Pub Date : 2025-11-01DOI: 10.1016/j.biochi.2025.07.026
Sana Tahir, Jannat Rahim, Saima Sadaf
Human interleukin-37 isoform 1 (IL-37b) is a key anti-inflammatory cytokine with significant therapeutic potential for inflammatory and immune-mediated disorders. However, its clinical translation is limited by poor understanding of disease-associated genetic variants and lack of an expression system for soluble production. While addressing both challenges, this study presents (a) a prioritized catalog of high-confidence, pathogenic IL-37b variants, and (b) a fusion-based expression platform for its soluble production, providing essential resources for future functional validations. Screening of over 3000 IL-37b variants using various computational tools and multi-algorithm consensus approach identified 25 potentially pathogenic non-synonymous single nucleotide variants (nsSNVs). Amongst these, 16 variants (e.g., D64 V/N, L72R, L111Q, V113F, C122R, F154S, I155 N, Y157C, E168G, G174A, I111T) were predicted to significantly destabilize IL-37b's structure and impair its interaction with the IL-18 receptor. Further, guided by complementary in-silico predictions, an aspartate-rich lunasin peptide yielded the highest soluble expression, constituting ∼40 % of total E. coli cellular proteins. The fusion expression system achieved ∼80 % solubility (compared to <10 % for wild-type IL-37b) and a yield of 167 mg/L following Ni2+-affinity purification under optimized conditions (25 °C, lactose autoinduction). The findings underscore the significance of complementary computational workflows in establishing an end-to-end pipeline for variant-to-solution analysis of IL-37b – a dual foundation linking in silico discovery to therapeutic development.
{"title":"In-silico prioritization of pathogenic Interleukin-37b variants and a fusion platform for high-yield soluble production","authors":"Sana Tahir, Jannat Rahim, Saima Sadaf","doi":"10.1016/j.biochi.2025.07.026","DOIUrl":"10.1016/j.biochi.2025.07.026","url":null,"abstract":"<div><div>Human interleukin-37 isoform 1 (IL-37b) is a key anti-inflammatory cytokine with significant therapeutic potential for inflammatory and immune-mediated disorders. However, its clinical translation is limited by poor understanding of disease-associated genetic variants and lack of an expression system for soluble production. While addressing both challenges, this study presents (a) a prioritized catalog of high-confidence, pathogenic IL-37b variants, and (b) a fusion-based expression platform for its soluble production, providing essential resources for future functional validations. Screening of over 3000 IL-37b variants using various computational tools and multi-algorithm consensus approach identified 25 potentially pathogenic non-synonymous single nucleotide variants (nsSNVs). Amongst these, 16 variants (e.g., D64 V/N, L72R, L111Q, V113F, C122R, F154S, I155 N, Y157C, E168G, G174A, I111T) were predicted to significantly destabilize IL-37b's structure and impair its interaction with the IL-18 receptor. Further, guided by complementary <em>in-silico</em> predictions, an aspartate-rich lunasin peptide yielded the highest soluble expression, constituting ∼40 % of total <em>E. coli</em> cellular proteins. The fusion expression system achieved ∼80 % solubility (compared to <10 % for wild-type IL-37b) and a yield of 167 mg/L following Ni<sup>2+</sup>-affinity purification under optimized conditions (25 °C, lactose autoinduction). The findings underscore the significance of complementary computational workflows in establishing an end-to-end pipeline for variant-to-solution analysis of IL-37b – a dual foundation linking <em>in silico</em> discovery to therapeutic development.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"238 ","pages":"Pages 102-111"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.biochi.2025.07.023
Alessandra Daniele-Silva , Janainna Xavier Fernandes , Adriana Marina e Silva Parente , Bruno Amorim-Carmo , Suedson de Carvalho Silva Rodrigues , Lucas Hilário Nogueira de Sousa , Elizabeth C.G. dos Santos , Thaís G. de Carvalho , Raimundo F. Araújo Júnior , Raudiney Frankilin Vasconcelos Mendes , Rafael Matos Ximenes , Arnóbio A. da Silva-Júnior , Luiz Alberto Lira Soares , Renata Mendonça Araújo , Matheus F. Fernandes-Pedrosa
Microbial infections are a public health problem that combined with the emergence of resistant microorganisms have boosted the search for new antibiotic agents. In this approach, the antibacterial and antibiofilm effects in vitro of TsAP-2 (peptide from the Tityus stigmurus scorpion venom) were evaluated. In addition, its antimicrobial action in the skin wound model infected with Staphylococcus aureus and Galleria mellonella larvae infected with a multidrug-resistant strain and the effect of the combination with conventional antibiotics in vitro were investigated. TsAP-2 demonstrated broad-spectrum antibacterial activity in vitro, with antibiofilm action against standard and multidrug-resistant strains during early biofilm formation. Furthermore, TsAP-2 exhibited additive and synergistic effects when combined with conventional antibiotics. TsAP-2 revealed antibacterial and healing activity in vivo, reducing wound area and necrosis, while promoting an increase in neovascularization and epithelialization. TsAP-2 decreased the number of resistant bacteria in infected larvae, increasing their survival rate. The structural conformation of the peptide was assessed using circular dichroism and its three-dimensional structure was determined through NMR spectroscopy. In zwitterionic vesicles, TsAP-2 revealed a random conformation and a predominant helical structure in the presence of anionic vesicles. The three-dimensional structure of TsAP-2 obtained by NMR analysis indicates a helical segment from the 7th to the 15th residue, with flexibility in the N and C-terminal peptide domains. Taken together, this approach indicates the ability of TsAP-2 to change its conformation when interacting with biomimetic medium, highlights its extensive pharmacological potential, being an attractive candidate for the exploration of new anti-infective drugs.
{"title":"In vitro and in vivo antibacterial activity of TsAP-2 from Tityus stigmurus scorpion venom in multidrug-resistant strains and its NMR three-dimensional structure","authors":"Alessandra Daniele-Silva , Janainna Xavier Fernandes , Adriana Marina e Silva Parente , Bruno Amorim-Carmo , Suedson de Carvalho Silva Rodrigues , Lucas Hilário Nogueira de Sousa , Elizabeth C.G. dos Santos , Thaís G. de Carvalho , Raimundo F. Araújo Júnior , Raudiney Frankilin Vasconcelos Mendes , Rafael Matos Ximenes , Arnóbio A. da Silva-Júnior , Luiz Alberto Lira Soares , Renata Mendonça Araújo , Matheus F. Fernandes-Pedrosa","doi":"10.1016/j.biochi.2025.07.023","DOIUrl":"10.1016/j.biochi.2025.07.023","url":null,"abstract":"<div><div>Microbial infections are a public health problem that combined with the emergence of resistant microorganisms have boosted the search for new antibiotic agents. In this approach, the antibacterial and antibiofilm effects <em>in vitro</em> of TsAP-2 (peptide from the <em>Tityus stigmurus</em> scorpion venom) were evaluated. In addition, its antimicrobial action in the skin wound model infected with <em>Staphylococcus aureus</em> and <em>Galleria mellonella</em> larvae infected with a multidrug-resistant strain and the effect of the combination with conventional antibiotics <em>in vitro</em> were investigated. TsAP-2 demonstrated broad-spectrum antibacterial activity <em>in vitro</em>, with antibiofilm action against standard and multidrug-resistant strains during early biofilm formation. Furthermore, TsAP-2 exhibited additive and synergistic effects when combined with conventional antibiotics. TsAP-2 revealed antibacterial and healing activity <em>in vivo,</em> reducing wound area and necrosis, while promoting an increase in neovascularization and epithelialization. TsAP-2 decreased the number of resistant bacteria in infected larvae, increasing their survival rate. The structural conformation of the peptide was assessed using circular dichroism and its three-dimensional structure was determined through NMR spectroscopy. In zwitterionic vesicles, TsAP-2 revealed a random conformation and a predominant helical structure in the presence of anionic vesicles. The three-dimensional structure of TsAP-2 obtained by NMR analysis indicates a helical segment from the 7th to the 15th residue, with flexibility in the <em>N</em> and <em>C</em>-terminal peptide domains. Taken together, this approach indicates the ability of TsAP-2 to change its conformation when interacting with biomimetic medium, highlights its extensive pharmacological potential, being an attractive candidate for the exploration of new anti-infective drugs.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"238 ","pages":"Pages 58-76"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.biochi.2025.08.006
Keiran McInnes, Sylvia Fanucchi
During COVID-19, systemic coagulopathy can lead to strokes and embolisms and may also contribute to long COVID. This coagulopathy is the result of overactivated platelets in circulation that lead to inappropriate clot formation. FOXP3 is a transcription factor involved in platelet development. Loss of FOXP3 function leads to abnormal platelets resembling those seen during COVID-19. Thus, FOXP3 may be dysregulated in COVID-19. The SARS-CoV-2 nucleocapsid (NC) is a multifunctional protein typically associated with viral genome packaging and virion assembly. However, it is also capable of binding DNA and may alter host gene expression. Here, potential interactions between the DNA-binding forkhead domain (FHD) of FOXP3 and the SARS-CoV-2 NC were investigated. Identification of a novel interaction between FOXP3 and SARS-CoV-2 NC may provide new clues to the pathophysiology of COVID-19. To address this aim, both proteins were overexpressed in T7 E. coli, purified via immobilised metal affinity chromatography, and monitored for interactions in the absence and presence of DNA using pull-down assays, electrophoretic mobility shift assays, and fluorescence anisotropy. A direct interaction was identified between the two proteins in the absence of DNA in vitro. Additionally, both proteins were found to bind DNA simultaneously under limiting conditions, but competed for binding under saturating conditions, where excess NC led to dissociation of FHD from the FHD–NC–DNA complex. This result implicates NC in FOXP3 dysfunction, potentially contributing to the coagulopathy and other symptoms observed during COVID-19. This work may inform future therapeutic strategies for severe COVID-19.
{"title":"A clot to uncover: SARS-CoV-2 nucleocapsid can outcompete the FOXP3 forkhead domain for DNA binding in vitro","authors":"Keiran McInnes, Sylvia Fanucchi","doi":"10.1016/j.biochi.2025.08.006","DOIUrl":"10.1016/j.biochi.2025.08.006","url":null,"abstract":"<div><div>During COVID-19, systemic coagulopathy can lead to strokes and embolisms and may also contribute to long COVID. This coagulopathy is the result of overactivated platelets in circulation that lead to inappropriate clot formation. FOXP3 is a transcription factor involved in platelet development. Loss of FOXP3 function leads to abnormal platelets resembling those seen during COVID-19. Thus, FOXP3 may be dysregulated in COVID-19. The SARS-CoV-2 nucleocapsid (NC) is a multifunctional protein typically associated with viral genome packaging and virion assembly. However, it is also capable of binding DNA and may alter host gene expression. Here, potential interactions between the DNA-binding forkhead domain (FHD) of FOXP3 and the SARS-CoV-2 NC were investigated. Identification of a novel interaction between FOXP3 and SARS-CoV-2 NC may provide new clues to the pathophysiology of COVID-19. To address this aim, both proteins were overexpressed in T7 <em>E. coli</em>, purified via immobilised metal affinity chromatography, and monitored for interactions in the absence and presence of DNA using pull-down assays, electrophoretic mobility shift assays, and fluorescence anisotropy. A direct interaction was identified between the two proteins in the absence of DNA <em>in vitro</em>. Additionally, both proteins were found to bind DNA simultaneously under limiting conditions, but competed for binding under saturating conditions, where excess NC led to dissociation of FHD from the FHD–NC–DNA complex. This result implicates NC in FOXP3 dysfunction, potentially contributing to the coagulopathy and other symptoms observed during COVID-19. This work may inform future therapeutic strategies for severe COVID-19.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"238 ","pages":"Pages 172-180"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RNA at the crossroads of structure, function, and disease","authors":"Didier Auboeuf , Cyril F. Bourgeois , Francesca Fiorini , Virginie Marcel","doi":"10.1016/j.biochi.2025.09.013","DOIUrl":"10.1016/j.biochi.2025.09.013","url":null,"abstract":"","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"238 ","pages":"Pages 1-2"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-25DOI: 10.1016/j.biochi.2025.10.013
Daniel Torrejón , Alexander Llontop , Alex Proléon , Fanny Lazo , Felix Urra , Armando Yarlequé , Dan E. Vivas-Ruiz
Snake envenomation remains a significant neglected tropical disease primarily treated with antivenoms, which, despite inherent limitations, continue to be the gold standard therapy. Snake venoms exhibit extensive compositional and functional diversity, posing challenges for universal antivenom efficacy. This study comprehensively evaluated venom composition, enzymatic activities, and immunological cross-reactivity across 24 Viperidae species from diverse geographic regions. Using protein profiling, enzymatic assays (proteolytic, amidolytic, clotting, and PLA2 activities), and phylogenetic analyses, we revealed marked interspecific variation. Bothrops species exhibited elevated SVMP-driven proteolytic activity, while Crotalus venoms demonstrated more balanced enzymatic profiles. Phylogenetic clustering highlighted evolutionary divergence and functional convergence among taxa. Immunoreactivity assays with Peruvian antibothropic, anticrotalic, and antilachesic antivenoms showed broad cross-recognition within Bothrops and Crotalus venoms, but limited efficacy against more distantly related Viperinae species. Western blot analyses confirmed these specificity patterns. Neutralization assays revealed differential inhibition: antibothropic antivenom effectively neutralized proteolytic activity, whereas anticrotalic antivenom preferentially inhibited PLA2-mediated effects. This functional variability highlights the biochemical complexity of viperid venoms and the constraints of current antivenoms. Our findings emphasize the urgent need to develop improved, broadly effective antivenom formulations capable of targeting the diverse toxin profiles of geographically and phylogenetically distinct viperid species, ultimately enhancing clinical management of snakebite envenomation worldwide.
{"title":"Functional and immunological variability of Viperid venoms across continents and cross-neutralization by Peruvian antivenoms","authors":"Daniel Torrejón , Alexander Llontop , Alex Proléon , Fanny Lazo , Felix Urra , Armando Yarlequé , Dan E. Vivas-Ruiz","doi":"10.1016/j.biochi.2025.10.013","DOIUrl":"10.1016/j.biochi.2025.10.013","url":null,"abstract":"<div><div>Snake envenomation remains a significant neglected tropical disease primarily treated with antivenoms, which, despite inherent limitations, continue to be the gold standard therapy. Snake venoms exhibit extensive compositional and functional diversity, posing challenges for universal antivenom efficacy. This study comprehensively evaluated venom composition, enzymatic activities, and immunological cross-reactivity across 24 Viperidae species from diverse geographic regions. Using protein profiling, enzymatic assays (proteolytic, amidolytic, clotting, and PLA<sub>2</sub> activities), and phylogenetic analyses, we revealed marked interspecific variation. <em>Bothrops</em> species exhibited elevated SVMP-driven proteolytic activity, while <em>Crotalus</em> venoms demonstrated more balanced enzymatic profiles. Phylogenetic clustering highlighted evolutionary divergence and functional convergence among taxa. Immunoreactivity assays with Peruvian antibothropic, anticrotalic, and antilachesic antivenoms showed broad cross-recognition within <em>Bothrops</em> and <em>Crotalus</em> venoms, but limited efficacy against more distantly related Viperinae species. Western blot analyses confirmed these specificity patterns. Neutralization assays revealed differential inhibition: antibothropic antivenom effectively neutralized proteolytic activity, whereas anticrotalic antivenom preferentially inhibited PLA<sub>2</sub>-mediated effects. This functional variability highlights the biochemical complexity of viperid venoms and the constraints of current antivenoms. Our findings emphasize the urgent need to develop improved, broadly effective antivenom formulations capable of targeting the diverse toxin profiles of geographically and phylogenetically distinct viperid species, ultimately enhancing clinical management of snakebite envenomation worldwide.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"240 ","pages":"Pages 88-99"},"PeriodicalIF":3.0,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145798995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-23DOI: 10.1016/j.biochi.2025.10.016
Munishwar Nath Gupta , Vladimir N. Uversky
The role of intrinsic disorder in enzymes has not attracted the attention which it deserves. This perspective discusses how tails and loops in structured proteins, as well as molten globular protein forms, in spite of being disordered, are associated with biocatalysis. Protein kinases illustrate the importance of structural disorder for the function of some enzymes in their native state. Intrinsic disorder actually facilitates moonlighting. Furthermore, disorder-based engineered biomolecular condensates are emerging as enzymatic microreactors.
{"title":"The functional significance of intrinsic disorder in enzymes","authors":"Munishwar Nath Gupta , Vladimir N. Uversky","doi":"10.1016/j.biochi.2025.10.016","DOIUrl":"10.1016/j.biochi.2025.10.016","url":null,"abstract":"<div><div>The role of intrinsic disorder in enzymes has not attracted the attention which it deserves. This perspective discusses how tails and loops in structured proteins, as well as molten globular protein forms, in spite of being disordered, are associated with biocatalysis. Protein kinases illustrate the importance of structural disorder for the function of some enzymes in their native state. Intrinsic disorder actually facilitates moonlighting. Furthermore, disorder-based engineered biomolecular condensates are emerging as enzymatic microreactors.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"241 ","pages":"Pages 116-124"},"PeriodicalIF":3.0,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1016/j.biochi.2025.10.014
Nataliia N. Gotmanova , Tatiana V. Bobik , Viacheslav A. Kriachkov , Alexander A. Ezhov , Anna V. Bacheva
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a pathological mutation that results in the abnormal expansion of more than 37 consecutive trinucleotide repeats (CAG) in the HTT gene. These repeats encode the polyglutamine tract (polyQ tract) in the huntingtin protein (Htt). Progressive lethal Huntington's chorea is characterized by impaired motor activity and marked cerebral atrophy. The disease affects neurons in specific areas of the central nervous system, mainly GABAergic neurons in the striatum and cortex. It is believed that the neuron-specific proteotoxicity of mutant Htt (mHtt) results from its conformational instability and tendency to aggregate due to elongation of the polyQ-tract. However, recent structural findings challenge these assumptions. To elucidate some key aspects of the molecular mechanisms of HD, we describe the transient expression of full-length normal or mutant huntingtin in HEK293T eukaryotic cells, and options of isolation and purification of huntingtin variants according to the optimized procedure. The short-termed overexpression of Htt/mHtt has been demonstrated to be associated with elevated proteasome and non-proteasome caspase activity, and change in subunit expression. The cellular response to mHtt production manifested primarily as an increase in β1, β5i and in less extent β1i subunits as well as 11Sαβ expression, as observed through both Western blot and RT-qPCR. The microscopy study also revealed an enhancement in the β1i subunit content in HEK293T cells overexpressed Htt and especially mHtt suggesting an immunoproteasome activation.
{"title":"The HEK293T cells manage overload by the overexpressed full-length Htt variants via proteasome activation","authors":"Nataliia N. Gotmanova , Tatiana V. Bobik , Viacheslav A. Kriachkov , Alexander A. Ezhov , Anna V. Bacheva","doi":"10.1016/j.biochi.2025.10.014","DOIUrl":"10.1016/j.biochi.2025.10.014","url":null,"abstract":"<div><div>Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a pathological mutation that results in the abnormal expansion of more than 37 consecutive trinucleotide repeats (CAG) in the HTT gene. These repeats encode the polyglutamine tract (polyQ tract) in the huntingtin protein (Htt). Progressive lethal Huntington's chorea is characterized by impaired motor activity and marked cerebral atrophy. The disease affects neurons in specific areas of the central nervous system, mainly GABAergic neurons in the striatum and cortex. It is believed that the neuron-specific proteotoxicity of mutant Htt (mHtt) results from its conformational instability and tendency to aggregate due to elongation of the polyQ-tract. However, recent structural findings challenge these assumptions. To elucidate some key aspects of the molecular mechanisms of HD, we describe the transient expression of full-length normal or mutant huntingtin in HEK293T eukaryotic cells, and options of isolation and purification of huntingtin variants according to the optimized procedure. The short-termed overexpression of Htt/mHtt has been demonstrated to be associated with elevated proteasome and non-proteasome caspase activity, and change in subunit expression. The cellular response to mHtt production manifested primarily as an increase in β1, β5i and in less extent β1i subunits as well as 11Sαβ expression, as observed through both Western blot and RT-qPCR. The microscopy study also revealed an enhancement in the β1i subunit content in HEK293T cells overexpressed Htt and especially mHtt suggesting an immunoproteasome activation.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"240 ","pages":"Pages 59-75"},"PeriodicalIF":3.0,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1016/j.biochi.2025.10.015
K. Jankowska , W. Wójtowicz , M. Wierzbinka , K. Raszczok , K. Bajdak-Rusinek
Alternative splicing of cluster of differentiation 44 (CD44), regulated by epithelial splicing regulatory protein 1 (ESRP1), plays a critical role in cancer progression. The switch between CD44 variant (CD44v) and standard (CD44s) isoforms is tightly linked to epithelial–mesenchymal transition (EMT), metastatic potential and cancer stem cell (CSC) maintenance. This review integrates recent isoform-resolved findings to elucidate the molecular mechanisms underlying CD44/ESRP1-mediated splicing and its involvement in oncogenic signaling pathways promoting invasion, plasticity and therapy resistance. We also examine cancer-specific CD44 isoform expression patterns and assess their prognostic and therapeutic relevance. We propose that isoform-specific profiling of the CD44/ESRP1 axis may serve as a predictive framework for metastasis and therapy response, paving the way for targeted splicing-based therapeutics.
{"title":"Isoform switching in the CD44/ESRP1 axis as a driver of EMT and cancer stemness across tumor types","authors":"K. Jankowska , W. Wójtowicz , M. Wierzbinka , K. Raszczok , K. Bajdak-Rusinek","doi":"10.1016/j.biochi.2025.10.015","DOIUrl":"10.1016/j.biochi.2025.10.015","url":null,"abstract":"<div><div>Alternative splicing of cluster of differentiation 44 (CD44), regulated by epithelial splicing regulatory protein 1 (ESRP1), plays a critical role in cancer progression. The switch between CD44 variant (CD44v) and standard (CD44s) isoforms is tightly linked to epithelial–mesenchymal transition (EMT), metastatic potential and cancer stem cell (CSC) maintenance. This review integrates recent isoform-resolved findings to elucidate the molecular mechanisms underlying CD44/ESRP1-mediated splicing and its involvement in oncogenic signaling pathways promoting invasion, plasticity and therapy resistance. We also examine cancer-specific CD44 isoform expression patterns and assess their prognostic and therapeutic relevance. We propose that isoform-specific profiling of the CD44/ESRP1 axis may serve as a predictive framework for metastasis and therapy response, paving the way for targeted splicing-based therapeutics.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"240 ","pages":"Pages 19-30"},"PeriodicalIF":3.0,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1016/j.biochi.2025.10.010
Lorenzo Seneci , Vivek Suranse , Marco Mancuso , Tobias Senoner , Bing Xie , Ivan Koludarov , Kartik Sunagar , Bryan G. Fry
Snake venoms have surged as model systems in evolutionary biology thanks to the dynamic diversification and accelerated evolution of many toxin families. Among these, phospholipase A2 (PLA2) constitute a prime example as they are ubiquitous across the venomous snake radiation and have evolved a wide variety of pathophysiological activities. This is especially true in vipers (family Viperidae), one of the most successful and medically significant venomous snake lineages worldwide. In this study, we gathered publicly available sequences of viper venom PLA2s to recreate the molecular phylogeny and toxicological evolution of this toxin family to date. Furthermore, we determined the selection regimes regulating the evolution of these toxins with a comparative approach that combines multiple methodologies of phylogenetic reconstruction and analysis of selection signatures. Our phylogeny confirms the basal position of Asp49 PLA2s (proteins with Asp at position 49), while derived clades, such as the non-enzymatic Lys49 myotoxins and the poorly characterised Ser49 type, are nested within. Neurotoxicity arose on multiple independent occasions (all within the Asp49 clade), with monomeric and dimeric forms only distantly related to each other. Positive Darwinian selection was widespread across the viper PLA2 tree, in line with previous research. However, purifying selection was also preponderant (perhaps due to structural constraints imposed by the pathophysiological targets of these toxins) and relatively neutral substitutions were observed in certain clades. Overall, this study provides novel insights into the evolutionary history of viper venom PLA2s through a comprehensive phylogenetic framework and highlights the need for complementary genomic and functional research into these toxins.
{"title":"Deadly innovations: Molecular phylogenetics and evolution of phospholipase A2 toxins in viperid snake venoms","authors":"Lorenzo Seneci , Vivek Suranse , Marco Mancuso , Tobias Senoner , Bing Xie , Ivan Koludarov , Kartik Sunagar , Bryan G. Fry","doi":"10.1016/j.biochi.2025.10.010","DOIUrl":"10.1016/j.biochi.2025.10.010","url":null,"abstract":"<div><div>Snake venoms have surged as model systems in evolutionary biology thanks to the dynamic diversification and accelerated evolution of many toxin families. Among these, phospholipase A<sub>2</sub> (PLA<sub>2</sub>) constitute a prime example as they are ubiquitous across the venomous snake radiation and have evolved a wide variety of pathophysiological activities. This is especially true in vipers (family Viperidae), one of the most successful and medically significant venomous snake lineages worldwide. In this study, we gathered publicly available sequences of viper venom PLA<sub>2</sub>s to recreate the molecular phylogeny and toxicological evolution of this toxin family to date. Furthermore, we determined the selection regimes regulating the evolution of these toxins with a comparative approach that combines multiple methodologies of phylogenetic reconstruction and analysis of selection signatures. Our phylogeny confirms the basal position of Asp49 PLA<sub>2</sub>s (proteins with Asp at position 49), while derived clades, such as the non-enzymatic Lys49 myotoxins and the poorly characterised Ser49 type, are nested within. Neurotoxicity arose on multiple independent occasions (all within the Asp49 clade), with monomeric and dimeric forms only distantly related to each other. Positive Darwinian selection was widespread across the viper PLA<sub>2</sub> tree, in line with previous research. However, purifying selection was also preponderant (perhaps due to structural constraints imposed by the pathophysiological targets of these toxins) and relatively neutral substitutions were observed in certain clades. Overall, this study provides novel insights into the evolutionary history of viper venom PLA<sub>2</sub>s through a comprehensive phylogenetic framework and highlights the need for complementary genomic and functional research into these toxins.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"240 ","pages":"Pages 137-152"},"PeriodicalIF":3.0,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1016/j.biochi.2025.10.012
Yuhong Hu , Stuart R. Green , Ningmei Wang , Jing Zhang , Han Wang , Ziheng Zhao , Yue Gao , Kenneth B. Storey , Jingze Liu , Hui Wang
MicroRNAs (miRNAs), a critical class of short non-coding RNAs, regulate metabolic processes associated with mammalian torpor (e.g., Mus musculus), though their precise functional mechanisms remain incompletely characterized. Here, we employ RNA-seq to profile miRNA expression in white adipose tissue (WAT) of active versus torpid C57BL/6 mice. Among 863 detected miRNAs, 12 showed significant differential expression during torpor. In silico prediction of miRNA targets revealed these miRNAs preferentially target cancer-related pathways, indicating their potential role in suppressing cell proliferation during metabolic depression. Intriguingly, steroid biosynthesis genes escaped miRNA-mediated inhibition, suggesting active endocrine modulation by WAT during torpor. Machine learning helped to identify biomarkers for torpor in the mice, specifically a minimum of three miRNAs were sufficient to distinguish adipose samples from control versus torpid conditions. Taken together, this study demonstrates the role of miRNAs as transcriptional regulators of cell signalling pathways within WAT during mouse torpor.
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