Archives of biochemistry and biophysics最新文献

{"title":"Bacterial expression, purification, and characterization of human cytochrome P450 3A4 without N-terminal modifications","authors":"Yudong Sun,&nbsp;Yoichi Osawa,&nbsp;Haoming Zhang","doi":"10.1016/j.abb.2024.110208","DOIUrl":"10.1016/j.abb.2024.110208","url":null,"abstract":"<div><div>In this communication we reported a bacterial system that over-expressed full-length wild-type (WT) human CYP3A4 in <em>Escherichia coli</em> (<em>E. coli</em>) at a level of 495 nmol/L culture. This level of expression was achieved by cloning the cDNA sequence of CYP3A4 WT to a pLW01-P450 vector and co-expressing it with chaperones GroEL/ES in bacterial C41(DE3) cells. Aided with a C-terminal His₅-tag, the expressed CYP3A4 WT was purified to homogeneity with a specific content of 14.3 ± 2.0 nmole P450/mg protein using a single Ni-Penta agarose column. Like the N-terminal modified form (CYP3A4-NF14), CYP3A4 WT binds substrate testosterone with a typical sigmoidal feature at slightly higher affinity. Functional characterization revealed that CYP3A4 WT exhibited lower testosterone 6β-hydroxylase activities than CYP3A4-NF14 in reconstituted phospholipid systems. In addition, it was found that the 6β-hydroxylase activity of CYP3A4 WT was less dependent on excess cytochrome P450 oxidoreductase (POR), compared with CYP3A4-NF14. These results suggest that the N-terminal membrane anchor of CYP3A4 WT enhances its interactions with POR and marginally increases testosterone binding.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"762 ","pages":"Article 110208"},"PeriodicalIF":3.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613642","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":"New insights into the function and molecular mechanisms of Ferredoxin-NADP+ reductase from Brucella ovis","authors":"Andrea Moreno ,&nbsp;Isabel Quereda-Moraleda ,&nbsp;Celia Lozano-Vallhonrat ,&nbsp;María Buñuel-Escudero ,&nbsp;Sabine Botha ,&nbsp;Christopher Kupitz ,&nbsp;Stella Lisova ,&nbsp;Ray Sierra ,&nbsp;Valerio Mariani ,&nbsp;Pamela Schleissner ,&nbsp;Leland B. Gee ,&nbsp;Katerina Dörner ,&nbsp;Christina Schmidt ,&nbsp;Huijong Han ,&nbsp;Marco Kloos ,&nbsp;Peter Smyth ,&nbsp;Joana Valerio ,&nbsp;Joachim Schulz ,&nbsp;Raphael de Wijn ,&nbsp;Diogo V.M. Melo ,&nbsp;Milagros Medina","doi":"10.1016/j.abb.2024.110204","DOIUrl":"10.1016/j.abb.2024.110204","url":null,"abstract":"<div><div>Bacterial ferredoxin(flavodoxin)-NADP⁺ reductases (FPR) primarily catalyze the transfer of reducing equivalents from NADPH to ferredoxin (or flavodoxin) to provide low potential reducing equivalents for the oxidoreductive metabolism. In addition, they can be implicated in regulating reactive oxygen species levels. Here we assess the functionality of FPR from <em>B. ovis</em> to understand its potential roles in the bacteria physiology. We prove that this FPR is active with the endogenous [2Fe–2S] Fdx ferredoxin, exhibiting a <em>K</em>_M^Fdx in the low micromolar range. At the molecular level, this study provides with the first structures of an FPR at room temperature obtained by serial femtosecond crystallography, envisaging increase in flexibility at both the adenine nucleotide moiety of FAD and the C-terminal tail. The produced microcrystals are in addition suitable for future mix-and-inject time-resolved studies with the NADP⁺/H coenzyme either at synchrotrons or XFELs. Furthermore, the study also predicts the ability of FPR to simultaneously interact with Fdx and NADP⁺/H.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"762 ","pages":"Article 110204"},"PeriodicalIF":3.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613641","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}

{"title":"High intensity interval training as a therapy: Mitophagy restoration in breast cancer","authors":"Kayvan Khoramipour ,&nbsp;Afsaneh Soltany ,&nbsp;Pouria Khosravi ,&nbsp;Maryam Hossein Rezaei ,&nbsp;Elham Madadizadeh ,&nbsp;Celia García-Chico ,&nbsp;Sergio Maroto-Izquierdo ,&nbsp;Karen Khoramipour","doi":"10.1016/j.abb.2024.110213","DOIUrl":"10.1016/j.abb.2024.110213","url":null,"abstract":"<div><div>Recent studies have highlighted the role of mitophagy in tumorigenesis. This study aimed to investigate the effects of high-intensity interval training (HIIT) on mitophagy in tumor tissues of mice with breast cancer. Twenty-eight female BALB/c mice were randomly assigned to four groups: Healthy Control (CO), Cancer (CA), Exercise (EX), and Cancer + Exercise (CA + EX). Mammary tumors were induced in the CA and CA + EX groups via 4T1 cell injections. Upon confirmation of tumor formation, the EX and CA + EX groups underwent 8 weeks (40 sessions) of HIIT, comprising 4–10 intervals of running at 80–100 % of maximum speed. The expression levels of mitophagy-related proteins, including parkin, PTEN-induced putative kinase 1 (PINK1), NIP3-like protein X (NIX), BCL2 interacting protein-3 (BINP3), microtubule-associated protein light chain 3-I (LC3-I), microtubule-associated protein light chain 3-II (LC3-II), AMP-activated protein kinase (AMPK), Unc-51 like autophagy activating kinase-1 (ULK1), and sirtuin-1 (SIRT1), were measured in breast and tumor tissues. Tumor volume relative to body weight was assessed weekly during the eight-week HIIT intervention. Protein expression of parkin, PINK1, NIX, BINP3, LC3-II, LC3-I, AMPK, ULK1, and SIRT1 was reduced in the breast tissue of the CA group, while HIIT restored expression levels across all measured variables (P &lt; 0.01). Additionally, tumor volume relative to body weight was significantly lower in the CA + EX group compared to the CA group from weeks 3–8 (P &lt; 0.01). These findings suggest that breast cancer suppresses mitophagy, yet HIIT effectively reverses this suppression, potentially reducing tumor burden. HIIT may thus represent a promising therapeutic strategy for managing breast cancer.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"762 ","pages":"Article 110213"},"PeriodicalIF":3.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613643","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":"Purification and catalysis of choline dehydrogenase from Escherichia coli","authors":"Xiuxiu Ma ,&nbsp;Fangling Xu ,&nbsp;Koukou Yu ,&nbsp;Fan Wang ,&nbsp;Quan Li ,&nbsp;Weifeng Liang ,&nbsp;Bing Liu ,&nbsp;Bo Zhang ,&nbsp;Jiapeng Zhu ,&nbsp;Jiao Li","doi":"10.1016/j.abb.2024.110212","DOIUrl":"10.1016/j.abb.2024.110212","url":null,"abstract":"<div><div>Choline dehydrogenase (CHDH) is a membrane-bound enzyme belonging to the glucose-methanol-choline (GMC) oxidoreductase superfamily, which is characterized by a crucial FAD-binding domain essential for catalytic function. CHDH catalyzes the oxidation of choline to betaine aldehyde, which is further oxidized to betaine, a vital osmoprotectant and methyl donor for cellular physiology and metabolism. However, the detailed catalytic mechanism of CHDH still remains poorly understood. In our investigation, we gained purity <em>E. coli</em> CHDH samples in DDM (n-dodecyl-β-D-maltoside) and SMA (styrene maleic acid) copolymer respectively and examined their structural composition and catalytic activity separately. Our findings demonstrated the effectiveness of SMA, commonly employed for extracting transmembrane proteins and can preserve the natural bio-membrane environment surrounding the enzyme, in extracting peripheral membrane proteins like CHDH here, which lacks transmembrane helices. CHDH exhibited a trimeric conformation in SMA, whereas it existed as monomers in DDM, as determined by our negative staining analysis. Our experiments also revealed that highly pure <em>E. coli</em> CHDH could only oxidize choline to betaine aldehyde but failed to further oxidize betaine aldehyde to betaine as determined by the biochemical and enzymatic reaction kinetic assays. In addition, the enzyme in SMA displayed greater catalytic activity compared to that in DDM. Furthermore, we confirmed the crucial role of His473, which is hypothesized to be a critical site for substrate binding from our structural comparative analysis between CHDH and its highly homologous choline oxidase, in the catalytic activity of the enzyme through gene mutation. Our work also sheds light on CHDH's contribution to cellular osmotic tolerance through gene knockout. This research enhances our better understanding of CHDH within cellular biochemistry and metabolic pathways.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"762 ","pages":"Article 110212"},"PeriodicalIF":3.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602866","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":"AI-assisted generation and in-depth in-silico evaluation of potential inhibitor targeting aurora kinase A (AURKA): An anticancer discovery exploiting synthetic lethality approach","authors":"Anand Kumar Pandey","doi":"10.1016/j.abb.2024.110209","DOIUrl":"10.1016/j.abb.2024.110209","url":null,"abstract":"<div><div>Genetic alterations are lead causative agents behind the complex pathologies of cancers which render all treatments unarmed. Such alterations in oncogenes can be treated by direct inhibition by specific drugs while alteration in tumor suppressor genes mediating loss of function is challenging to treat. Identification of synthetic lethal partners to specific tumor suppressor genes and mediating their inhibition can be a potential approach to deal with loss of function mutations. Aurora kinase A (AURKA) has been established as an effective synthetic lethal partner of several tumor suppressor genes and is overexpressed in cancerous conditions, mediating adverse pathologies. The present AI-assisted study deals with the generation of novel inhibitor compounds against AURKA and the exhaustive evaluation of the best compound using molecular docking, molecular dynamic simulation, MM/PBSA, and QM/MMGBSA-based analysis. Out of the 200 novel compounds generated using features of ATP binding pocket of AURKA and previously reported inhibitor, compound 1 (4-{5-fluoro-6-[(1Z)-3-hydrazinyl-3-oxo-2-phenylprop-1-en-1-yl]pyridin-2-yl}benzoic acid) was identified as the most potent candidate with high negative binding energy of −10.4 kcal/mol in molecular docking analysis. The molecular dynamic simulation analysis resulted in major conformational changes in the conserved DFG motif and loop 277–291 of AURKA in the apo-AURKA compared to AURKA-compound 1 complex thus maintaining open ATP binding cavity in apo-form and inhibiting the entry of ATP to its binding site in complex form. The free energy landscape displayed a persistence of folded states of the enzyme in complex form. The MM/PBSA revealed effective Gibb's free energy of binding of −11 kcal/mol for compound 1 inhibiting AURKA. The QM/MMGBSA analysis resulted in a significantly high negative binding energy of −13.98 kcal/mol proving significant inhibition potential of compound 1 against AURKA. Therefore, further in-vitro investigation can provide a novel effective, and safe treatment against a wide range of cancers by targeting a well-established cancer target AURKA.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"762 ","pages":"Article 110209"},"PeriodicalIF":3.8,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566671","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":"Identification of positions in human aldolase a that are neutral for apparent KM","authors":"Liskin Swint-Kruse,&nbsp;Tyler A. Martin ,&nbsp;Tiffany Wu ,&nbsp;Larissa L. Dougherty ,&nbsp;Aron W. Fenton","doi":"10.1016/j.abb.2024.110183","DOIUrl":"10.1016/j.abb.2024.110183","url":null,"abstract":"<div><div>According to evolutionary theory, many naturally-occurring amino acid substitutions are expected to be neutral or near-neutral, with little effect on protein structure or function. Accordingly, most changes observed in human exomes are also expected to be neutral. As such, accurate algorithms for identifying medically-relevant changes must discriminate rare, non-neutral substitutions against a background of neutral substitutions. However, due to historical biases in biochemical experiments, the data available to train and validate prediction algorithms mostly contains non-neutral substitutions, with few examples of neutral substitutions. Thus, available training sets have the opposite composition of the desired test sets. Towards improving a dataset of these critical negative controls, we have concentrated on identifying neutral positions – those positions for which most of the possible 19 amino acid substitutions have little effect on protein structure or function. Here, we used a strategy based on multiple sequence alignments to identify putative neutral positions in human aldolase A, followed by biochemical assays for 147 aldolase substitutions. Results showed that most variants had little effect on either the apparent Michaelis constant for substrate fructose-1,6-bisphosphate or its apparent cooperativity. Thus, these data are useful for training and validating prediction algorithms. In addition, we created a database of these and other biochemically characterized aldolase variants along with aldolase sequences and characteristics derived from sequence and structure analyses. This database is publicly available at <span><span><em>https://github.com/liskinsk/Aldolase-variant-and-sequence-database</em></span><svg><path></path></svg></span>.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110183"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493525","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}

{"title":"Liquiritigenin inhibits the migration, invasion, and EMT of prostate cancer through activating ER stress","authors":"Chi Wang ,&nbsp;Bo Liu ,&nbsp;Weichao Dan ,&nbsp;Yi Wei ,&nbsp;Mengxing Li ,&nbsp;Chendong Guo ,&nbsp;Yishuai Zhang ,&nbsp;Hongjun Xie","doi":"10.1016/j.abb.2024.110184","DOIUrl":"10.1016/j.abb.2024.110184","url":null,"abstract":"<div><div>Liquiritigenin (LQ) is a monomeric compound found in licorice, a leguminous plant, and has been reported to exhibit antitumor effects in various lines of cancer cells. However, the underlying molecular mechanisms by which LQ exerts its antitumor effects remain largely unknown. In this study, the effects of LQ on the migration, invasion, and epithelial-mesenchymal transition (EMT) of prostate cancer (PCa) cells were investigated. We found that LQ effectively inhibited the migration and invasion of PCa cells in vitro, and this effect was further confirmed in xenograft lung metastasis models. In addition, LQ was found to activate endoplasmic reticulum stress (ER stress) in PCa cells. Further studies found that LQ upregulated the expression of inositol-requiring enzyme type 1α (IRE1). When IRE1 was knocked down, we observed a weakened inhibitory effect of LQ treatment on the migration and invasion of PCa cells. This observation suggests that LQ may inhibit the migration, invasion and EMT of PCa cells through activating the IRE1 branch of ER stress. In conclusion, our research may provide a novel therapeutic strategy for PCa.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110184"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493526","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}

{"title":"The electric regulation mechanism of drug molecules intercalating with DNA","authors":"Lijun He ,&nbsp;Liang She ,&nbsp;Liyan Wang ,&nbsp;Cheng Mi ,&nbsp;Kang Ma ,&nbsp;Mi Yu ,&nbsp;Xing Long ,&nbsp;Chaopeng Zhang","doi":"10.1016/j.abb.2024.110203","DOIUrl":"10.1016/j.abb.2024.110203","url":null,"abstract":"<div><div>The insertion of small drug molecules into DNA can change its electrical properties, thereby controlling the probability of its electrical transmission. This characteristic has enabled its widespread application in molecular electronics. However, the current understanding of the intercalation properties and electronic transmission mechanisms is still not deep enough, which severely restricts its practical application. In this paper, the density functional theory and the non-equilibrium Green's function formula are combined to bind three different small drug molecules to the same sequence of DNA through intercalation, in order to discuss the impact of intercalation and molecular structure on the electrical properties of DNA. After inserting two MAR70 molecules, the conductivity decreased from 2.38 × 10⁻⁵ G₀ to 3.37 × 10⁻⁷ G₀. Upon the insertion of Nogalamycin, the conductivity dropped to 2.01 × 10⁻⁵ G₀, only slightly lower than that of bare B-DNA. However, when cyanomorpholinodoxorubicin was inserted, the conductivity was 2.65 × 10⁻⁶ G₀. In our study, we observed some common characteristics. After intercalating with drug molecules, new energy levels were induced, altering the positions of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energy levels, resulting in a narrowed bandgap and consequently reduced conductivity of the complex. Furthermore, the conductivity was also related to the number of inserted drug molecules, fewer inserted molecules led to a decrease in conductivity. The results of this study indicate that embedding drug molecules can reduce or regulate the conductivity of DNA, providing new insights for its application in the field of nanoelectronics.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"762 ","pages":"Article 110203"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566702","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":"Rituximab induces ferroptosis and RSL3 overcomes rituximab resistance in diffuse large B-cell lymphoma cells","authors":"Haiyi Wu ,&nbsp;Linqing Zou ,&nbsp;Ying Jin ,&nbsp;Guishuan Wang ,&nbsp;William C. Cho ,&nbsp;Wenqing Li ,&nbsp;Yifeng Cai ,&nbsp;Guoqi Song","doi":"10.1016/j.abb.2024.110188","DOIUrl":"10.1016/j.abb.2024.110188","url":null,"abstract":"<div><div>Diffuse large B-cell lymphoma (DLBCL) is the most common malignant lymphoma in adults, and the use of rituximab has greatly improved the survival of DLBCL patients. Currently, the first-line treatment regimen for DLBCL is still rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), which significantly improves outcomes for DLBCL patients. However, a percentage of patients still experience refractory or relapsed disease. Since Dr. Brent R Stockwell proposed ferroptosis in 2012, Roudkenar, M. H. Roushandeh, A. M. Valashedi, M. R. and others proved the importance of ferroptosis in cancer drug resistance. The purpose of this study was to elucidate whether rituximab could exert anticancer effects on DLBCL cells by promoting ferroptosis. Cell viability was assessed using the Cell Counting Kit-8. The results showed that rituximab exposure induced ferroptosis in OCI-LY1 cells. However, combination with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, indicating that ferroptosis plays a key role in rituximab-induced cell death. Western blotting was performed to detect the levels of specific ferroptosis-associated proteins in DLBCL. Moreover, GSH depletion and MDA upregulation was assessed using GSH assays and MDA assay kits in rituximab-treated OCI-LY1 cells. In addition, rituximab failed to induce ferroptosis in rituximab-resistant cell lines. Treatment with RSL3 enhanced the effects of rituximab on DLBCL cells by inhibiting cell viability. In conclusion, we report for the first time that rituximab induces ferroptosis in lymphoma cells, at least partially through the SLC7A11/GPX4 axis. We also identify targeting ferroptosis as a promising therapeutic option for both sensitive cells and resistant cells in the treatment of DLBCL.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110188"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142553551","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":"The cGAS-STING mediated crosstalk between innate immunity and autophagy in leishmaniasis using mathematical modeling: Uncovering new therapeutic avenues","authors":"Anil Tambekar,&nbsp;Vrushali Guhe,&nbsp;Shailza Singh","doi":"10.1016/j.abb.2024.110201","DOIUrl":"10.1016/j.abb.2024.110201","url":null,"abstract":"<div><div>The present paper deals with the investigation into the cGAS-STING pathway, focusing on the signaling of interferons through mathematical modeling and identifying a significant positive feedback loop regulated by STING for activation of type 1 interferons (IFN-1). Cyclic GMP-AMP synthase (cGAS) is responsible for detecting cytosolic DNA and initiating the STING (stimulator of interferon genes) pathway, which in turn causes the synthesis of pro-inflammatory cytokines and type I interferons. In addition to being crucial for pathogen identification, this route interacts with autophagy, a cellular mechanism that is necessary for immunological homeostasis and pathogen removal. In the context of Leishmania infection, the cGAS-STING signaling axis has come to light as a critical mediator of the crosstalk between innate immunity and autophagy. Further, the protein-protein interaction studies underscored the significance of two distinct domains in mediating interactions with IRF3 and LC3. Importantly, our findings suggest the possibility of manipulating STING concomitantly to regulate IRF3 and LC3 independently. This study remarkably advances our understanding of STING's multifaceted roles, particularly in regulating IFN-1 and autophagy, highlighting its pivotal role as a cross-talk point in leishmaniasis.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"762 ","pages":"Article 110201"},"PeriodicalIF":3.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563885","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}