortality Predictors in Traumatic Brain Injury","authors":"A. Băetu, Liliana Mirea, Cristian Cobilinschi, I. Grințescu, I. Grințescu","doi":"10.3390/ijms25147763","DOIUrl":"https://doi.org/10.3390/ijms25147763","url":null,"abstract":"Coagulopathy and traumatic brain injury (TBI) are complexly intertwined. In isolated TBI, coagulopathy may contribute to hemorrhagic lesion development, progression, or recurrence, as it may lead to a particular pattern of coagulopathy called TBI-induced coagulopathy (TBI-IC). We performed a retrospective and descriptive evaluation of 63 patients admitted to the Emergency Clinical Hospital Bucharest with the diagnosis of moderate/severe brain injury. In addition to demographic data, all included patients had a complete paraclinical evaluation that included rotational thromboelastometric (ROTEM) blood-clot analysis. The platelet component (PLTEM) and the endotheliopathy activation and stress index score (EASIX) were calculated. These parameters were presented comparatively according to survival at 30 days and helped define the two study groups: survivors and non-survivors at 30 days. The contribution of platelets to clot strength is derived from maximum clot elasticity (MCE) and maximum clot firmness (MCF). MCE is defined as (MCF × 100)/(100 − MCF), and PLTEM is defined as EXTEM MCE—FIBTEM MCE. EASIX is a novel biomarker recently studied in TBI patients, calculated according to the following formula: lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelets (109 cells/L). Regarding the demographic data, there were no significant differences between the survivors and non-survivors. All ROTEM parameters related to clot amplitude (A5, A10, A20, MCF in EXTEM and FIBTEM channels) were higher in the group of patients who survived. Also, PLTEM was decreased in the group of deceased patients (89.71 ± 22.86 vs. 132.3 ± 16.56 p < 0.0001). The cut-off point determined with the ROC curve is 114.10, with a sensitivity of 94.74% and a specificity of 93.18%, for the detection of the negative prognosis (death at 30 days). The EASIX score was significantly higher in the patients who survived the traumatic event, with a median difference value of 1.15 (p < 0.0001). The ROC analysis of this biomarker highlights a cut-off point of 2.12, with a sensitivity of 88.64% and a specificity of 94.74% (AUC = 0.95, p < 0.0001), for the prediction of mortality. The comparative analysis of the two studied markers was performed using the Cox proportional hazard ratio and highlighted the greater influence that PLTEM has on survival time (b value = −0.05, p < 0.0001) compared to EASIX (b value = 0.49, p = 0.0026). The present retrospective study indicates the potential of the TBI-IC reflecting parameters PLTEM and EASIX as markers of mortality prognosis. Larger prospective studies are needed to confirm their combined prognostic value and use in decision-making and reduction in the burden of disease by adequate allocation of resources in a personalized and timely manner.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"(E)-2-Benzylidenecyclanones: Part XIX. Reaction of (E)-2-(4′-X-Benzylidene)-1-tetralones with Cellular Thiols: Comparison of Thiol Reactivities of Open-Chain Chalcones and Their Six- and Seven-Membered Cyclic Analogs","authors":"Fatemeh Kenari, Zoltán Pintér, S. Molnár, I. Borges, A. Camargo, H. Napolitano, P. Perjési","doi":"10.3390/ijms25147773","DOIUrl":"https://doi.org/10.3390/ijms25147773","url":null,"abstract":"Non-enzyme-catalyzed thiol addition onto the α,β-unsaturated carbonyl system is associated with several biological effects. Kinetics and diastereoselectivity of non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) and N-acetylcysteine (NAC) to the six-membered cyclic chalcone analogs 2a and 2b were investigated at different pH values (pH 3.2, 7.4 and 8.0). The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended both on the substitution and the pH. The stereochemical outcome of the reactions was evaluated using high-pressure liquid chromatography with UV detection (HPLC-UV). The structures of the formed thiol-conjugates and the retro-Michael products (Z)-2a and (Z)-2b were confirmed by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Frontier molecular orbitals and the Fukui function calculations were carried out to investigate their effects on the six-membered cyclic analogs. Data were compared with those obtained with the open-chain (1) and the seven-membered (3) analogs. The observed reactivities do not directly relate to the difference in in vitro cancer cell cytotoxicity of the compounds.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dementia after Ischemic Stroke, from Molecular Biomarkers to Therapeutic Options","authors":"Vikalpa Dammavalam, Deborah Rupert, Marcos Lanio, Zhaosheng Jin, Neil A Nadkarni, Stella E. Tsirka, Sergio D. Bergese","doi":"10.3390/ijms25147772","DOIUrl":"https://doi.org/10.3390/ijms25147772","url":null,"abstract":"Ischemic stroke is a leading cause of disability worldwide. While much of post-stroke recovery is focused on physical rehabilitation, post-stroke dementia (PSD) is also a significant contributor to poor functional outcomes. Predictive tools to identify stroke survivors at risk for the development of PSD are limited to brief screening cognitive tests. Emerging biochemical, genetic, and neuroimaging biomarkers are being investigated in an effort to unveil better indicators of PSD. Additionally, acetylcholinesterase inhibitors, NMDA receptor antagonists, dopamine receptor agonists, antidepressants, and cognitive rehabilitation are current therapeutic options for PSD. Focusing on the chronic sequelae of stroke that impair neuroplasticity highlights the need for continued investigative trials to better assess functional outcomes in treatments targeted for PSD.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}