Pub Date : 2025-02-01DOI: 10.1016/j.abb.2024.110270
Mohd Waseem , Shubhashis Das , Debarati Mondal , Anuj Kumari , Ritu Kulshreshtha , Jitendra K. Thakur , Naidu Subbarao
Candida glabrata is one of the most common causes of invasive candidiasis. Rising treatment failures from resistance to current antifungal drugs highlight the need for new antifungals. Overexpression of efflux pump transporter genes is significantly associated with the development of multidrug resistance. In this study, we have identified novel and potential inhibitors of ABC transporter Cdr1 of Candida glabrata (CgCdr1) by employing high throughput virtual screening of large chemical datasets from five different chemical libraries (ZINC, DrugBank, ChemDiv antifungal, ChemDiv Kinases, and ChEMBL bioassay). As a result many molecules were predicted to have higher binding affinity toward the CgCdr1, in which a naturally occurring compound, pentagalloyl glucose, was identified to significantly reduce the growth of Candida glabrata with an IC50 value of 16.97 ± 2.1 μM. Molecular dynamics studies showed stable binding of pentagalloyl glucose with CgCdr1 protein. In summary, our research identifies pentagalloyl glucose as a novel antifungal compound that has the potential to be used for inhibiting the growth of Candida glabrata.
{"title":"Identification of ABC transporter Cdr1 inhibitors of Candida glabrata","authors":"Mohd Waseem , Shubhashis Das , Debarati Mondal , Anuj Kumari , Ritu Kulshreshtha , Jitendra K. Thakur , Naidu Subbarao","doi":"10.1016/j.abb.2024.110270","DOIUrl":"10.1016/j.abb.2024.110270","url":null,"abstract":"<div><div><em>Candida glabrata is</em> one of the most common causes of invasive candidiasis. Rising treatment failures from resistance to current antifungal drugs highlight the need for new antifungals. Overexpression of efflux pump transporter genes is significantly associated with the development of multidrug resistance. In this study, we have identified novel and potential inhibitors of ABC transporter Cdr1 of <em>Candida glabrata</em> (<em>Cg</em>Cdr1) by employing high throughput virtual screening of large chemical datasets from five different chemical libraries (ZINC, DrugBank, ChemDiv antifungal, ChemDiv Kinases, and ChEMBL bioassay). As a result many molecules were predicted to have higher binding affinity toward the <em>Cg</em>Cdr1, in which a naturally occurring compound, pentagalloyl glucose, was identified to significantly reduce the growth of <em>Candida glabrata</em> with an IC<sub>50</sub> value of 16.97 ± 2.1 μM. Molecular dynamics studies showed stable binding of pentagalloyl glucose with <em>Cg</em>Cdr1 protein. In summary, our research identifies pentagalloyl glucose as a novel antifungal compound that has the potential to be used for inhibiting the growth of <em>Candida glabrata</em>.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110270"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833759","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 : 2025-02-01DOI: 10.1016/j.abb.2024.110273
Chenyan Zhang , Yile Tian , Xinli Liu , Xuezhou Yang , Shanfeng Jiang , Ge Zhang , Changqing Yang , Wenjing Liu , Weihong Guo , Wenzhe Zhao , Dachuan Yin
Mechanical unloading can lead to homeostasis imbalance and severe muscle disease, in which muscle atrophy was one of the disused diseases. However, there were limited therapeutic targets for such diseases. In this study, miR-495 was found dramatically reduced in atrophic skeletal muscle induced by mechanical unloading models both in vitro and in vivo, including the random positioning model (RPM), tail-suspension (TS) model, and aged mice model. Enforced miR-495 expression by its mimic could enormously facilitate the differentiation and regeneration of both mouse myoblast C2C12 cells and muscle satellite cells. Furthermore, MyoD was proved as the directly interacted gene of miR-495, and their interaction was crucial for myotube formation. Enforced miR-495 expression could intensively strengthen the muscle mass, in situ muscular electrophysiological indexes, including peak tetanic tension (Po) and peak twitch tension (Pt), and the cross-sectional areas (CSA) of muscle fibers via targeting MyoD and inactivating the Myostatin/TGF-β/Smad3 signaling pathway, indicating that miR-495 can be proposed as an effective target for muscle atrophy treatment induced by in the mechanical unloading, random rotating and aging.
{"title":"MiR-495 reverses in the mechanical unloading, random rotating and aging induced muscle atrophy via targeting MyoD and inactivating the Myostatin/TGF-β/Smad3 axis","authors":"Chenyan Zhang , Yile Tian , Xinli Liu , Xuezhou Yang , Shanfeng Jiang , Ge Zhang , Changqing Yang , Wenjing Liu , Weihong Guo , Wenzhe Zhao , Dachuan Yin","doi":"10.1016/j.abb.2024.110273","DOIUrl":"10.1016/j.abb.2024.110273","url":null,"abstract":"<div><div>Mechanical unloading can lead to homeostasis imbalance and severe muscle disease, in which muscle atrophy was one of the disused diseases. However, there were limited therapeutic targets for such diseases. In this study, miR-495 was found dramatically reduced in atrophic skeletal muscle induced by mechanical unloading models both <em>in vitro</em> and <em>in vivo</em>, including the random positioning model (RPM), tail-suspension (TS) model, and aged mice model. Enforced miR-495 expression by its mimic could enormously facilitate the differentiation and regeneration of both mouse myoblast C2C12 cells and muscle satellite cells<em>.</em> Furthermore, MyoD was proved as the directly interacted gene of miR-495, and their interaction was crucial for myotube formation. Enforced miR-495 expression could intensively strengthen the muscle mass, <em>in situ</em> muscular electrophysiological indexes, including peak tetanic tension (Po) and peak twitch tension (Pt), and the cross-sectional areas (CSA) of muscle fibers via targeting MyoD and inactivating the Myostatin/TGF-β/Smad3 signaling pathway, indicating that miR-495 can be proposed as an effective target for muscle atrophy treatment induced by in the mechanical unloading, random rotating and aging.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110273"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862909","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 : 2025-02-01DOI: 10.1016/j.abb.2024.110287
Ting Zhou , Xiaorong Li , Fangfang Zhao , Jing Zhou , Binghui Sun
Background
Lactamase β (LACTB) inhibits the metastasis and progression of multiple malignant tumors. However, little is known about its role in endometrial cancer (EC). Our study aimed to investigate the function and potential molecular mechanism of LACTB in modulating EC progression.
Methods
LACTB expression was measured via immunohistochemistry staining, Western blot and qRT-PCR. The role of LACTB in EC was investigated both in vivo and in vitro by employing xenograft mice models and using colony formation, EdU, and Transwell assays, along with flow cytometric analysis. In addition, to assess LACTB function on lipid metabolism, lipid droplets in EC cells were labeled with Nile red. Western blot, immunofluorescence staining, co-immunoprecipitation, ubiquitination assay, and cycloheximide chase assay and rescue experiments were performed to confirm the interaction between LACTB, p53, and MDM2 in EC.
Results
LACTB expression was downregulated in EC. LACTB inhibited the malignant phenotypes and reprogramed lipid metabolism in EC cells. Moreover, LACTB significantly upregulated p53 by attenuating the MDM2-mediated ubiquitination and degradation of p53. Besides, LACTB silencing facilitated the malignant phenotypes and reprogramed lipid metabolism in EC cells; this was reversed with p53 overexpression. LACTB knockdown facilitated EC progression via downregulating p53 in vivo.
Conclusion
LACTB repressed EC cell proliferation and metastasis, and reprogramed lipid metabolism via attenuating the MDM2-mediated ubiquitination and degradation of p53.
{"title":"Lactamase β reprograms lipid metabolism to inhibit the progression of endometrial cancer through attenuating MDM2-mediated p53 ubiquitination and degradation","authors":"Ting Zhou , Xiaorong Li , Fangfang Zhao , Jing Zhou , Binghui Sun","doi":"10.1016/j.abb.2024.110287","DOIUrl":"10.1016/j.abb.2024.110287","url":null,"abstract":"<div><h3>Background</h3><div>Lactamase β (LACTB) inhibits the metastasis and progression of multiple malignant tumors. However, little is known about its role in endometrial cancer (EC). Our study aimed to investigate the function and potential molecular mechanism of LACTB in modulating EC progression.</div></div><div><h3>Methods</h3><div>LACTB expression was measured via immunohistochemistry staining, Western blot and qRT-PCR. The role of LACTB in EC was investigated both in vivo and in vitro by employing xenograft mice models and using colony formation, EdU, and Transwell assays, along with flow cytometric analysis. In addition, to assess LACTB function on lipid metabolism, lipid droplets in EC cells were labeled with Nile red. Western blot, immunofluorescence staining, co-immunoprecipitation, ubiquitination assay, and cycloheximide chase assay and rescue experiments were performed to confirm the interaction between LACTB, p53, and MDM2 in EC.</div></div><div><h3>Results</h3><div>LACTB expression was downregulated in EC. LACTB inhibited the malignant phenotypes and reprogramed lipid metabolism in EC cells. Moreover, LACTB significantly upregulated p53 by attenuating the MDM2-mediated ubiquitination and degradation of p53. Besides, LACTB silencing facilitated the malignant phenotypes and reprogramed lipid metabolism in EC cells; this was reversed with p53 overexpression. LACTB knockdown facilitated EC progression via downregulating p53 in vivo.</div></div><div><h3>Conclusion</h3><div>LACTB repressed EC cell proliferation and metastasis, and reprogramed lipid metabolism via attenuating the MDM2-mediated ubiquitination and degradation of p53.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110287"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920680","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 : 2025-02-01DOI: 10.1016/j.abb.2024.110277
Manasi S. Pote, Rajesh N. Gacche
Exosomes are membrane-bound extracellular vesicles that play a role in exchanging biological products across membranes and serve as intermediaries in intercellular communication to maintain normal homeostasis. Numerous molecules, including lipids, proteins, and nucleic acids are enclosed in exosomes. Exosomes are constantly released into the extracellular environment and exhibit distinct characteristics based on the secreted cells that produce them. Exosome-mediated cell-to-cell communication has reportedly been shown to affect multiple cancer hallmarks, such as immune response modulation, pre-metastatic niche formation, angiogenesis, stromal cell reprogramming, extracellular matrix architecture remodeling, or even drug resistance, and eventually the development and metastasis of cancer cells. Exosomes can be used as therapeutic targets and possible diagnostic biomarkers by selectively loading oncogenic molecules into them. We highlight the important roles that exosomes play in cancer development in this review, which may lead to the development of fresh approaches for future clinical uses.
{"title":"Exosomal signaling in cancer metastasis: Molecular insights and therapeutic opportunities","authors":"Manasi S. Pote, Rajesh N. Gacche","doi":"10.1016/j.abb.2024.110277","DOIUrl":"10.1016/j.abb.2024.110277","url":null,"abstract":"<div><div>Exosomes are membrane-bound extracellular vesicles that play a role in exchanging biological products across membranes and serve as intermediaries in intercellular communication to maintain normal homeostasis. Numerous molecules, including lipids, proteins, and nucleic acids are enclosed in exosomes. Exosomes are constantly released into the extracellular environment and exhibit distinct characteristics based on the secreted cells that produce them. Exosome-mediated cell-to-cell communication has reportedly been shown to affect multiple cancer hallmarks, such as immune response modulation, pre-metastatic niche formation, angiogenesis, stromal cell reprogramming, extracellular matrix architecture remodeling, or even drug resistance, and eventually the development and metastasis of cancer cells. Exosomes can be used as therapeutic targets and possible diagnostic biomarkers by selectively loading oncogenic molecules into them. We highlight the important roles that exosomes play in cancer development in this review, which may lead to the development of fresh approaches for future clinical uses.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110277"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871093","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 : 2025-02-01DOI: 10.1016/j.abb.2024.110286
Haifang Hao , Yuan Bian , Na Yang , Xingzhao Ji , Jie Bao , Kongkai Zhu
c-Src, also known as cellular Src, is a non-receptor tyrosine kinase that plays a crucial role in various cellular processes, including cell proliferation, adhesion, and migration. Its dysregulation has been implicated in the development and progression of several diseases, particularly cancer. Current therapeutic agents targeting c-Src are primarily small molecules binding to its kinase domain. However, drug resistance often reduces the effectiveness of these drugs. The SH3 domain of c-Src is a highly conserved functional region with a low propensity for developing drug resistance, whereas there are no existing anti-cancer drugs specifically binding to this domain. In this study, structure-based virtual screening and thermal shift experimental verification identified three molecules that showed potent binding affinity with SH3 domain of c-Src. Subsequent kinase activity assay validated the inhibitory activity of these compounds against c-Src, with IC50 values ranging from 60.42 to 122.2 nM. Next, cell-level assays and preliminary study were conducted to further evaluate the efficacy of the identified active compounds. In conclusion, the present work has provided new chemical templates as lead structures for the future development of new antitumor therapeutics targeting the c-Src SH3 domain to overcome drug resistance.
{"title":"Discovery of anti-tumor small molecule lead compounds targeting the SH3 domain of c-Src protein through virtual screening and biological evaluation","authors":"Haifang Hao , Yuan Bian , Na Yang , Xingzhao Ji , Jie Bao , Kongkai Zhu","doi":"10.1016/j.abb.2024.110286","DOIUrl":"10.1016/j.abb.2024.110286","url":null,"abstract":"<div><div>c-Src, also known as cellular Src, is a non-receptor tyrosine kinase that plays a crucial role in various cellular processes, including cell proliferation, adhesion, and migration. Its dysregulation has been implicated in the development and progression of several diseases, particularly cancer. Current therapeutic agents targeting c-Src are primarily small molecules binding to its kinase domain. However, drug resistance often reduces the effectiveness of these drugs. The SH3 domain of c-Src is a highly conserved functional region with a low propensity for developing drug resistance, whereas there are no existing anti-cancer drugs specifically binding to this domain. In this study, structure-based virtual screening and thermal shift experimental verification identified three molecules that showed potent binding affinity with SH3 domain of c-Src. Subsequent kinase activity assay validated the inhibitory activity of these compounds against c-Src, with IC<sub>50</sub> values ranging from 60.42 to 122.2 nM. Next, cell-level assays and preliminary study were conducted to further evaluate the efficacy of the identified active compounds. In conclusion, the present work has provided new chemical templates as lead structures for the future development of new antitumor therapeutics targeting the c-Src SH3 domain to overcome drug resistance.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110286"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913626","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 : 2025-02-01DOI: 10.1016/j.abb.2024.110257
Mohamed M. Fathy, Omnia A. Saad, Heba M. Fahmy
Silica shell is considered to be a promising design that enhances nanocomposite stability, cellular internalization, and consequentially therapeutic impacts by overcoming their aggregation under physiological conditions. This study addressed synthesizing silica-layered iron oxide-based nanoparticles (SCINPs) with different shell thicknesses (1-SCINPs, 2-SCINPs, 3-SCINPs, and 4-SCINPs). Also, the impact of shell thickness on the nanoparticle's cellular internalization and the radio-sensitizing effect of prepared nano-formulations were assessed. The physical properties of the synthesized nanoparticles were examined using transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), vibrating sample magnetometry (VSM), and X-ray diffraction (XRD). Cytotoxicity assay, oxidative stress parameters, and comet assay were used to investigate the radio-sensitizing effect of various nanoformulations. Results revealed that the mean diameter of prepared oxide-based nanoparticles (INPs) was about 12.63 ± 1.36 nm, and the shell thickness for 1-SCINPs, 2-SCINPs, 3-SCINPs, and 4-SCINPs was 22.58 ± 3.51, 26.13 ± 1.40, 46.95 ± 3.10 and 60.30 ± 4.30 nm, respectively. Interestingly, we found that in cells treated with 40 μg/ml of INPs, their viability decreased to 44.6 %. Meanwhile, the viability was 41.69 % and 39.4 % for cells treated with 1-SCINPs and 2-SCINPs, respectively. This means that a thicker silica shell led to a decreased impact on radiosensitization. This was attributed to the influence of surface properties and size of SCINPs on their cellular uptake and the secondary electrons' entrapment within thicker shells upon radiation exposure. Cell viability test, comet assay and oxidative stress parameters show that 2-SCINPs formulations had the most potent radiosensitizing effect (with the highest dose enhancement factor equal to 2.1) when combined with radio-treatment. The results suggest that optimizing the silica shell thickness is critical for maximizing the therapeutic efficacy of SCINPs, with 2-SCINPs showing the highest radiosensitization effect.
{"title":"Radiosensitization impact assessment of silica-layered iron oxide nanocomposites with various shell thickness","authors":"Mohamed M. Fathy, Omnia A. Saad, Heba M. Fahmy","doi":"10.1016/j.abb.2024.110257","DOIUrl":"10.1016/j.abb.2024.110257","url":null,"abstract":"<div><div>Silica shell is considered to be a promising design that enhances nanocomposite stability, cellular internalization, and consequentially therapeutic impacts by overcoming their aggregation under physiological conditions. This study addressed synthesizing silica-layered iron oxide-based nanoparticles (SCINPs) with different shell thicknesses (1-SCINPs, 2-SCINPs, 3-SCINPs, and 4-SCINPs). Also, the impact of shell thickness on the nanoparticle's cellular internalization and the radio-sensitizing effect of prepared nano-formulations were assessed. The physical properties of the synthesized nanoparticles were examined using transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), vibrating sample magnetometry (VSM), and X-ray diffraction (XRD). Cytotoxicity assay, oxidative stress parameters, and comet assay were used to investigate the radio-sensitizing effect of various nanoformulations. Results revealed that the mean diameter of prepared oxide-based nanoparticles (INPs) was about 12.63 ± 1.36 nm, and the shell thickness for 1-SCINPs, 2-SCINPs, 3-SCINPs, and 4-SCINPs was 22.58 ± 3.51, 26.13 ± 1.40, 46.95 ± 3.10 and 60.30 ± 4.30 nm, respectively. Interestingly, we found that in cells treated with 40 μg/ml of INPs, their viability decreased to 44.6 %. Meanwhile, the viability was 41.69 % and 39.4 % for cells treated with 1-SCINPs and 2-SCINPs, respectively. This means that a thicker silica shell led to a decreased impact on radiosensitization. This was attributed to the influence of surface properties and size of SCINPs on their cellular uptake and the secondary electrons' entrapment within thicker shells upon radiation exposure. Cell viability test, comet assay and oxidative stress parameters show that 2-SCINPs formulations had the most potent radiosensitizing effect (with the highest dose enhancement factor equal to 2.1) when combined with radio-treatment. The results suggest that optimizing the silica shell thickness is critical for maximizing the therapeutic efficacy of SCINPs, with 2-SCINPs showing the highest radiosensitization effect.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110257"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823974","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 : 2025-02-01DOI: 10.1016/j.abb.2024.110266
Sharon Natasha Cox , Vito Porcelli , Simona Romano , Luigi Palmieri , Deborah Fratantonio
Exosome-like nanovesicles (ELNs) of food origin have received great attention in the last decade, due to the hypothesis that they contain bioactive molecules. ELNs purified from edible species have been shown to be protective and are able to regulate intestinal homeostasis. Despite ELNs being potential rising stars in modern healthy diets and biomedical applications, further research is needed to address underlying knowledge gaps, especially related to the specific molecular mechanism through which they exert their action. Here, we investigate the cellular uptake of blueberry-derived ELNs (B-ELNs) using a human stabilized intestinal cell line (HIEC-6) and assess the ability of B-ELNs to modulate the expression of inflammatory genes in response to lipopolysaccharide (LPS). Our findings show that B-ELNs are internalized by HIEC-6 cells and transport labeled RNA cargo into them. Pretreatment with B-ELNs reduces LPS-induced ROS generation and cell viability loss, while modulating the expression of 28 inflammatory genes compared to control. Pathway analysis demonstrates their ability to suppress inflammatory responses triggered by LPS. In conclusion, our data indicate that B-ELNs are up taken by HIEC-6 cells and can modulate inflammatory responses after LPS stimulation, suggesting a therapeutic potential. This study demonstrates the role of B-ELNs in regulating crucial biological processes, like anti-inflammatory responses, which could support intestinal health.
{"title":"Blueberry-derived exosome like nanovesicles carry RNA cargo into HIEC-6 cells and down-regulate LPS-induced inflammatory gene expression: A proof-of-concept study","authors":"Sharon Natasha Cox , Vito Porcelli , Simona Romano , Luigi Palmieri , Deborah Fratantonio","doi":"10.1016/j.abb.2024.110266","DOIUrl":"10.1016/j.abb.2024.110266","url":null,"abstract":"<div><div>Exosome-like nanovesicles (ELNs) of food origin have received great attention in the last decade, due to the hypothesis that they contain bioactive molecules. ELNs purified from edible species have been shown to be protective and are able to regulate intestinal homeostasis. Despite ELNs being potential rising stars in modern healthy diets and biomedical applications, further research is needed to address underlying knowledge gaps, especially related to the specific molecular mechanism through which they exert their action. Here, we investigate the cellular uptake of blueberry-derived ELNs (B-ELNs) using a human stabilized intestinal cell line (HIEC-6) and assess the ability of B-ELNs to modulate the expression of inflammatory genes in response to lipopolysaccharide (LPS). Our findings show that B-ELNs are internalized by HIEC-6 cells and transport labeled RNA cargo into them. Pretreatment with B-ELNs reduces LPS-induced ROS generation and cell viability loss, while modulating the expression of 28 inflammatory genes compared to control. Pathway analysis demonstrates their ability to suppress inflammatory responses triggered by LPS. In conclusion, our data indicate that B-ELNs are up taken by HIEC-6 cells and can modulate inflammatory responses after LPS stimulation, suggesting a therapeutic potential. This study demonstrates the role of B-ELNs in regulating crucial biological processes, like anti-inflammatory responses, which could support intestinal health.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110266"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823930","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}
In the presented study, we evaluated changes in the molecular structures of lipids and proteins in organs/tissues at the early stage of obesity induced by a high-calorie diet (HCD), using animal models. We examined several different molecular parameters and the organs most affected by obesity. Fourier transform infrared (FTIR) spectroscopy combined with Principal Component Analysis (PCA) and Receiver Operating Characteristic (ROC) analysis were used to evaluate molecular changes in tissues taken from HCD-induced obese Wistar rats and their lean counterparts. We observed that at the early stage of obesity, changes occurred mainly in lipid structures, primarily affecting white epididymal adipose tissue (WAT) and the liver (Lr). No changes in protein molecular structures were observed in any of the examined organs. PCA showed distinctly different organ/tissue compositions, in terms of molecular parameters, for both groups. In turn, ROC analysis indicated that fatty acid chain length (FACL), lipid unsaturation (L_Unsat), and carbonyl/lipid ratio (Carb/L) for WAT, and FACL and lipid/protein ratio (L/P) for Lr, were the molecular parameters, whose levels differentiated the most between both groups. We demonstrated that studies using FTIR spectroscopy combined with advanced data mining methods could deepen the current knowledge about obesity and the biochemical changes occurring in the organs affected by this disease. Thus, they can help in the future with better and faster diagnosis and prevention of obesity and its complications.
{"title":"Effects of high-calorie diet-induced obesity on molecular structures of lipids and proteins - A multi-organ study using FTIR spectroscopy","authors":"Kaja Piana , Agata Ziomber-Lisiak , Blazej Ruszczycki , Andrzej Bugajski , Magdalena Szczerbowska-Boruchowska","doi":"10.1016/j.abb.2025.110325","DOIUrl":"10.1016/j.abb.2025.110325","url":null,"abstract":"<div><div>In the presented study, we evaluated changes in the molecular structures of lipids and proteins in organs/tissues at the early stage of obesity induced by a high-calorie diet (HCD), using animal models. We examined several different molecular parameters and the organs most affected by obesity. Fourier transform infrared (FTIR) spectroscopy combined with Principal Component Analysis (PCA) and Receiver Operating Characteristic (ROC) analysis were used to evaluate molecular changes in tissues taken from HCD-induced obese Wistar rats and their lean counterparts. We observed that at the early stage of obesity, changes occurred mainly in lipid structures, primarily affecting white epididymal adipose tissue (WAT) and the liver (Lr). No changes in protein molecular structures were observed in any of the examined organs. PCA showed distinctly different organ/tissue compositions, in terms of molecular parameters, for both groups. In turn, ROC analysis indicated that fatty acid chain length (FACL), lipid unsaturation (L_Unsat), and carbonyl/lipid ratio (Carb/L) for WAT, and FACL and lipid/protein ratio (L/P) for Lr, were the molecular parameters, whose levels differentiated the most between both groups. We demonstrated that studies using FTIR spectroscopy combined with advanced data mining methods could deepen the current knowledge about obesity and the biochemical changes occurring in the organs affected by this disease. Thus, they can help in the future with better and faster diagnosis and prevention of obesity and its complications.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110325"},"PeriodicalIF":3.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078446","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 : 2025-01-30DOI: 10.1016/j.abb.2025.110323
Thomas P. Burghardt
Background
Human ventriculum myosin (βmys) powers contraction sometimes in complex with myosin binding protein C (MYBPC3). The latter regulates βmys activity and impacts cardiac function. Single residue variants (SRVs) change protein sequence in βmys or MYBPC3 causing inheritable heart diseases by affecting the βmys/MYBPC3 complex. Muscle genetics encode instructions for contraction informing native protein construction, functional integration, and inheritable disease impairment. A digital model decodes these instructions and evolves by processing new information content from diverse data modalities using a human partner-driven virtuous cycle optimization.
Methods
A general neural-network contraction model characterizes SRV impacts on human health. It rationalizes phenotype and pathogenicity assignment given the SRVs characteristics and, in this sense, decodes βmys/MYBPC3 complex genetics and implicitly captures ventricular muscle functionality. When an SRV modified domain locates to an inter-protein contact in βmys/MYBPC3 it affects complex coordination. Domains involved, one in βmys and the other in MYBPC3, form coordinated domains (co-domains). Bilateral co-domains imply potential for their SRV modification probabilities to respond jointly to a common perturbation revealing location. Human genetic diversity from the serial founder effect is the common systemic perturbation coupling co-domains subsequently mapped by a method called 2-dimensional correlation genetics (2D-CG).
Results
Interpreting general neural-network contraction model output involves 2D-CG co-domain mapping providing structural insights with natural language expression. It aligns machine-learned intelligence from the neural network model with human provided structural insight from the 2D-CG map, and other data from the literature, to form a neural-symbolic hybrid model integrating genetic and protein-interaction data into a nascent digital twin. The process forms a template for combining new information content from diverse data modalities into an evolving digital model. This nascent digital twin interprets SRV implications for disease mechanism discovery.
{"title":"Neural-symbolic hybrid model for myosin complex in cardiac ventriculum decodes structural bases for inheritable heart disease from its genetic encoding","authors":"Thomas P. Burghardt","doi":"10.1016/j.abb.2025.110323","DOIUrl":"10.1016/j.abb.2025.110323","url":null,"abstract":"<div><h3>Background</h3><div>Human ventriculum myosin (βmys) powers contraction sometimes in complex with myosin binding protein C (MYBPC3). The latter regulates βmys activity and impacts cardiac function. Single residue variants (SRVs) change protein sequence in βmys or MYBPC3 causing inheritable heart diseases by affecting the βmys/MYBPC3 complex. Muscle genetics encode instructions for contraction informing native protein construction, functional integration, and inheritable disease impairment. A digital model decodes these instructions and evolves by processing new information content from diverse data modalities using a human partner-driven virtuous cycle optimization.</div></div><div><h3>Methods</h3><div>A general neural-network contraction model characterizes SRV impacts on human health. It rationalizes phenotype and pathogenicity assignment given the SRVs characteristics and, in this sense, decodes βmys/MYBPC3 complex genetics and implicitly captures ventricular muscle functionality. When an SRV modified domain locates to an inter-protein contact in βmys/MYBPC3 it affects complex coordination. Domains involved, one in βmys and the other in MYBPC3, form coordinated domains (co-domains). Bilateral co-domains imply potential for their SRV modification probabilities to respond jointly to a common perturbation revealing location. Human genetic diversity from the serial founder effect is the common systemic perturbation coupling co-domains subsequently mapped by a method called 2-dimensional correlation genetics (2D-CG).</div></div><div><h3>Results</h3><div>Interpreting general neural-network contraction model output involves 2D-CG co-domain mapping providing structural insights with natural language expression. It aligns machine-learned intelligence from the neural network model with human provided structural insight from the 2D-CG map, and other data from the literature, to form a neural-symbolic hybrid model integrating genetic and protein-interaction data into a nascent digital twin. The process forms a template for combining new information content from diverse data modalities into an evolving digital model. This nascent digital twin interprets SRV implications for disease mechanism discovery.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110323"},"PeriodicalIF":3.8,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073606","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 : 2025-01-27DOI: 10.1016/j.abb.2025.110317
Maryam Jamil , Sana Zafar , Tehmina Bibi , Parveen Akhtar Buttar , Bushra Shal , Kifayatullah Shah , Fakhar ud Din , Eun Kyoung Seo , Salman Khan
<div><h3>Aim</h3><div>The aim of the current study was to investigate the potential therapeutic effect of kaurenoic acid (KA) against Monosodium Urate Crystals (MSU)-induced acute gout by downregulation of NF-κB signaling pathway, mitigating inflammation and oxidative stress. KA potentially targeted NF-κB pathway activation and provided comprehensive insights through multiple approaches. This was accomplished by advanced analytical techniques. This methodology highlighted the efficacy of KA in acute gout attacks offering new approach for gout management.</div></div><div><h3>Methods</h3><div>In-vivo model of acute gout was established in BALB/c mice. Anti-inflammatory and urate-lowering potential was determined through pain behavioral evaluation, biochemical analysis, histological and immunohistochemical assays, radiological assessments, Fourier Transform Infrared (FTIR) analysis, and computational analysis.</div></div><div><h3>Results</h3><div>The paw edema, joint thickness, and the frequency and duration of acute gout flare-ups were all significantly (p < 0.001) decreased by the administration of KA. A considerable reversal of inflammation and deterioration was observed in the KA-treated groups in X-ray examination. The FTIR spectroscopy indicated the changes in the molecular makeup of tissues, and modifications of biomolecules including proteins, lipids, and carbohydrates. Histopathological changes showed marked (p < 0.001) improvements in cellular structure of the paw, and inflammatory cell infiltration in the treatment groups. Trichrome staining revealed suppressed collagen deposition, inflammation, and tissue repair in the paw. In paw tissues, the KA therapy up-regulated IκB-α expression while down-regulating toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression. On the other hand, KA therapy greatly increased antioxidants and decreased oxidative stress indicators significantly (p < 0.001). According to Evans's blue permeability analysis, results showed that the treatment groups' vascular permeability was intensely reduced in comparison to the diseased group. Molecular docking studies indicated that KA appeared to have a high tendency to bind to protein targets. KA was associated with the drop in the cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β).</div></div><div><h3>Conclusion</h3><div>In conclusion, this study highlighted the potential therapeutic effect of KA in alleviating MSU-induced gout by suppressing the NF-κB signaling pathway. The anti-inflammatory and antioxidant activity was demonstrated by behavioral studies and advanced biochemical evaluations including blood analysis and oxido-nitrosative stress markers. Histopathological analysis, including H&E staining, immunohistochemistry, and Masson Trichrome staining, revealed tissue preservation, while FTIR and X-ray revealed structural improvements. M
{"title":"Suppression of TLR4/NF-κB signaling by kaurenoic acid in a mice model of monosodium urate crystals-induced acute gout","authors":"Maryam Jamil , Sana Zafar , Tehmina Bibi , Parveen Akhtar Buttar , Bushra Shal , Kifayatullah Shah , Fakhar ud Din , Eun Kyoung Seo , Salman Khan","doi":"10.1016/j.abb.2025.110317","DOIUrl":"10.1016/j.abb.2025.110317","url":null,"abstract":"<div><h3>Aim</h3><div>The aim of the current study was to investigate the potential therapeutic effect of kaurenoic acid (KA) against Monosodium Urate Crystals (MSU)-induced acute gout by downregulation of NF-κB signaling pathway, mitigating inflammation and oxidative stress. KA potentially targeted NF-κB pathway activation and provided comprehensive insights through multiple approaches. This was accomplished by advanced analytical techniques. This methodology highlighted the efficacy of KA in acute gout attacks offering new approach for gout management.</div></div><div><h3>Methods</h3><div>In-vivo model of acute gout was established in BALB/c mice. Anti-inflammatory and urate-lowering potential was determined through pain behavioral evaluation, biochemical analysis, histological and immunohistochemical assays, radiological assessments, Fourier Transform Infrared (FTIR) analysis, and computational analysis.</div></div><div><h3>Results</h3><div>The paw edema, joint thickness, and the frequency and duration of acute gout flare-ups were all significantly (p < 0.001) decreased by the administration of KA. A considerable reversal of inflammation and deterioration was observed in the KA-treated groups in X-ray examination. The FTIR spectroscopy indicated the changes in the molecular makeup of tissues, and modifications of biomolecules including proteins, lipids, and carbohydrates. Histopathological changes showed marked (p < 0.001) improvements in cellular structure of the paw, and inflammatory cell infiltration in the treatment groups. Trichrome staining revealed suppressed collagen deposition, inflammation, and tissue repair in the paw. In paw tissues, the KA therapy up-regulated IκB-α expression while down-regulating toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression. On the other hand, KA therapy greatly increased antioxidants and decreased oxidative stress indicators significantly (p < 0.001). According to Evans's blue permeability analysis, results showed that the treatment groups' vascular permeability was intensely reduced in comparison to the diseased group. Molecular docking studies indicated that KA appeared to have a high tendency to bind to protein targets. KA was associated with the drop in the cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β).</div></div><div><h3>Conclusion</h3><div>In conclusion, this study highlighted the potential therapeutic effect of KA in alleviating MSU-induced gout by suppressing the NF-κB signaling pathway. The anti-inflammatory and antioxidant activity was demonstrated by behavioral studies and advanced biochemical evaluations including blood analysis and oxido-nitrosative stress markers. Histopathological analysis, including H&E staining, immunohistochemistry, and Masson Trichrome staining, revealed tissue preservation, while FTIR and X-ray revealed structural improvements. M","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110317"},"PeriodicalIF":3.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045268","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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