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Search Results (614)

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Keywords = enzymatic therapy

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17 pages, 5735 KiB  
Article
Combination of Rhamnetin and RXP03 Mitigates Venom-Induced Toxicity in Murine Models: Preclinical Insights into Dual-Target Antivenom Therapy
by Jianqi Zhao, Guangyao Liu, Xiao Shi and Chunhong Huang
Toxins 2025, 17(6), 280; https://doi.org/10.3390/toxins17060280 - 4 Jun 2025
Viewed by 13
Abstract
Snakebite is a significant global public health challenge, and the limited application of antivenom has driven the exploration of novel therapies. Combination therapy using small-molecule drugs targeting phospholipases A2 (PLA2) and metalloproteinases (SVMP) in venom shows great potential. Although Rhamnetin and RXP03 [...] Read more.
Snakebite is a significant global public health challenge, and the limited application of antivenom has driven the exploration of novel therapies. Combination therapy using small-molecule drugs targeting phospholipases A2 (PLA2) and metalloproteinases (SVMP) in venom shows great potential. Although Rhamnetin and RXP03 exhibit notable anti-phospholipase and anti-metalloproteinase activities, respectively, their antiophidic potential remains poorly explored. This study aims to evaluate the inhibitory effects of Rhamnetin and RXP03 on snake venom toxicity. Methodologically, we conducted in vitro enzymatic assays to quantify PLA2/SVMP inhibition, murine models of envenomation (subcutaneous/intramuscular venom injection) to assess local tissue damage and systemic toxicity, and histopathological/biochemical analyses. In vitro experiments demonstrated that Rhamnetin effectively inhibited PLA2 activity while RXP03 showed potent suppression of SVMP activity, with their combination significantly reducing venom-induced hemorrhagic activity. In murine models, the combined therapy markedly alleviated venom-triggered muscle toxicity and ameliorated oxidative stress. Furthermore, the combination enhanced motor performance and survival rate in mice, improved serum biochemical parameters, corrected coagulation disorders, and attenuated pathological damage in liver, kidney, heart, and lung tissues. This research demonstrates that dual-targeted therapy against metalloproteinases and phospholipases in snake venom can effectively prevent a series of injuries caused by snake venom. Collectively, the combined application of Rhamnetin and RXP03 exhibits significant inhibitory effects on a variety of venom-induced toxicities, providing pharmacological evidence for the development of antivenom therapies. However, the efficacy validation in this study was limited to murine models, and there is a discrepancy with clinical needs for delayed treatment in real-world envenomation scenarios. Despite these limitations, the findings provide robust preclinical evidence supporting the Rhamnetin–RXP03 combination therapy as a cost-effective, broad-spectrum antivenom strategy. Future studies are required to optimize dosing regimens and evaluate clinical translatability. Full article
(This article belongs to the Section Animal Venoms)
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22 pages, 28590 KiB  
Article
Screening and Validation: AI-Aided Discovery of Dipeptidyl Peptidase-4 Inhibitory Peptides from Hydrolyzed Rice Proteins
by Cheng Cheng, Huizi Cui, Xiangyu Yu and Wannan Li
Foods 2025, 14(11), 1916; https://doi.org/10.3390/foods14111916 - 28 May 2025
Viewed by 184
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors play a critical role in the management of type 2 diabetes; however, some synthetic drugs may cause adverse effects. Natural peptides derived from rice offer a promising alternative due to their favorable biocompatibility and development potential. In this study, [...] Read more.
Dipeptidyl peptidase-4 (DPP-4) inhibitors play a critical role in the management of type 2 diabetes; however, some synthetic drugs may cause adverse effects. Natural peptides derived from rice offer a promising alternative due to their favorable biocompatibility and development potential. In this study, an AI-assisted virtual screening pipeline integrating machine learning, molecular docking, and molecular dynamics (MD) simulations was established to identify and evaluate rice-derived DPP-4 inhibitory peptides. A random forest classification model achieved 85.37% accuracy in predicting inhibitory activity. Peptides generated by simulated enzymatic hydrolysis were screened based on machine learning and docking scores, and four proline-rich peptides (PPPPPPPPA, PPPSPPPV, PPPPPY, and CPPPPAAY) were selected for MD analysis. The simulation results showed that PPPSPPPV formed a stable complex with the DPP-4 catalytic triad (Ser592–Asp670–His702) through electrostatic and hydrophobic interactions, with low structural fluctuation (RMSF < 1.75 Å). In vitro assays revealed that PPPPPY exhibited the strongest DPP-4 inhibitory activity (IC50 = 153.2 ± 5.7 μM), followed by PPPPPPPPA (177.0 ± 6.0 μM) and PPPSPPPV (216.3 ± 4.5 μM). This study presents an efficient approach combining virtual screening and experimental validation, offering a structural and mechanistic foundation for the development of natural DPP-4 inhibitory peptides as candidates for functional foods or adjunct diabetes therapies. Full article
(This article belongs to the Section Food Physics and (Bio)Chemistry)
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21 pages, 5060 KiB  
Article
Acquired Resistance to Decitabine Associated with the Deoxycytidine Kinase A180P Mutation: Implications for the Order of Hypomethylating Agents in Myeloid Malignancies Treatment
by Kristina Simonicova, Lubos Janotka, Helena Kavcova, Ivana Borovska, Zdena Sulova, Albert Breier and Lucia Messingerova
Int. J. Mol. Sci. 2025, 26(11), 5083; https://doi.org/10.3390/ijms26115083 - 25 May 2025
Viewed by 273
Abstract
The backbone of therapy for elderly patients with myelodysplastic syndromes and acute myeloid leukemia consists of hypomethylating agents 5-aza-2’-deoxycytidine (DAC) and 5-azacytidine (AZA). However, resistance frequently emerges during treatment. To investigate the mechanisms of resistance, we generated DAC-resistant variants of the acute myeloid [...] Read more.
The backbone of therapy for elderly patients with myelodysplastic syndromes and acute myeloid leukemia consists of hypomethylating agents 5-aza-2’-deoxycytidine (DAC) and 5-azacytidine (AZA). However, resistance frequently emerges during treatment. To investigate the mechanisms of resistance, we generated DAC-resistant variants of the acute myeloid leukemia cell lines, MOLM-13 and SKM-1, through their prolonged cultivation in increasing concentrations of DAC. The resistant cell variants, MOLM-13/DAC and SKM-1/DAC, exhibited cross-resistance to cytarabine and gemcitabine, but remained sensitive to AZA. Existing studies have suggested that the loss of deoxycytidine kinase (DCK) may play an important role in DAC resistance. DCK is critical for DAC activation, but the precise mechanisms of its downregulation remain incompletely understood. We identified a novel point mutation (A180P) in DCK, which results in acquired DAC resistance. Although the DCK mRNA was actively transcribed, the mutant protein was not detected in DAC-resistant cells. The transfection of HEK293 cells with the mutant DCK, combined with proteasomal inhibition, revealed rapid proteasomal degradation, establishing a mechanistic link between the A180P mutation and DCK loss, not previously described. This highlights the importance of also evaluating DCK at the protein and/or enzymatic activity levels in patients. The loss of functional DCK impairs the phosphorylation of deoxynucleosides, conferring resistance to DAC, gemcitabine, and cytarabine, but AZA, phosphorylated by uridine–cytidine kinase, remains effective and may represent a therapeutic alternative for patients with acquired DAC resistance. Full article
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26 pages, 803 KiB  
Review
Bioactive Plant Compounds as Alternatives Against Antifungal Resistance in the Candida Strains
by Thainá dos Santos Dantas, Janaina Carla Barbosa Machado, Magda Rhayanny Assunção Ferreira and Luiz Alberto Lira Soares
Pharmaceutics 2025, 17(6), 687; https://doi.org/10.3390/pharmaceutics17060687 - 23 May 2025
Viewed by 251
Abstract
The pathogenicity of Candida spp. poses a persistent challenge, particularly in hospital environments where these species proliferate and cause opportunistic infections. Many strains have developed resistance to commonly used antifungal agents, including azoles, polyenes, and echinocandins, complicating treatment, especially in immuno-compromised patients. Understanding [...] Read more.
The pathogenicity of Candida spp. poses a persistent challenge, particularly in hospital environments where these species proliferate and cause opportunistic infections. Many strains have developed resistance to commonly used antifungal agents, including azoles, polyenes, and echinocandins, complicating treatment, especially in immuno-compromised patients. Understanding the mechanisms underlying antifungal resistance, such as mutations in genes involved in ergosterol biosynthesis, efflux pump activity, and enzymatic pathways, is crucial for developing targeted interventions. Given the challenges associated with discovering new antifungal agents, medicinal plants have emerged as a promising source of bioactive compounds with anti-Candida activity. Secondary metabolites, including terpenoids, alkaloids, flavonoids, and tannins, exhibit various mechanisms of action, such as biofilm inhibition, membrane disruption, and oxidative stress induction. However, challenges such as extract standardization, and the lack of clinical studies continue to limit their therapeutic application. This review underscores the potential of medicinal plants as complementary or alternative strategies to conventional antifungal therapies, emphasizing the need for multidisciplinary research to overcome these hurdles and harness the therapeutic potential of natural products. Full article
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15 pages, 1251 KiB  
Article
Benchmarking Nanopore Sequencing for CLN2 (TPP1) Mutation Detection: Integrating Rapid Genomics and Orthogonal Validation for Precision Diagnostics
by Betül Teker, Gökce Akan, Hasan Hüseyin Kazan, Özge Özgen, Suzin Tatonyan, Mehmet Cihan Balci, Meryem Karaca, Fulya Kurekci, Edibe Pembegül Yıldız, Olcay Güngor, Adnan Deniz, Asuman Gedikbasi, Fatmahan Atalar, Gülden Fatma Gokcay and Mehves Poda
Int. J. Mol. Sci. 2025, 26(11), 5037; https://doi.org/10.3390/ijms26115037 - 23 May 2025
Viewed by 213
Abstract
CLN2 disease (neuronal ceroid lipofuscinosis type 2) is an ultra-rare lysosomal storage disorder caused by mutations in the TPP1/CLN2 gene, resulting in impaired tripeptidyl peptidase 1 (TPP1) activity. The timely initiation of enzyme replacement therapy is pivotal for attenuating progressive and irreversible neurodegeneration. [...] Read more.
CLN2 disease (neuronal ceroid lipofuscinosis type 2) is an ultra-rare lysosomal storage disorder caused by mutations in the TPP1/CLN2 gene, resulting in impaired tripeptidyl peptidase 1 (TPP1) activity. The timely initiation of enzyme replacement therapy is pivotal for attenuating progressive and irreversible neurodegeneration. This study aimed to benchmark the performance of Oxford Nanopore long-read sequencing (ONT-LRS) for targeted TPP1 mutation detection in a Turkish CLN2 cohort and to assess its concordance with orthogonal validation methods, including Sanger sequencing and enzymatic activity assays. Using a custom-designed primer panel, the entire TPP1 gene (6846 bp) was sequenced on the Oxford Nanopore (ONT) MinIon platform in seven clinically confirmed CLN2 index patients and sixteen unaffected family members. Detected variants were validated via Sanger sequencing and correlated with TPP1 enzyme activity in leucocytes and dried blood spots. Four pathogenic or likely pathogenic TPP1 variants were identified: c.622C>T (p.Arg208*), c.857A>G (p.Asn286Ser), c.1204G>T (p.Glu402*), and c.225A>G (p.Gln75=), along with fourteen additional benign variants. Variant allele frequencies were 50% for c.622C>T, 28.6% for c.1204G>T, 14.3% for c.857A>G, and 7.1% for c.225A>G. Notably, this is the first report to document the homozygous state of the c.857A>G variant and the compound heterozygous configuration of the c225A>G and c.622C>T variants in CLN2 patients, thereby expanding the known mutational landscape. In contrast, the globally common variant c.509-1G>C was not observed, suggesting regional variation in TPP1 mutation patterns. Consistent with the prior Turkish studies, c.622C>T (p.Arg208*) was the most prevalent variant, followed by c.1204G>T (p.Glu402*). TPP1 enzymatic activity was significantly reduced in all affected individuals (p < 0.0001), supporting the functional relevance of the identified variants. ONT-LRS offers a robust, cost-effective platform for high-resolution analysis of the TPP1 gene. Integrating molecular and biochemical data improves diagnostic precision and supports timely, targeted interventions for CLN2 disease, particularly in regions with high consanguinity and limited diagnostic infrastructure. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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17 pages, 1276 KiB  
Review
Deep Caries Lesions Revisited: A Narrative Review
by Irina Maria Gheorghiu, Sergiu Ciobanu, Ion Roman, Stana Păunică, Anca Silvia Dumitriu and Alexandru Andrei Iliescu
J. Mind Med. Sci. 2025, 12(1), 37; https://doi.org/10.3390/jmms12010037 - 23 May 2025
Viewed by 242
Abstract
Background/Objectives: Deep caries lesions represent an actual concern in preserving tooth vitality and preventing irreversible pulpitis. As presently the non-selective approach is considered an overtreatment, the concept of selective caries removal is highly recommended. The goal of this narrative review is to [...] Read more.
Background/Objectives: Deep caries lesions represent an actual concern in preserving tooth vitality and preventing irreversible pulpitis. As presently the non-selective approach is considered an overtreatment, the concept of selective caries removal is highly recommended. The goal of this narrative review is to focus on current trends in carious dentine excavation and adjunctive therapies. Methods: A keyword-based selection of scientific publications issued in the last six years, i.e., 2019–2024, was conducted with the search engine of PubMed (MEDLINE) and ScienceDirect databases, using the following keywords: deep carious lesion; caries removal; indirect pulp capping; adjunctive antimicrobial therapy; adjunctive anti-enzymatic therapy; biomimetic restorative dentistry. Discussions: In deep caries management, the current trends of carious dentine excavation recommend preferentially partial caries removal technique as less risky to pulp exposure and more conservative compared to the stepwise technique (SW). Presently, advanced additional procedures such as antimicrobial photodynamic therapy and an anti-enzymatic approach are also considered for caries arrest. Conclusions: Selective caries removal and adjunctive photodynamic antimicrobial therapy are procedures of choice in preserving pulp vitality. Anti-enzymatic therapies impede decoupling with time of adhesive restorations from the smear layer. Biomimetic restorative dentistry and smart materials introduce the principles of artificial intelligence in the therapeutic approach of deep caries. Full article
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31 pages, 4011 KiB  
Review
Progress and Prospects of Triazoles in Advanced Therapies for Parasitic Diseases
by Jaime A. Isern, Renzo Carlucci, Guillermo R. Labadie and Exequiel O. J. Porta
Trop. Med. Infect. Dis. 2025, 10(5), 142; https://doi.org/10.3390/tropicalmed10050142 - 20 May 2025
Viewed by 402
Abstract
Parasitic diseases represent a severe global burden, with current treatments often limited by toxicity, drug resistance, and suboptimal efficacy in chronic infections. This review examines the emerging role of triazole-based compounds, originally developed as antifungals, in advanced antiparasitic therapy. Their unique structural properties, [...] Read more.
Parasitic diseases represent a severe global burden, with current treatments often limited by toxicity, drug resistance, and suboptimal efficacy in chronic infections. This review examines the emerging role of triazole-based compounds, originally developed as antifungals, in advanced antiparasitic therapy. Their unique structural properties, particularly those of 1,2,3- and 1,2,4-triazole isomers, facilitate diverse binding interactions and favorable pharmacokinetics. By leveraging innovative synthetic approaches, such as click chemistry (copper-catalyzed azide–alkyne cycloaddition) and structure-based design, researchers have repurposed and optimized triazole scaffolds to target essential parasite pathways, including sterol biosynthesis via CYP51 and other novel enzymatic routes. Preclinical studies in models of Chagas disease, leishmaniasis, malaria, and helminth infections demonstrate that derivatives like posaconazole, ravuconazole, and DSM265 exhibit potent in vitro and in vivo activity, although their primarily static effects have limited their success as monotherapies in chronic cases. Combination strategies and hybrid molecules have demonstrated the potential to enhance efficacy and mitigate drug resistance. Despite challenges in achieving complete parasite clearance and managing potential toxicity, interdisciplinary efforts across medicinal chemistry, parasitology, and clinical research highlight the significant potential of triazoles as components of next-generation, patient-friendly antiparasitic regimens. These findings support the further optimization and clinical evaluation of triazole-based agents to improve treatments for neglected parasitic diseases. Full article
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21 pages, 856 KiB  
Review
Melatonin in Glaucoma: Integrative Mechanisms of Intraocular Pressure Control and Neuroprotection
by Xinyu Hou and Yingzi Pan
Biomedicines 2025, 13(5), 1213; https://doi.org/10.3390/biomedicines13051213 - 16 May 2025
Viewed by 359
Abstract
Background: Glaucoma is a leading cause of irreversible visual loss worldwide, characterized by progressive retinal ganglion cell (RGC) degeneration and optic nerve damage. Current therapies mainly focus on lowering intraocular pressure (IOP), yet fail to address pressure-independent neurodegenerative mechanisms. Melatonin, an endogenously [...] Read more.
Background: Glaucoma is a leading cause of irreversible visual loss worldwide, characterized by progressive retinal ganglion cell (RGC) degeneration and optic nerve damage. Current therapies mainly focus on lowering intraocular pressure (IOP), yet fail to address pressure-independent neurodegenerative mechanisms. Melatonin, an endogenously produced indoleamine, has gained attention for its potential in modulating both IOP and neurodegeneration through diverse cellular pathways. This review evaluates the therapeutic relevance of melatonin in glaucoma by examining its mechanistic actions and emerging delivery approaches. Methods: A comprehensive literature search was conducted via PubMed and Medline to identify studies published between 2000 and 2025 on melatonin’s roles in glaucoma. Included articles discussed its effects on IOP regulation, RGC survival, oxidative stress, mitochondrial integrity, and inflammation. Results: Evidence supports melatonin’s involvement in IOP reduction via MT receptor activation and its synergism with adrenergic and enzymatic regulators. Moreover, it protects RGCs by mitigating oxidative stress, preventing mitochondrial dysfunction, and inhibiting apoptotic and inflammatory cascades. Recent advances in ocular drug delivery systems enhance its bioavailability and therapeutic potential. Conclusions: Melatonin represents a multi-target candidate for glaucoma treatment. Further clinical studies are necessary to establish optimal dosing strategies, delivery methods, and long-term safety in patients. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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15 pages, 6399 KiB  
Article
Characterisation of Mesenchymal Stromal Cells (MSCs) from Human Adult Thymus as a Potential Cell Source for Regenerative Medicine
by Martina Ramsperger-Gleixner, Chang Li, Nina Wallon, Annika Kuckhahn, Volker Weisbach, Michael Weyand and Christian Heim
J. Clin. Med. 2025, 14(10), 3474; https://doi.org/10.3390/jcm14103474 - 15 May 2025
Viewed by 275
Abstract
Background: Mesenchymal stem cell-based therapy may be indicated in ischaemic heart disease. The use of autologous adipose-derived mesenchymal stromal cells (AdMSCs) offers regenerative potential due to their paracrine effects. The aim of this study was to expand and characterise adult human thymus-derived MSCs [...] Read more.
Background: Mesenchymal stem cell-based therapy may be indicated in ischaemic heart disease. The use of autologous adipose-derived mesenchymal stromal cells (AdMSCs) offers regenerative potential due to their paracrine effects. The aim of this study was to expand and characterise adult human thymus-derived MSCs harvested during open heart surgery with respect to their stem cell and paracrine properties. Methods: Enzymatically and non-enzymatically isolated human thymic AdMSCs (ThyAdMSCs) were cultured in xeno-free media containing pooled human platelet lysate (pPL). MSC characterisation was performed. Ex vivo expanded ThyAdMSCs were differentiated into three lineages. Proliferative capacity and immunomodulatory properties were assessed by proliferation assays and mixed lymphocyte reaction, respectively. Gene expression analysis was performed by qPCR. Results: Both isolation methods yielded fibroblast-like cells with plastic adherence and high proliferation. Flow cytometry revealed distinct expression of MSC markers in the absence of haematopoietic cell surface markers. Ex vivo expanded ThyAdMSCs could be differentiated into adipocytes, osteocytes, and chondrocytes. Activated peripheral blood mononuclear cells were significantly reduced when co-cultured with ThyAdMSCs, indicating their ability to inhibit immune cells in vitro. Gene expression analysis showed significantly less IFNγ and TNFα, indicating an alteration of the activated and pro-inflammatory state in the presence of ThyAdMSCs. Conclusions: These results demonstrate an efficient method to generate AdMSCs from human thymus. These MSCs have a strong immunomodulatory capacity and are, therefore, a promising cell source for regenerative medicine. The culture conditions are crucial for cells to proliferate in culture. Further research could explore the use of ThyAdMSCs or their secretome in surgical procedures. Full article
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22 pages, 4214 KiB  
Article
Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy
by Amy F. Geard, Giulia Massaro, Michael P. Hughes, Patrick Arbuthnot, Simon N. Waddington and Ahad A. Rahim
Pharmaceutics 2025, 17(5), 650; https://doi.org/10.3390/pharmaceutics17050650 - 15 May 2025
Viewed by 327
Abstract
Background/Objectives: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA1 gene. Type 1 Gaucher disease is characterised by substrate accumulation in the visceral organs, which occurs in combination with acute and chronic neurodegeneration that distinguish [...] Read more.
Background/Objectives: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA1 gene. Type 1 Gaucher disease is characterised by substrate accumulation in the visceral organs, which occurs in combination with acute and chronic neurodegeneration that distinguish type 2 and type 3 GD, respectively. We have previously shown the efficacy of neonatal AAV9 gene therapy for treating type 2 GD and aimed to investigate post-symptomatic administration into a model of type 1 disease. Current murine models of type 1 disease are limited in their recapitulation of early onset phenotypic manifestation and thus we aimed to create a novel model of type 1 in which to test the efficacy of adult gene therapy. Methods: The novel AAV-GD1 model was created through intracerebroventricular injection of AAV9 containing the human GBA1 gene under control of the neuron-specific synapsin promoter (AAV9.hSynI.hGBA1) to the pre-existing acute K14-lnl/lnl model of type 2 GD. Administration of AAV9.hSynI.hGBA1 aimed to restore glucocerebrosidase expression in the brain and extend the lifespan beyond 14 days, allowing the visceral pathology to develop further. The organ pathology was characterised by immunohistochemistry at various time points. Once visceral disease was confirmed, an intravenous injection of AAV9 containing a ubiquitously active CAG promoter driving hGBA1 (AAV9.CAG.hGBA1) was administered to post-symptomatic mice. Animals were aged for 2 and 4 months post-treatment with AAV9.CAG.hGBA1, and immunohistochemistry and enzymatic activity were assessed to investigate therapeutic efficacy. Results: The AAV-GD1 model displayed visceral pathology in the spleen, lung, and liver from 2 months of age. This allowed us to validate the efficacy of adult gene therapy; intravenous administration of AAV9.CAG.hGBA1 transiently ameliorated the lung pathology and rescued the spleen pathology up to 4 months post-administration. Conclusions: The creation of the novel AAV-GD1 model with more aggressive visceral pathology presents a unique opportunity for investigation of new therapies to treat type 1 GD. AAV9.CAG.hGBA1 represents a potential therapeutic option for all forms of Gaucher disease. Full article
(This article belongs to the Section Gene and Cell Therapy)
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25 pages, 2812 KiB  
Article
Dual Proteomics Strategies to Dissect and Quantify the Components of Nine Medically Important African Snake Venoms
by Damien Redureau, Fernanda Gobbi Amorim, Thomas Crasset, Imre Berger, Christiane Schaffitzel, Stefanie Kate Menzies, Nicholas R. Casewell and Loïc Quinton
Toxins 2025, 17(5), 243; https://doi.org/10.3390/toxins17050243 - 13 May 2025
Viewed by 509
Abstract
Snakebite envenoming constitutes a significant global health issue, particularly in Africa, where venomous species such as Echis vipers and Dendroaspis mambas pose substantial risks to human health. This study employs a standardized venomics workflow to comprehensively characterize and comparatively quantify the venom composition [...] Read more.
Snakebite envenoming constitutes a significant global health issue, particularly in Africa, where venomous species such as Echis vipers and Dendroaspis mambas pose substantial risks to human health. This study employs a standardized venomics workflow to comprehensively characterize and comparatively quantify the venom composition of nine medically relevant snake species chosen from among the deadliest in Africa. Utilizing shotgun venom proteomics and venom gland transcriptomics, we report detailed profiles of venom complexity, highlighting the relative abundance of dominant toxin families such as three-finger toxins and Kunitz-type proteins in Dendroaspis, and metalloproteinases and phospholipases A2 in Echis. We delineate here the relative abundance and structural diversity of venom components. Key to our proteomic approach is the implementation of Multi-Enzymatic Limited Digestion (MELD), which improved protein sequence coverage and enabled the identification of rare toxin families such as hyaluronidases and renin-like proteases, by multiplying the overlap of generated peptides and enhancing the characterization of both toxin and non-toxin components within the venoms. The culmination of these efforts resulted in the construction of a detailed toxin database, providing insights into the biological roles and potential therapeutic targets of venom proteins and peptides. The findings here compellingly validate the MELD technique, reinforcing its reproducibility as a valuable characterization approach applied to venomics. This research significantly advances our understanding of venom complexity in African snake species, including representatives of both Viperidae and Elapidae families. By elucidating venom composition and toxin profiles, our study paves the way for the development of targeted therapies aimed at mitigating the morbidity and mortality associated with snakebite envenoming globally. Full article
(This article belongs to the Special Issue Toxins: From the Wild to the Lab)
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20 pages, 486 KiB  
Review
Mitochondrial Oxidative Phosphorylation System Dysfunction in Schizophrenia
by Constanza Morén, David Olivares-Berjaga, Albert Martínez-Pinteño, Miquel Bioque, Natàlia Rodríguez, Patricia Gassó, Lourdes Martorell and Eduard Parellada
Int. J. Mol. Sci. 2025, 26(9), 4415; https://doi.org/10.3390/ijms26094415 - 6 May 2025
Viewed by 384
Abstract
Schizophrenia (SCZ) is a severe, chronic mental disorder of unknown etiology and limited therapeutic options. Bioenergetic deficits in the oxidative phosphorylation system (OXPHOS) during early postnatal brain development may underlie disrupted neuronal metabolism and synaptic signaling, contributing to the neurodevelopmental and behavioral disturbances [...] Read more.
Schizophrenia (SCZ) is a severe, chronic mental disorder of unknown etiology and limited therapeutic options. Bioenergetic deficits in the oxidative phosphorylation system (OXPHOS) during early postnatal brain development may underlie disrupted neuronal metabolism and synaptic signaling, contributing to the neurodevelopmental and behavioral disturbances observed in patients. This narrative review summarizes updated evidence linking mitochondrial-OXPHOS dysfunction to SCZ pathophysiology. The novelty lies in the focus on OXPHOS dysfunction at the enzymatic/functional level, rather than on genetic, transcriptional, or oxidative parameters. While complex I impairment has long been highlighted and proposed as a peripheral marker of the disease, recent studies also report alterations in other OXPHOS complexes and their precursors. These findings suggest that OXPHOS dysfunction is not isolated to a single enzymatic component but affects broader mitochondrial function, alongside oxidative stress, contributing to disease progression through mechanisms involving apoptosis, accelerated aging, and synaptic deterioration. OXPHOS dysfunction in both central and peripheral tissues further supports its relevance to SCZ. Overall, the literature points to mitochondrial OXPHOS abnormalities as a significant biological feature of SCZ. Whether these alterations are causal factors or consequences of disease processes remains unclear. Understanding OXPHOS dysregulation may open new avenues for targeted therapies. Full article
(This article belongs to the Section Molecular Biology)
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28 pages, 2126 KiB  
Review
Snake Venom Compounds: A New Frontier in the Battle Against Antibiotic-Resistant Infections
by Barathan Muttiah and Alfizah Hanafiah
Toxins 2025, 17(5), 221; https://doi.org/10.3390/toxins17050221 - 1 May 2025
Viewed by 848
Abstract
The occurrence of antibiotic-resistant bacteria is a serious global health issue, and it emphasizes the need for novel antimicrobial agents. This review explores the potential of snake venom as another alternative strategy against antimicrobial resistance. Snake venoms are complex combinations of bioactive peptides [...] Read more.
The occurrence of antibiotic-resistant bacteria is a serious global health issue, and it emphasizes the need for novel antimicrobial agents. This review explores the potential of snake venom as another alternative strategy against antimicrobial resistance. Snake venoms are complex combinations of bioactive peptides and proteins, including metalloproteases (MPs), serine proteases (SPs), phospholipase A2 (PLA2) enzymes, three-finger toxins (3FTXs), cysteine-rich secretory proteins (CRISPs), L-amino acid oxidases (LAAOs), and antimicrobial peptides (AMPs). The antibacterial products possess wide-spectrum antibacterial activity against resistant microbes via diverse mechanisms such as cell membrane disruption, enzymatic hydrolysis of microbial structures, generation of oxidative stress, inhibition of biofilms, and immunomodulation. Strong antimicrobial activity is reported by most studies, but these are mostly restricted to in vitro testing with low translational use. Although preliminary insights into molecular targets and physiological effects exist, further studies are needed to clarify long-term safety and therapeutic potential. Special attention is given to snake venom-derived extracellular vesicles (SVEVs), which enhance the therapeutic potential of venom toxins by protecting them from degradation, improving bioavailability, and facilitating targeted delivery. Furthermore, innovative delivery strategies such as PEGylation, liposomes, hydrogels, microneedle patches, biopolymer films, and nanoparticles are discussed for their role in reducing systemic toxicity and enhancing antimicrobial efficacy. The rational modification of venom-derived peptides further expands their therapeutic utility by improving pharmacokinetics and minimizing off-target effects. Together, these approaches highlight the translational potential of snake venom-based therapies as next-generation antimicrobials in the fight against resistant infections. By outlining these challenges and directions, this review positions snake venom as an overlooked but fertile resource in the battle against antibiotic resistance. Full article
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53 pages, 1615 KiB  
Review
From Synaptic Plasticity to Neurodegeneration: BDNF as a Transformative Target in Medicine
by Corneliu Toader, Matei Serban, Octavian Munteanu, Razvan-Adrian Covache-Busuioc, Mihaly Enyedi, Alexandru Vlad Ciurea and Calin Petru Tataru
Int. J. Mol. Sci. 2025, 26(9), 4271; https://doi.org/10.3390/ijms26094271 - 30 Apr 2025
Cited by 1 | Viewed by 1650
Abstract
The brain-derived neurotrophic factor (BDNF) has become one of the cornerstones of neuropathology, influencing synaptic plasticity, cognitive resilience, and neuronal survival. Apart from its molecular biology, BDNF is a powerful target for transformative benefit in precision medicine, leading to innovative therapeutic approaches for [...] Read more.
The brain-derived neurotrophic factor (BDNF) has become one of the cornerstones of neuropathology, influencing synaptic plasticity, cognitive resilience, and neuronal survival. Apart from its molecular biology, BDNF is a powerful target for transformative benefit in precision medicine, leading to innovative therapeutic approaches for neurodegenerative and psychiatric diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Nevertheless, clinical applicability is obstructed by hurdles in delivery, patient-specific diversity, and pleiotropic signaling. Here, we summarize findings in BDNF research, including its regulatory pathways and diagnostic/prognostic biomarkers and integrative therapeutic approaches. We describe innovative delivery systems, such as lipid nanoparticle-based mRNA therapies and CRISPR-dCas9-based epigenetic editing that bypass obstacles such as BBB (blood–brain barrier) and enzymatic degradation. The recent implementation of multiplex panels combining BDNF biodynamic indicators with tau and amyloid-β signaling markers showcases novel levels of specificity for both early detection and potential therapeutic monitoring. Humanized preclinical models like iPSC-derived neurons and organoids point to the key role of BDNF in neurodeveloping and neurodegenerative processes, paralleling advances in bridging preclinical observation and clinical environments. Moreover, novel therapeutic tools delivering TrkB activators or the implementation of AI-based dynamic care platforms enable tailored and scalable treatments. This review also aims to extend a framework used in the understanding of BDNF’s relevance to traditional neurodegenerative models by situating more recent work detailing BDNF’s actions in ischemic tissues and the gut–brain axis in the context of systemic health. Finally, we outline a roadmap for the incorporation of BDNF-centered therapies into worldwide healthcare, highlighting ethical issues, equity, and interdisciplinary decomposition. The therapeutic potential of BDNF heralds a new era in neuroscience and medicine, revolutionizing brain health and paving the way for the advancement of precision medicine. Full article
(This article belongs to the Special Issue Molecular Research on the Neurodegenerative Diseases)
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24 pages, 2742 KiB  
Article
Mono-CYP CHO Model: A Recombinant Chinese Hamster Ovary Cell Platform for Investigating CYP-Specific Tamoxifen Metabolism
by Christian Schulz, Sarah Stegen, Friedrich Jung and Jan-Heiner Küpper
Int. J. Mol. Sci. 2025, 26(9), 3992; https://doi.org/10.3390/ijms26093992 - 23 Apr 2025
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Abstract
The metabolism of drugs and foreign substances in humans typically involves multiple enzymatic steps, particularly in phase-1 biotransformation in the liver, where various cytochrome P450 monooxygenases (CYPs) play crucial roles. This complexity can lead to a wide range of metabolites. Understanding the contributions [...] Read more.
The metabolism of drugs and foreign substances in humans typically involves multiple enzymatic steps, particularly in phase-1 biotransformation in the liver, where various cytochrome P450 monooxygenases (CYPs) play crucial roles. This complexity can lead to a wide range of metabolites. Understanding the contributions of individual CYPs and their interactions within these intricate enzyme cascades can be challenging. We recently developed an in vitro biotransformation platform employing various Chinese Hamster Ovarian (CHO) cell clones. These clones express human cytochrome P450 oxidoreductase (CPR), and each is defined by a specific human CYP enzyme expression, thus exhibiting no detectable endogenous CYP enzyme activity (mono-CYP CHO platform). In this study, we investigated whether the mono-CYP CHO platform is a suitable tool for modeling complex drug metabolization reactions in vitro. Tamoxifen (TAM) was selected as a model substance due to its role as a prodrug widely used in breast cancer therapy, where its main active metabolite, endoxifen, arises from a two-step metabolism primarily involving the CYP system. Specifically, the combined activity of CYP3A4 and CYP2D6 is believed to be essential for efficient endoxifen production. However, the physiological metabolization pathway of TAM is more complex and interconnected, and the reasons for TAM’s therapeutic success and variability among patients are not yet fully understood. Analogous to our recently introduced mono-CYP3A4 CHO cells, we generated a CHO cell line expressing human CPR and CYP2D6, including analysis of CYP2D6 expression and specific activity. Comparative studies on the metabolization of TAM were performed with both mono-CYP CHO models individually and in co-culture with intact cells as well as with isolated microsomes. Supernatants were analyzed by HPLC to calculate individual CYP activity for each metabolite. All the picked mono-CYP2D6 clones expressed similar CYP2D6 protein amounts but showed different enzyme activities. Mono-CYP2D6 clone 18 was selected as the most suitable for TAM metabolization based on microsomal activity assays. TAM conversion with mono-CYP2D6 and -3A4 clones, as well as the combination of both, resulted in the formation of the expected main metabolites. Mono-CYP2D6 cells and microsomes produced the highest detected amounts of 4-hydroxytamoxifen and endoxifen, along with N-desmethyltamoxifen and small amounts of N,N-didesmethyltamoxifen. N-desmethyltamoxifen was the only TAM metabolite detected in notable quantities in mono-CYP3A4, while 4-hydroxytamoxifen and endoxifen were present only in trace amounts. In CYP2D6/3A4 co-culture and equal mixtures of both CYP microsomes, all metabolites were detected at concentrations around 50% of those in individual clones, indicating no significant synergistic effects. In conclusion, our mono-CYP CHO model confirmed the essential role of CYP2D6 in synthesizing the active TAM metabolite endoxifen and indicated that CYP2D6 is also involved in producing the by-metabolite N,N-didesmethyltamoxifen. The differences in metabolite spectra between the two mono-CYP models highlight the CYP specificity and sensitivity of our in vitro system. Full article
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