Pub Date : 2024-11-01DOI: 10.1016/j.bbrc.2024.150944
Sweta Kumari, Ankita Adhikary, Kusum Kumari Singh
SAP18 protein was originally discovered in association with the SIN3 transcriptional repressor complex. Subsequent biochemical fractionation studies identified SAP18 as a component of another distinct trimeric complex termed as the apoptosis- and splicing-associated protein (ASAP) complex. The existence of SAP18 in distinct complexes highlights its dual role in transcriptional and splicing regulation. In our study, we aim to define the in vivo interactome of SAP18 using proximity-dependent biotin identification (BioID). Mass spectrometry analysis of streptavidin-purified biotinylated proteins revealed new SIN3-associated interactors, including RBBP4 and SAP30BP. Notably, we identified 72 spliceosomal proteins as highly enriched interactors. Additionally, a complementary immunoprecipitation assay validated novel interactions of SAP18 with the prespliceosomal components SNRNP70, SNRPA, SF3B1, U2AF1, and the SR protein SRSF1. Mutational analysis using a C-terminal SAP18 double point mutant, which is known to be deficient in ASAP-interaction, demonstrated a debilitated interaction with the prespliceosomal proteins. Altogether, our results present a refined understanding of the SAP18 interactome, uncovering its association with the prespliceosome in conjugation with ASAP components.
{"title":"BioID proximity mapping reveals novel SAP18 interactions in the prespliceosomal complex","authors":"Sweta Kumari, Ankita Adhikary, Kusum Kumari Singh","doi":"10.1016/j.bbrc.2024.150944","DOIUrl":"10.1016/j.bbrc.2024.150944","url":null,"abstract":"<div><div>SAP18 protein was originally discovered in association with the SIN3 transcriptional repressor complex. Subsequent biochemical fractionation studies identified SAP18 as a component of another distinct trimeric complex termed as the apoptosis- and splicing-associated protein (ASAP) complex. The existence of SAP18 in distinct complexes highlights its dual role in transcriptional and splicing regulation. In our study, we aim to define the <em>in vivo</em> interactome of SAP18 using proximity-dependent biotin identification (BioID). Mass spectrometry analysis of streptavidin-purified biotinylated proteins revealed new SIN3-associated interactors, including RBBP4 and SAP30BP. Notably, we identified 72 spliceosomal proteins as highly enriched interactors. Additionally, a complementary immunoprecipitation assay validated novel interactions of SAP18 with the prespliceosomal components SNRNP70, SNRPA, SF3B1, U2AF1, and the SR protein SRSF1. Mutational analysis using a C-terminal SAP18 double point mutant, which is known to be deficient in ASAP-interaction, demonstrated a debilitated interaction with the prespliceosomal proteins. Altogether, our results present a refined understanding of the SAP18 interactome, uncovering its association with the prespliceosome in conjugation with ASAP components.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150944"},"PeriodicalIF":2.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614236","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 : 2024-11-01DOI: 10.1016/j.bbrc.2024.150937
Mingkai Zhu , Yan Li , Dong Liu , Zhiyuan Gong
Immune responses play crucial roles in liver regeneration following partial hepatectomy (PH). Previous studies using the rodent PH models have shown that liver regeneration following PH has sex disparity. However, the sex disparity in the immune responses to PH and its relationship with sex-biased liver regeneration has not been investigated yet. In the current study, we applied the zebrafish PH model to study these issues and found that male zebrafish have earlier immune responses than female zebrafish following PH. By depleting macrophages before PH, we confirmed that liver regeneration following PH in zebrafish requires the participation of macrophages. In addition, activation of estrogen receptors inhibited the upregulation of inflammatory factors in male livers and reduced hepatocyte proliferation at the early stage of PH-induced liver regeneration. Therefore, the male-biased liver regeneration and immune responses in zebrafish following PH could be regulated by estrogen receptor activities.
{"title":"Estrogen receptors regulate sex disparity in the immune responses during zebrafish liver regeneration following partial hepatectomy","authors":"Mingkai Zhu , Yan Li , Dong Liu , Zhiyuan Gong","doi":"10.1016/j.bbrc.2024.150937","DOIUrl":"10.1016/j.bbrc.2024.150937","url":null,"abstract":"<div><div>Immune responses play crucial roles in liver regeneration following partial hepatectomy (PH). Previous studies using the rodent PH models have shown that liver regeneration following PH has sex disparity. However, the sex disparity in the immune responses to PH and its relationship with sex-biased liver regeneration has not been investigated yet. In the current study, we applied the zebrafish PH model to study these issues and found that male zebrafish have earlier immune responses than female zebrafish following PH. By depleting macrophages before PH, we confirmed that liver regeneration following PH in zebrafish requires the participation of macrophages. In addition, activation of estrogen receptors inhibited the upregulation of inflammatory factors in male livers and reduced hepatocyte proliferation at the early stage of PH-induced liver regeneration. Therefore, the male-biased liver regeneration and immune responses in zebrafish following PH could be regulated by estrogen receptor activities.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150937"},"PeriodicalIF":2.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603042","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 : 2024-10-30DOI: 10.1016/j.bbrc.2024.150921
I Wayan Mudianta , Josephine Elizabeth Siregar , Andita Fitri Mutiara Rizki , Wihda Aisarul Azmi , Normalita Eka Pravitasari , Gusnia Meilin Gholam , Fadillaisyia Riandani Putri , Rhesi Kristiana , Ni Kadek Dita Cahyani , I Made Artika
This study examined the antimalarial activity of a furanosesquiterpene, furodysinin, one of the major metabolites of the dorid nudibranch Hypselodoris tryoni. The nudibranchs were collected from Balinese waters and the metabolites were purified by chromatography. Ex vivo rodent malaria Plasmodium berghei assays were conducted to determine the metabolite antimalarial activity. In silico molecular docking was employed to investigate the interaction between furodysinin against wild-type P. berghei and atovaquone-resistant P. berghei (Y268C). This study reported for the first time that the furodysinin displayed a promising antimalarial activity based on the ex vivo tests against wild-type P. berghei and atovaquone-resistant P. berghei. In silico molecular docking study showed that furodysinin inhibits the parasite mitochondrial cytochrome b (cyt b) by binding to the protein Qo pocket (ef-helix) where it interacts with residue 268, the mutation of which is known to confer resistance to atovaquone. Furodysinin binds to the mutated tyrosine at residue 268, which has changed to cysteine, forming an alkyl bond with C268 at a distance of 4.6 Å. Therefore, we predict that furodysinin has a target in Plasmodium mitochondria.
{"title":"Expanding the occurrence of antimalarial metabolites in dorid nudibranch Hypselodoris tryoni","authors":"I Wayan Mudianta , Josephine Elizabeth Siregar , Andita Fitri Mutiara Rizki , Wihda Aisarul Azmi , Normalita Eka Pravitasari , Gusnia Meilin Gholam , Fadillaisyia Riandani Putri , Rhesi Kristiana , Ni Kadek Dita Cahyani , I Made Artika","doi":"10.1016/j.bbrc.2024.150921","DOIUrl":"10.1016/j.bbrc.2024.150921","url":null,"abstract":"<div><div>This study examined the antimalarial activity of a furanosesquiterpene, furodysinin, one of the major metabolites of the dorid nudibranch <em>Hypselodoris tryoni</em>. The nudibranchs were collected from Balinese waters and the metabolites were purified by chromatography. <em>Ex vivo</em> rodent malaria <em>Plasmodium berghei</em> assays were conducted to determine the metabolite antimalarial activity. <em>In silico</em> molecular docking was employed to investigate the interaction between furodysinin against wild-type <em>P. berghei</em> and atovaquone-resistant <em>P. berghei</em> (Y268C). This study reported for the first time that the furodysinin displayed a promising antimalarial activity based on the <em>ex vivo</em> tests against wild-type <em>P. berghei</em> and atovaquone-resistant <em>P. berghei</em>. <em>In silico</em> molecular docking study showed that furodysinin inhibits the parasite mitochondrial cytochrome <em>b</em> (cyt <em>b</em>) by binding to the protein Qo pocket (ef-helix) where it interacts with residue 268, the mutation of which is known to confer resistance to atovaquone. Furodysinin binds to the mutated tyrosine at residue 268, which has changed to cysteine, forming an alkyl bond with C268 at a distance of 4.6 Å. Therefore, we predict that furodysinin has a target in <em>Plasmodium</em> mitochondria.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"737 ","pages":"Article 150921"},"PeriodicalIF":2.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582010","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 : 2024-10-30DOI: 10.1016/j.bbrc.2024.150928
Sen Takeshita, Yasuhiro Iida
Deep mycosis is a severe fungal disease that could result in fatal outcomes. However, there is still a demand for highly effective and safe antifungal drugs, given the side effects of the existing treatments and the increase in the resistance to them. In this study, we evaluated the involvement of the lipid kinase Fab1 and its activator Vac14 (Fab1/Vac14) in tip growth in Saccharomyces cerevisiae INVSc1, along with their impact on cell proliferation, using a genetic approach to inhibit them. The results revealed that Fab1/Vac14 inhibition suppressed growth and caused an increase in the rate of β-1,3-glucanase (BGL2) fused with emerald green fluorescent protein (EmGFP) (BGL2-EmGFP) localization at the tip. The inhibition of the endocytic pathway using a lysosome inhibitor also resulted in an increased localization of BGL2-EmGFP at the tip. The overexpression of wild-type BGL2-EmGFP, but not that of the inactive mutant BGL2, led to a complete loss of the cell proliferation ability. These findings suggested that the Fab1/Vac14 complex could be a novel target for the development of antifungal drugs based on tip growth regulation, possibly via excessive cell wall degradation.
{"title":"Impact of Fab1/Vac14 inhibition on β-1,3-glucanase localization at the tip in Saccharomyces cerevisiae","authors":"Sen Takeshita, Yasuhiro Iida","doi":"10.1016/j.bbrc.2024.150928","DOIUrl":"10.1016/j.bbrc.2024.150928","url":null,"abstract":"<div><div>Deep mycosis is a severe fungal disease that could result in fatal outcomes. However, there is still a demand for highly effective and safe antifungal drugs, given the side effects of the existing treatments and the increase in the resistance to them. In this study, we evaluated the involvement of the lipid kinase Fab1 and its activator Vac14 (Fab1/Vac14) in tip growth in <em>Saccharomyces cerevisiae</em> INVSc1, along with their impact on cell proliferation, using a genetic approach to inhibit them. The results revealed that Fab1/Vac14 inhibition suppressed growth and caused an increase in the rate of β-1,3-glucanase (BGL2) fused with emerald green fluorescent protein (EmGFP) (BGL2-EmGFP) localization at the tip. The inhibition of the endocytic pathway using a lysosome inhibitor also resulted in an increased localization of BGL2-EmGFP at the tip. The overexpression of wild-type BGL2-EmGFP, but not that of the inactive mutant BGL2, led to a complete loss of the cell proliferation ability. These findings suggested that the Fab1/Vac14 complex could be a novel target for the development of antifungal drugs based on tip growth regulation, possibly via excessive cell wall degradation.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"739 ","pages":"Article 150928"},"PeriodicalIF":2.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613547","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 : 2024-10-29DOI: 10.1016/j.bbrc.2024.150889
Zheng-Juan Wang , Jia Yuan , Lin Tang
NMN is a precursor in the biosynthesis of NAD+, a molecule that plays a crucial role within cells. Supplementation with NMN can elevate NAD+ levels in the blood, improving symptoms of diabetes, neurodegenerative diseases, and cancer, as well as providing anti-aging benefits. Escherichia coli was engineered to heterologously express nicotinamide phosphoribosyltransferase (Nampt), enabling the recombinant E. coli to synthesize NAD derivatives from nicotinamide. The 3D structure of Nadv complexed with NAM and NMN was determined to explore the molecular mechanism by which Nadv catalyzes NMN synthesis. NAM binds at two sites: one at the catalytic site and one at the allosteric binding site, while NMN binds exclusively at the catalytic site. In both structural models, a loop between β15 and β16 is missing, likely due to its high flexibility, leading to diffuse electron density. Compared with other resolved Nampt structures, an additional 12-amino-acid loop was identified after α-helix 12 near the catalytic site. This study lays the groundwork for the engineering of Nadv, facilitating its efficient application in biological synthesis of NMN.
{"title":"The structural Basis of NMN synthesis catalyzed by NadV from Haemophilus ducreyi","authors":"Zheng-Juan Wang , Jia Yuan , Lin Tang","doi":"10.1016/j.bbrc.2024.150889","DOIUrl":"10.1016/j.bbrc.2024.150889","url":null,"abstract":"<div><div>NMN is a precursor in the biosynthesis of NAD<sup>+</sup>, a molecule that plays a crucial role within cells. Supplementation with NMN can elevate NAD<sup>+</sup> levels in the blood, improving symptoms of diabetes, neurodegenerative diseases, and cancer, as well as providing anti-aging benefits. <em>Escherichia coli</em> was engineered to heterologously express nicotinamide phosphoribosyltransferase (Nampt), enabling the recombinant <em>E. coli</em> to synthesize NAD derivatives from nicotinamide. The 3D structure of Nadv complexed with NAM and NMN was determined to explore the molecular mechanism by which Nadv catalyzes NMN synthesis. NAM binds at two sites: one at the catalytic site and one at the allosteric binding site, while NMN binds exclusively at the catalytic site. In both structural models, a loop between β15 and β16 is missing, likely due to its high flexibility, leading to diffuse electron density. Compared with other resolved Nampt structures, an additional 12-amino-acid loop was identified after α-helix 12 near the catalytic site. This study lays the groundwork for the engineering of Nadv, facilitating its efficient application in biological synthesis of NMN.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150889"},"PeriodicalIF":2.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592632","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}
Diverse studies have shown a relationship between dysregulated microRNAs (miRNAs), including miRNA-29b and miRNA-9, and several diseases. So, it is hypothesized that miRNAs can be studied as potential agents to be exploited in biomedical applications, due to their ability to take part in gene expression regulation at a post-transcriptional level. Considering the possibility of using miRNAs, it is important to characterize and validate this bioproduct, structurally and functionally. The goal of this work is to optimize an assay that can detect and biophysically characterize a miRNA sample without interference from the respective precursor form, by using molecular beacons (MB). MBs are hairpin-shaped probes composed of nucleic acid labeled with a quencher at the 3′ end and a fluorophore (reporter) at the 5’ end. Here, MB loops were designed so MB-9-1 and MB-29-1 would be complementary to the miRNA-9-1-5p and the miRNA-29b-1-3p, respectively. The MBs designed in this work specifically identified each target miRNA, even in artificial mixtures or complex samples, and the obtained fluorescence was directly proportional to miRNA concentration. Even if the precursor forms (pre-miRNAs) were present in the samples, no significant signal was shown, allowing the distinction between both forms. The outcomes of this work confirm the MBs potential to assess and characterize miRNA samples to be exploited in biochemical, biophysical, or biomedical fields.
{"title":"Biophysical characterization of microRNA mixtures based on Molecular Beacons","authors":"Micaela Riscado , Leonor Mariano , Carla Cruz , Chantal Pichon , Fani Sousa","doi":"10.1016/j.bbrc.2024.150913","DOIUrl":"10.1016/j.bbrc.2024.150913","url":null,"abstract":"<div><div>Diverse studies have shown a relationship between dysregulated microRNAs (miRNAs), including miRNA-29b and miRNA-9, and several diseases. So, it is hypothesized that miRNAs can be studied as potential agents to be exploited in biomedical applications, due to their ability to take part in gene expression regulation at a post-transcriptional level. Considering the possibility of using miRNAs, it is important to characterize and validate this bioproduct, structurally and functionally. The goal of this work is to optimize an assay that can detect and biophysically characterize a miRNA sample without interference from the respective precursor form, by using molecular beacons (MB). MBs are hairpin-shaped probes composed of nucleic acid labeled with a quencher at the 3′ end and a fluorophore (reporter) at the 5’ end. Here, MB loops were designed so MB-9-1 and MB-29-1 would be complementary to the miRNA-9-1-5p and the miRNA-29b-1-3p, respectively. The MBs designed in this work specifically identified each target miRNA, even in artificial mixtures or complex samples, and the obtained fluorescence was directly proportional to miRNA concentration. Even if the precursor forms (pre-miRNAs) were present in the samples, no significant signal was shown, allowing the distinction between both forms. The outcomes of this work confirm the MBs potential to assess and characterize miRNA samples to be exploited in biochemical, biophysical, or biomedical fields.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"736 ","pages":"Article 150913"},"PeriodicalIF":2.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.bbrc.2024.150917
Chao Zhang , Zhiyao Fu , Ren Zhang
Aging is associated with a decline in physiological functions and an increased risk of metabolic disorders. The liver, a key organ in metabolism, undergoes significant changes during aging that can contribute to systemic metabolic dysfunction. This study investigates the expression of genes involved in the tricarboxylic acid (TCA) cycle, a critical pathway for energy production, in the aging liver. We analyzed RNA sequencing data from the Genotype-Tissue Expression (GTEx) project to assess age-related changes in gene expression in the human liver. To validate our findings, we conducted complementary studies in young and old mice, examining the expression of key TCA cycle genes using quantitative real-time PCR. Our analysis of the GTEx dataset revealed a significant reduction in the expression of many genes that are critical for metabolism, including fat mass and obesity associated (FTO) and adiponectin receptor 1 (ADIPOR1). The most overrepresented pathway among the statistically enriched ones was the TCA cycle, with multiple genes exhibiting downregulation in older humans. This reduction was consistent with findings in aging mice, which also showed decreased expression of several TCA cycle genes. These results suggest a conserved pattern of age-related downregulation of TCA cycle, potentially leading to diminished mitochondrial function and energy production in the liver. The reduced expression of TCA cycle genes in the aging liver may contribute to metabolic dysfunction and increased susceptibility to age-related diseases. Understanding the molecular basis of these changes provides new insights into the aging process and highlights potential targets for interventions aimed at promoting healthy aging and preventing metabolic disorders.
{"title":"Reduced expressions of TCA cycle genes during aging in humans and mice","authors":"Chao Zhang , Zhiyao Fu , Ren Zhang","doi":"10.1016/j.bbrc.2024.150917","DOIUrl":"10.1016/j.bbrc.2024.150917","url":null,"abstract":"<div><div>Aging is associated with a decline in physiological functions and an increased risk of metabolic disorders. The liver, a key organ in metabolism, undergoes significant changes during aging that can contribute to systemic metabolic dysfunction. This study investigates the expression of genes involved in the tricarboxylic acid (TCA) cycle, a critical pathway for energy production, in the aging liver. We analyzed RNA sequencing data from the Genotype-Tissue Expression (GTEx) project to assess age-related changes in gene expression in the human liver. To validate our findings, we conducted complementary studies in young and old mice, examining the expression of key TCA cycle genes using quantitative real-time PCR. Our analysis of the GTEx dataset revealed a significant reduction in the expression of many genes that are critical for metabolism, including fat mass and obesity associated (FTO) and adiponectin receptor 1 (ADIPOR1). The most overrepresented pathway among the statistically enriched ones was the TCA cycle, with multiple genes exhibiting downregulation in older humans. This reduction was consistent with findings in aging mice, which also showed decreased expression of several TCA cycle genes. These results suggest a conserved pattern of age-related downregulation of TCA cycle, potentially leading to diminished mitochondrial function and energy production in the liver. The reduced expression of TCA cycle genes in the aging liver may contribute to metabolic dysfunction and increased susceptibility to age-related diseases. Understanding the molecular basis of these changes provides new insights into the aging process and highlights potential targets for interventions aimed at promoting healthy aging and preventing metabolic disorders.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150917"},"PeriodicalIF":2.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587371","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 : 2024-10-29DOI: 10.1016/j.bbrc.2024.150925
Kushagra Nagori , Madhulika Pradhan , Kartik T. Nakhate
Cognitive decline, an important comorbidity of type 2 diabetes (T2D), is attributed to oxidative stress and impaired cholinergic signaling in the brain. The α7 nicotinic acetylcholine receptor (α7nAChR) is densely distributed in the hippocampus and cortex, and exerts neuroprotective and procognitive actions. Ethyl gallate (EG), a natural phenolic antioxidant compound, showed high in-silico binding affinity towards α7nAChR and brain penetrability. Therefore, the present study aimed to evaluate the involvement of α7nAChR in the potential of EG to ameliorate T2D-induced Alzheimer's disease-like condition. T2D was induced by intraperitoneal (i.p.) injection of streptozotocin (35 mg/kg) in rats on high-fat diet. Diabetic animals were treated with EG (10 and 20 mg/kg, i.p.) for four weeks, and their learning and memory performance was evaluated by the Morris water maze (MWM). Further, the brains were subjected to biochemical analysis of antioxidants like glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and oxidative stress marker malonaldehyde (MDA). While diabetic rats showed a significant decline in cognitive performance in the MWM, a substantial improvement was noticed following EG treatment. Further, the diabetes-associated reductions in GSH, SOD, and CAT levels, along with increased MDA contents in the brain, were effectively restored by EG. Interestingly, pre-treatment with α7nAChR antagonist methyllycaconitine (1 mg/kg, i.p.) attenuated the effects of EG on behavioral and biochemical parameters. The results suggest that EG may augment cholinergic signaling in the brain via α7nAChR to mitigate oxidative stress, consequently alleviating T2D-associated dementia. Therefore, EG could be a potential candidate for addressing cognitive impairment comorbid with T2D.
{"title":"Ethyl gallate ameliorates diabetes-induced Alzheimer's disease-like phenotype in rats via activation of α7 nicotinic receptors and mitigation of oxidative stress","authors":"Kushagra Nagori , Madhulika Pradhan , Kartik T. Nakhate","doi":"10.1016/j.bbrc.2024.150925","DOIUrl":"10.1016/j.bbrc.2024.150925","url":null,"abstract":"<div><div>Cognitive decline, an important comorbidity of type 2 diabetes (T2D), is attributed to oxidative stress and impaired cholinergic signaling in the brain. The α7 nicotinic acetylcholine receptor (α7nAChR) is densely distributed in the hippocampus and cortex, and exerts neuroprotective and procognitive actions. Ethyl gallate (EG), a natural phenolic antioxidant compound, showed high <em>in-silico</em> binding affinity towards α7nAChR and brain penetrability. Therefore, the present study aimed to evaluate the involvement of α7nAChR in the potential of EG to ameliorate T2D-induced Alzheimer's disease-like condition. T2D was induced by intraperitoneal (i.p.) injection of streptozotocin (35 mg/kg) in rats on high-fat diet. Diabetic animals were treated with EG (10 and 20 mg/kg, i.p.) for four weeks, and their learning and memory performance was evaluated by the Morris water maze (MWM). Further, the brains were subjected to biochemical analysis of antioxidants like glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and oxidative stress marker malonaldehyde (MDA). While diabetic rats showed a significant decline in cognitive performance in the MWM, a substantial improvement was noticed following EG treatment. Further, the diabetes-associated reductions in GSH, SOD, and CAT levels, along with increased MDA contents in the brain, were effectively restored by EG. Interestingly, pre-treatment with α7nAChR antagonist methyllycaconitine (1 mg/kg, i.p.) attenuated the effects of EG on behavioral and biochemical parameters. The results suggest that EG may augment cholinergic signaling in the brain via α7nAChR to mitigate oxidative stress, consequently alleviating T2D-associated dementia. Therefore, EG could be a potential candidate for addressing cognitive impairment comorbid with T2D.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"737 ","pages":"Article 150925"},"PeriodicalIF":2.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567636","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 : 2024-10-29DOI: 10.1016/j.bbrc.2024.150924
He Wang , Haidu Yuan , Jianhao Zhang , Wenjing Yan
Bacterial infections are becoming a significant threat to global human health due to the growing prevalence of biofilm-related infections and the rise in antibiotic resistance. D/l-cysteine functionalized chiral gold nanoparticles (D/P-Au NPs or L/P-Au NPs) have demonstrated a potent antibacterial effect against E. coli, while the mechanism remains to be elucidated through additional research. Threonine deaminase (TD) is a crucial enzyme involved in branched-chain amino acid (BCAA) biosynthesis in E. coli and is involved in cysteine's antimicrobial effects. This study investigated the interaction between chiral Au NPs (D/P-Au NPs or L/P-Au NPs) and TD as well as its effect on enzyme activity. It demonstrates that chiral Au NPs interact with TD through hydrophobic forces, forming a ground state complex that induces changes in the secondary structure of TD and reduces enzyme activity in a concentration-dependent manner. We found that the exogenous supplementation of isoleucine and valine (2 mg/mL) significantly reduced the antibacterial activity of chiral Au NPs, especially for L/P-Au NPs. The proteomics results indicate that the expression of ilvA and ilvB was down-regulated after L/P-Au NPs treatment, which would interfere with the synthesis of BCAAs. These results demonstrate that chiral Au NPs cause cell death of E. coli partly due to inhibition of TD enzyme activity and the synthesis of branched-chain amino acids.
由于与生物膜相关的感染日益普遍以及抗生素耐药性的增加，细菌感染正成为全球人类健康的重大威胁。D/l-半胱氨酸功能化手性金纳米粒子（D/P-Au NPs 或 L/P-Au NPs）对大肠杆菌具有强效抗菌作用，但其作用机制仍有待进一步研究阐明。苏氨酸脱氨酶（TD）是参与大肠杆菌支链氨基酸（BCAA）生物合成的关键酶，也参与了半胱氨酸的抗菌作用。本研究探讨了手性 Au NPs（D/P-Au NPs 或 L/P-Au NPs）与 TD 之间的相互作用及其对酶活性的影响。研究表明，手性 Au NPs 通过疏水力与 TD 相互作用，形成基态复合物，诱导 TD 二级结构发生变化，并以浓度依赖的方式降低酶活性。我们发现，外源补充异亮氨酸和缬氨酸（2 mg/mL）会显著降低手性 Au NPs 的抗菌活性，尤其是 L/P-Au NPs。蛋白质组学结果表明，L/P-Au NPs 处理后，ilvA 和 ilvB 的表达下调，这将干扰 BCAAs 的合成。这些结果表明，手性 Au NPs 导致大肠杆菌细胞死亡的部分原因是抑制了 TD 酶的活性和支链氨基酸的合成。
{"title":"Targeting threonine deaminase with chiral Au NPs: A novel strategy for E. coli inhibition","authors":"He Wang , Haidu Yuan , Jianhao Zhang , Wenjing Yan","doi":"10.1016/j.bbrc.2024.150924","DOIUrl":"10.1016/j.bbrc.2024.150924","url":null,"abstract":"<div><div>Bacterial infections are becoming a significant threat to global human health due to the growing prevalence of biofilm-related infections and the rise in antibiotic resistance. D/<span>l</span>-cysteine functionalized chiral gold nanoparticles (D/P-Au NPs or L/P-Au NPs) have demonstrated a potent antibacterial effect against <em>E. coli</em>, while the mechanism remains to be elucidated through additional research. Threonine deaminase (TD) is a crucial enzyme involved in branched-chain amino acid (BCAA) biosynthesis in <em>E. coli</em> and is involved in cysteine's antimicrobial effects. This study investigated the interaction between chiral Au NPs (D/P-Au NPs or L/P-Au NPs) and TD as well as its effect on enzyme activity. It demonstrates that chiral Au NPs interact with TD through hydrophobic forces, forming a ground state complex that induces changes in the secondary structure of TD and reduces enzyme activity in a concentration-dependent manner. We found that the exogenous supplementation of isoleucine and valine (2 mg/mL) significantly reduced the antibacterial activity of chiral Au NPs, especially for L/P-Au NPs. The proteomics results indicate that the expression of <em>ilvA</em> and <em>ilvB</em> was down-regulated after L/P-Au NPs treatment, which would interfere with the synthesis of BCAAs. These results demonstrate that chiral Au NPs cause cell death of <em>E. coli</em> partly due to inhibition of TD enzyme activity and the synthesis of branched-chain amino acids.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"737 ","pages":"Article 150924"},"PeriodicalIF":2.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560712","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 : 2024-10-29DOI: 10.1016/j.bbrc.2024.150915
Junchao Zhang, Jinfa Huang, Qian Yang, Lingling Zeng, Kaixian Deng
Macrophage–myofibroblast transdifferentiation (MMT), a fibrotic process impacting diverse tissue types, has garnered recent scholarly interest. Within damaged tissues, the role of myofibroblasts is pivotal in the accumulation of excessive fibrous connective tissue, leading to persistent scarring or organ dysfunction. Consequently, the examination of MMT-related fibrosis is imperative. This review underscores MMT as a fundamental mechanism in myofibroblast generation during tissue fibrosis, and its exploration is crucial for elucidating the regulatory mechanisms underlying this process. Gaining insight into these mechanisms promises to facilitate the development of therapeutic approaches aimed at inhibiting and reversing fibrosis, thereby offering potential avenues for the treatment of fibrotic diseases.
{"title":"Regulatory mechanisms of macrophage–myofibroblast transdifferentiation: A potential therapeutic strategy for fibrosis","authors":"Junchao Zhang, Jinfa Huang, Qian Yang, Lingling Zeng, Kaixian Deng","doi":"10.1016/j.bbrc.2024.150915","DOIUrl":"10.1016/j.bbrc.2024.150915","url":null,"abstract":"<div><div>Macrophage–myofibroblast transdifferentiation (MMT), a fibrotic process impacting diverse tissue types, has garnered recent scholarly interest. Within damaged tissues, the role of myofibroblasts is pivotal in the accumulation of excessive fibrous connective tissue, leading to persistent scarring or organ dysfunction. Consequently, the examination of MMT-related fibrosis is imperative. This review underscores MMT as a fundamental mechanism in myofibroblast generation during tissue fibrosis, and its exploration is crucial for elucidating the regulatory mechanisms underlying this process. Gaining insight into these mechanisms promises to facilitate the development of therapeutic approaches aimed at inhibiting and reversing fibrosis, thereby offering potential avenues for the treatment of fibrotic diseases.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"737 ","pages":"Article 150915"},"PeriodicalIF":2.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560716","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}
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