Pub Date : 2025-01-28DOI: 10.1016/j.bbrc.2025.151416
Yuma Aoki , Lei Wang , Masumi Tsuda , Yusuke Saito , Takenori Kubota , Yoshitaka Oda , Satoshi Hirano , Jian Ping Gong , Shinya Tanaka
Pancreatic cancer is known as one of the poor prognostic cancers, and the most of patients are unable to undergo radical resection due to local progression or distant metastasis at initial diagnosis. In spite of the advancements in surgery and chemotherapy, there are many cases of recurrence after surgery or chemoradiotherapy mainly due to the presence of cancer stem cells (CSCs). CSCs are potential therapeutic target, but current issue is that an identification of CSCs is difficult since they are only present in a small number of tumor cells. Here we demonstrate that hydrogel PCDME can rapidly induce pancreatic cancer cell spheroids with elevated levels of stem cell markers including Sox2, Oct3/4, and Nanog, and the growth rate was reduced. CSCs showed activation of YAP/TAZ signaling, and microarray analysis showed markedly elevated expression of thioredoxin-interacting protein (TXNIP). Primary pancreatic cancer cells also increased TXNIP in addition to stemness markers on gel. In metabolic analysis, CSCs showed a shift of energy production from glycolysis to oxidative phosphorylation (OXPHOS). Furthermore, knockdown of TXNIP on PCDME gel using shRNAs decreased growth speed and in vivo tumorigenicity, suggesting that TXNIP may be involved in CSCs induction.
{"title":"Hydrogel PCDME creates pancreatic cancer stem cells in OXPHOS metabolic state with TXNIP elevation","authors":"Yuma Aoki , Lei Wang , Masumi Tsuda , Yusuke Saito , Takenori Kubota , Yoshitaka Oda , Satoshi Hirano , Jian Ping Gong , Shinya Tanaka","doi":"10.1016/j.bbrc.2025.151416","DOIUrl":"10.1016/j.bbrc.2025.151416","url":null,"abstract":"<div><div>Pancreatic cancer is known as one of the poor prognostic cancers, and the most of patients are unable to undergo radical resection due to local progression or distant metastasis at initial diagnosis. In spite of the advancements in surgery and chemotherapy, there are many cases of recurrence after surgery or chemoradiotherapy mainly due to the presence of cancer stem cells (CSCs). CSCs are potential therapeutic target, but current issue is that an identification of CSCs is difficult since they are only present in a small number of tumor cells. Here we demonstrate that hydrogel PCDME can rapidly induce pancreatic cancer cell spheroids with elevated levels of stem cell markers including <em>Sox2</em>, <em>Oct3/4</em>, and <em>Nanog,</em> and the growth rate was reduced. CSCs showed activation of YAP/TAZ signaling, and microarray analysis showed markedly elevated expression of <em>thioredoxin-interacting protein</em> (<em>TXNIP</em>). Primary pancreatic cancer cells also increased <em>TXNIP</em> in addition to stemness markers on gel. In metabolic analysis, CSCs showed a shift of energy production from glycolysis to oxidative phosphorylation (OXPHOS). Furthermore, knockdown of TXNIP on PCDME gel using shRNAs decreased growth speed and <em>in vivo</em> tumorigenicity, suggesting that TXNIP may be involved in CSCs induction.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151416"},"PeriodicalIF":2.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143355559","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}
Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) is a TNF superfamily cytokine primarily acknowledged for its ability to selectively induce apoptosis in cancer cells. Beyond its antitumor effects, recent literature emphasizes the pleiotropic functions of TRAIL in physiological states and acute/chronic non-malignant diseases indicating its potential to be a breakthrough in diagnostics. This review explores the current understanding of the dynamic role of circulating soluble TRAIL (sTRAIL) and its potential as both a diagnostic and prognostic marker. Multiple in vitro, in vivo, and clinical studies in a wide range of neoplastic and non-neoplastic diseases including infectious diseases have been carried out to explore the potential role of sTRAIL in disease pathogenesis and as well as the possibilities of using it as a diagnostic and prognostic marker. The expression of sTRAIL seems to be context-dependent suggesting further research, particularly towards establishing disease-specific cutoff values. However, the lack of standardization in the serum sTRAIL estimation and the absence of reference intervals remain significant barriers to its clinical application. Addressing these challenges is essential for using circulating sTRAIL as an accurate diagnostic and prognostic marker in clinical practice.
{"title":"Exploring the dynamic role of circulating soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a diagnostic and prognostic marker; a review","authors":"K.K.H. Niroshika , K. Weerakoon , I.M.N. Molagoda , K.W. Samarakoon , H.T. Weerakoon , R.G.P.T. Jayasooriya","doi":"10.1016/j.bbrc.2025.151415","DOIUrl":"10.1016/j.bbrc.2025.151415","url":null,"abstract":"<div><div>Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) is a TNF superfamily cytokine primarily acknowledged for its ability to selectively induce apoptosis in cancer cells. Beyond its antitumor effects, recent literature emphasizes the pleiotropic functions of TRAIL in physiological states and acute/chronic non-malignant diseases indicating its potential to be a breakthrough in diagnostics. This review explores the current understanding of the dynamic role of circulating soluble TRAIL (sTRAIL) and its potential as both a diagnostic and prognostic marker. Multiple <em>in vitro</em>, <em>in vivo,</em> and clinical studies in a wide range of neoplastic and non-neoplastic diseases including infectious diseases have been carried out to explore the potential role of sTRAIL in disease pathogenesis and as well as the possibilities of using it as a diagnostic and prognostic marker. The expression of sTRAIL seems to be context-dependent suggesting further research, particularly towards establishing disease-specific cutoff values. However, the lack of standardization in the serum sTRAIL estimation and the absence of reference intervals remain significant barriers to its clinical application. Addressing these challenges is essential for using circulating sTRAIL as an accurate diagnostic and prognostic marker in clinical practice.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151415"},"PeriodicalIF":2.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350225","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 : 2025-01-27DOI: 10.1016/j.bbrc.2025.151400
Jiaen Song , Jun Qiao , Zhongyi Cheng , Junling Guo , Qiong Wang , Zhemin Zhou , Laichuang Han
Nitrile Hydratase (NHase), an industrially significant enzyme, catalyzes the conversion of nitriles into amides. High activity and thermostability are crucial for its broad applications. Compared with classical evaluation and subsequent combination of single-point mutations, redesigning coevolutionary residues offers a more precise approach by targeting key functional sites and facilitating efficient computational design and iteration. Here, we proposed an optimized strategy for redesigning coevolutionary residues to enhance the robustness of NHase, a heterotetrameric protein. We conducted an extensive analysis of 80 coevolutionary residue pairs in NHase from Pseudonocardia thermophila JCM3095 (PtNHase) and identified 21 hotspot designable residue pairs lacking explicit interactions. Virtual saturating combinatorial mutations were applied to these pairs, yielding 27 positive candidates from 8379 theoretical mutations based on changes in folding free energy. After screening and iterative combinations, the optimal mutant A3 (αG86Y/αK57L/αE183F) was obtained, whose specific activity toward acrylonitrile and half-life at 65 °C were increased from 1656.8 ± 21.2 U/mg and 20.1 min in WT to 2370.1 ± 102.7 U/mg and 62.3 min, respectively. Benefiting from higher activity and thermostability, the whole-cell catalyst of A3 significantly facilitated the bioconversion of acrylonitrile to acrylamide. Molecular dynamics simulations further revealed that the newly formed inter-residue interactions stabilized the active site and enhanced the flexibility of the substrate channel, thereby improving both activity and thermostability. This study not only developed a highly robust NHase, but also established a framework for the design of other industrial enzymes.
{"title":"Computational design of coevolutionary residues for improved stability and activity of nitrile hydratase","authors":"Jiaen Song , Jun Qiao , Zhongyi Cheng , Junling Guo , Qiong Wang , Zhemin Zhou , Laichuang Han","doi":"10.1016/j.bbrc.2025.151400","DOIUrl":"10.1016/j.bbrc.2025.151400","url":null,"abstract":"<div><div>Nitrile Hydratase (NHase), an industrially significant enzyme, catalyzes the conversion of nitriles into amides. High activity and thermostability are crucial for its broad applications. Compared with classical evaluation and subsequent combination of single-point mutations, redesigning coevolutionary residues offers a more precise approach by targeting key functional sites and facilitating efficient computational design and iteration. Here, we proposed an optimized strategy for redesigning coevolutionary residues to enhance the robustness of NHase, a heterotetrameric protein. We conducted an extensive analysis of 80 coevolutionary residue pairs in NHase from <em>Pseudonocardia thermophila</em> JCM3095 (PtNHase) and identified 21 hotspot designable residue pairs lacking explicit interactions. Virtual saturating combinatorial mutations were applied to these pairs, yielding 27 positive candidates from 8379 theoretical mutations based on changes in folding free energy. After screening and iterative combinations, the optimal mutant A3 (αG86Y/αK57L/αE183F) was obtained, whose specific activity toward acrylonitrile and half-life at 65 °C were increased from 1656.8 ± 21.2 U/mg and 20.1 min in WT to 2370.1 ± 102.7 U/mg and 62.3 min, respectively. Benefiting from higher activity and thermostability, the whole-cell catalyst of A3 significantly facilitated the bioconversion of acrylonitrile to acrylamide. Molecular dynamics simulations further revealed that the newly formed inter-residue interactions stabilized the active site and enhanced the flexibility of the substrate channel, thereby improving both activity and thermostability. This study not only developed a highly robust NHase, but also established a framework for the design of other industrial enzymes.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"750 ","pages":"Article 151400"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073608","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.bbrc.2025.151368
Jia-xing Liu , Yu-kai Zhang , Wei Zhan , Jun-hao Xie , Qi-hong Xu , Jing zhang , Xiang Tai
Background
Acute lung injury (ALI) is a critical condition characterized by severe inflammation and oxidative stress, leading to high morbidity and mortality. Despite advances in understanding ALI pathophysiology, effective treatment options remain limited. The increasing global burden of ALI, driven by factors such as infections, trauma, and environmental pollutants, emphasizes the urgent need for new therapeutic strategies. This study investigates the role of ubiquitin-specific protease 11 (USP11) in modulating Forkhead box protein O1 (FOXO1) to promote autophagy and alleviate oxidative stress in lung epithelial cells, which could provide novel insights into ALI therapeutic strategies.
Materials and methods
Bioinformatics were utilized to analyze the expression pattern of USP11 and FOXO1 in ALI, and their functions were detected based on gain- and loss-of function studies in vitro and in vivo. Besides, the effects of USP11 on FOXO1 stability and autophagy were examined through Western blot, immunofluorescence, and co-immunoprecipitation assays.
Results
USP11 was found to be significantly downregulated in ALI, and its over-expression stabilized FOXO1, enhancing autophagy in lung epithelial cells. USP11 over-expression reduced oxidative stress and inflammatory cytokine production in vitro and in vivo. These results highlight the protective role of the USP11-FOXO1 axis in mitigating ALI pathophysiology.
Conclusions
This study identifies USP11 as a key regulator of FOXO1 and autophagy in ALI. The stabilization of FOXO1 through USP11 represents a promising therapeutic strategy for reducing oxidative stress and inflammation in ALI, warranting further clinical investigation.
{"title":"USP11 promotes autophagy to attenuate LPS-induced oxidative stress in lung epithelial cells by stabilizing FOXO1 levels","authors":"Jia-xing Liu , Yu-kai Zhang , Wei Zhan , Jun-hao Xie , Qi-hong Xu , Jing zhang , Xiang Tai","doi":"10.1016/j.bbrc.2025.151368","DOIUrl":"10.1016/j.bbrc.2025.151368","url":null,"abstract":"<div><h3>Background</h3><div>Acute lung injury (ALI) is a critical condition characterized by severe inflammation and oxidative stress, leading to high morbidity and mortality. Despite advances in understanding ALI pathophysiology, effective treatment options remain limited. The increasing global burden of ALI, driven by factors such as infections, trauma, and environmental pollutants, emphasizes the urgent need for new therapeutic strategies. This study investigates the role of ubiquitin-specific protease 11 (USP11) in modulating Forkhead box protein O1 (FOXO1) to promote autophagy and alleviate oxidative stress in lung epithelial cells, which could provide novel insights into ALI therapeutic strategies.</div></div><div><h3>Materials and methods</h3><div>Bioinformatics were utilized to analyze the expression pattern of USP11 and FOXO1 in ALI, and their functions were detected based on gain- and loss-of function studies <em>in vitro</em> and <em>in vivo</em>. Besides, the effects of USP11 on FOXO1 stability and autophagy were examined through Western blot, immunofluorescence, and co-immunoprecipitation assays.</div></div><div><h3>Results</h3><div>USP11 was found to be significantly downregulated in ALI, and its over-expression stabilized FOXO1, enhancing autophagy in lung epithelial cells. USP11 over-expression reduced oxidative stress and inflammatory cytokine production <em>in vitro</em> and <em>in vivo</em>. These results highlight the protective role of the USP11-FOXO1 axis in mitigating ALI pathophysiology.</div></div><div><h3>Conclusions</h3><div>This study identifies USP11 as a key regulator of FOXO1 and autophagy in ALI. The stabilization of FOXO1 through USP11 represents a promising therapeutic strategy for reducing oxidative stress and inflammation in ALI, warranting further clinical investigation.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151368"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143175450","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 : 2025-01-27DOI: 10.1016/j.bbrc.2025.151394
Dahai Hou , Wuxia Zhao , Qi Yang , Fang Wang , Wenya Wu , Linyu Xu , Wenchao Yao , Dongdong Sun , Yimiao Zhu , Xiaoyu Wu
The study investigates the potential mechanisms by which curcumol exerts colon anti-cancer effects through angiogenesis and immune infiltration. Using The Cancer Genome Atlas (TCGA) database, we found abnormal levels of IGF2BP3 in both paraneoplastic and colon cancer tissues. Firstly, in vivo experiments were conducted to detect the colon anti-cancer and pro-apoptotic effects of curcumol. Immunofluorescence and immunoblotting experiments elucidated that curcumol regulates immune infiltration and angiogenesis in colon cancer through IGF2BP3, and the interaction between curcumol and IGF2BP3 was predicted. Additionally, IGF2BP3 overexpression (IGF2BP3-OE) was further used to verify the colon anti-cancer mechanism of curcumol. The results of the experiment revealed that IGF2BP3 expression is upregulated in colon cancer tissues and correlates with poor patient survival. Our study demonstrated that curcumol significantly inhibits colon cancer tumor growth by promoting apoptosis and inhibiting proliferation through the induction of apoptosis-related proteins Bax and Cleaved-Caspase 3, and the depletion of Bcl-2. Curcumol also downregulated IGF2BP3, promoting the infiltration of immune-activated helper T cells (CD4+ T), cytotoxic T cells (CD8+ T), and natural killer (NK) cells in tumor tissues, while reducing the number of immune-suppressing regulatory T cells (Treg) and inhibiting the angiogenesis-related protein CD31. Molecular docking experiments identified IGF2BP3 as a direct target of curcumol. When IGF2BP3 was overexpressed, the inhibitory effect of curcumol on angiogenesis in colon cancer tissues was reversed. In summary, curcumol promotes immune cell infiltration in tumor tissues by downregulating IGF2BP3, thereby inhibiting the proliferation and angiogenesis of colon cancer cells.
{"title":"Curcumol promotes immune cell invasion and inhibits angiogenesis in colon cancer by decreasing IGF2BP3 expression","authors":"Dahai Hou , Wuxia Zhao , Qi Yang , Fang Wang , Wenya Wu , Linyu Xu , Wenchao Yao , Dongdong Sun , Yimiao Zhu , Xiaoyu Wu","doi":"10.1016/j.bbrc.2025.151394","DOIUrl":"10.1016/j.bbrc.2025.151394","url":null,"abstract":"<div><div>The study investigates the potential mechanisms by which curcumol exerts colon anti-cancer effects through angiogenesis and immune infiltration. Using The Cancer Genome Atlas (TCGA) database, we found abnormal levels of IGF2BP3 in both paraneoplastic and colon cancer tissues. Firstly, in vivo experiments were conducted to detect the colon anti-cancer and pro-apoptotic effects of curcumol. Immunofluorescence and immunoblotting experiments elucidated that curcumol regulates immune infiltration and angiogenesis in colon cancer through IGF2BP3, and the interaction between curcumol and IGF2BP3 was predicted. Additionally, IGF2BP3 overexpression (IGF2BP3-OE) was further used to verify the colon anti-cancer mechanism of curcumol. The results of the experiment revealed that IGF2BP3 expression is upregulated in colon cancer tissues and correlates with poor patient survival. Our study demonstrated that curcumol significantly inhibits colon cancer tumor growth by promoting apoptosis and inhibiting proliferation through the induction of apoptosis-related proteins Bax and Cleaved-Caspase 3, and the depletion of Bcl-2. Curcumol also downregulated IGF2BP3, promoting the infiltration of immune-activated helper T cells (CD4<sup>+</sup> T), cytotoxic T cells (CD8<sup>+</sup> T), and natural killer (NK) cells in tumor tissues, while reducing the number of immune-suppressing regulatory T cells (Treg) and inhibiting the angiogenesis-related protein CD31. Molecular docking experiments identified IGF2BP3 as a direct target of curcumol. When IGF2BP3 was overexpressed, the inhibitory effect of curcumol on angiogenesis in colon cancer tissues was reversed. In summary, curcumol promotes immune cell infiltration in tumor tissues by downregulating IGF2BP3, thereby inhibiting the proliferation and angiogenesis of colon cancer cells.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"750 ","pages":"Article 151394"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121949","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.bbrc.2025.151396
Dong Wang, Long Sun, Xiaoman Niu, Lei Ren, Xin Yang
Background
Helicobacter pylori (H. pylori) infection promotes gastric cancer (GC) through various mechanisms. It causes inflammation and damage to the gastric mucosa, thereby increasing the risk of developing GC. Sphingolipids can act as signaling molecules that activate or inhibit intracellular signaling pathways, and abnormal sphingolipid metabolism may promote tumorigenesis and metastasis. This study aimed to explore the relationship among sphingosine kinase 2 (SphK2) expression, GC progression, and H. pylori infection.
Methods
Expression profile data for SphK2 were extracted from public datasets. Normal human gastric mucosal and GC cells were co-incubated with H. pylori, and SphK2 expression in these cells was detected using western blotting. GC cells with SphK2 overexpression and knockdown were established, and the effects of SphK2 and H. pylori on the proliferation, migration, and invasion abilities of GC cells were verified using CCK-8, EdU, and Transwell assays. The expression of Ras/MEK/ERK pathway-related proteins was detected using western blotting, and the secretion of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in GC cells was detected using ELISA.
Results
SphK2 is highly expressed in GC cells and is associated with a poor prognosis. The expression of SphK2 in GC cells is related to H. pylori infection. SphK2 overexpression promotes the proliferation, migration, and invasion of GC cells and enhances the pro-inflammatory effects of H. pylori.
Conclusion
SphK2 promotes the progression of H. pylori-positive GC by activating the Ras/MEK/ERK pathway.
{"title":"SphK2 promotes the progression of Helicobacter pylori-positive gastric cancer by regulating the Ras/MEK/ERK pathway","authors":"Dong Wang, Long Sun, Xiaoman Niu, Lei Ren, Xin Yang","doi":"10.1016/j.bbrc.2025.151396","DOIUrl":"10.1016/j.bbrc.2025.151396","url":null,"abstract":"<div><h3>Background</h3><div><em>Helicobacter pylori</em> (<em>H. pylori</em>) infection promotes gastric cancer (GC) through various mechanisms. It causes inflammation and damage to the gastric mucosa, thereby increasing the risk of developing GC. Sphingolipids can act as signaling molecules that activate or inhibit intracellular signaling pathways, and abnormal sphingolipid metabolism may promote tumorigenesis and metastasis. This study aimed to explore the relationship among sphingosine kinase 2 (SphK2) expression, GC progression, and <em>H. pylori</em> infection.</div></div><div><h3>Methods</h3><div>Expression profile data for SphK2 were extracted from public datasets. Normal human gastric mucosal and GC cells were co-incubated with <em>H. pylori</em>, and SphK2 expression in these cells was detected using western blotting. GC cells with SphK2 overexpression and knockdown were established, and the effects of SphK2 and <em>H. pylori</em> on the proliferation, migration, and invasion abilities of GC cells were verified using CCK-8, EdU, and Transwell assays. The expression of Ras/MEK/ERK pathway-related proteins was detected using western blotting, and the secretion of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in GC cells was detected using ELISA.</div></div><div><h3>Results</h3><div>SphK2 is highly expressed in GC cells and is associated with a poor prognosis. The expression of SphK2 in GC cells is related to <em>H. pylori</em> infection. SphK2 overexpression promotes the proliferation, migration, and invasion of GC cells and enhances the pro-inflammatory effects of <em>H. pylori.</em></div></div><div><h3>Conclusion</h3><div>SphK2 promotes the progression of <em>H. pylori</em>-positive GC by activating the Ras/MEK/ERK pathway.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"751 ","pages":"Article 151396"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143312206","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.bbrc.2025.151387
Chengxiang Fu , Zhaoyuan He , Tian Liu , Yaxiang Luo , Shouli Yi , Xiaoyu Chen , Xiaoge Duan , Jiakang He , Hongcai Chen , Mingsheng Jiang , Hailan Chen
Aptamers, a kind of short nucleotide sequences with high specificity and affinity with targets, have attracted extensive attention in recent years. Molecular docking method (MDM) is the most common method to explore the binding mode and recognition mechanism of aptamers and small molecules, which generally use the target to dock with the highest scoring tertiary structural model of the aptamer, and the highest scoring result is used as the predicted model. However, this prediction results may miss out the true interaction pattern due to the fact that aptamers are not completely rigid and the natural aptamers conformations are not in a single state. Thus, evaluation of the binding pattern from two or more tertiary structural modes might be more accurate. The use of chloramphenicol (CAP) has been banned because it causes myelosuppression and aplastic anemia in humans. However, CAP is still abused and is often studied as a target for detection. Two CAP aptamers (Apt-11 and Apt-16) were used as cases in this study. All secondary structures of these two aptamers were predicted using the UNAFold Web Server tool, and then the corresponding tertiary structure models were built using the RNA Composer tool and Discovery Studio 4.5 Client software. The resulted six tertiary structure models were docked with CAP respectively. By optimizing the docking conditions, multiple groups of docking outcomes were obtained, including the tertiary structure, its binding free energy, and the binding site. The results suggested that there may be multiple binding sites in the same tertiary structure, and the binding energy of the same tertiary structure as well as the proportion of multiple binding sites vary greatly. In addition, it was found that Autodock4 works well in analyzing the binding mode between screened aptamers with its defined target, but cannot be used to identify that whether an aptamer could bind well with other molecule with big structural difference from the target. The CAP aptamer was tailored according to the molecular docking results, and the potential binding sites with CAP were verified by a colloidal gold colorimetry assay. In conclusion, we propose a method to explore the binding patterns between aptamer and its targets by using multiple optimized docking data from different tertiary structures of the aptamer, which provides a theoretical basis for the study of the binding mode of aptamers and targets, as well as the optimization and modification of aptamers.
{"title":"Multi-group structure analysis and molecular docking of aptamers and small molecules: A case study of chloramphenicol","authors":"Chengxiang Fu , Zhaoyuan He , Tian Liu , Yaxiang Luo , Shouli Yi , Xiaoyu Chen , Xiaoge Duan , Jiakang He , Hongcai Chen , Mingsheng Jiang , Hailan Chen","doi":"10.1016/j.bbrc.2025.151387","DOIUrl":"10.1016/j.bbrc.2025.151387","url":null,"abstract":"<div><div>Aptamers, a kind of short nucleotide sequences with high specificity and affinity with targets, have attracted extensive attention in recent years. Molecular docking method (MDM) is the most common method to explore the binding mode and recognition mechanism of aptamers and small molecules, which generally use the target to dock with the highest scoring tertiary structural model of the aptamer, and the highest scoring result is used as the predicted model. However, this prediction results may miss out the true interaction pattern due to the fact that aptamers are not completely rigid and the natural aptamers conformations are not in a single state. Thus, evaluation of the binding pattern from two or more tertiary structural modes might be more accurate. The use of chloramphenicol (CAP) has been banned because it causes myelosuppression and aplastic anemia in humans. However, CAP is still abused and is often studied as a target for detection. Two CAP aptamers (Apt-11 and Apt-16) were used as cases in this study. All secondary structures of these two aptamers were predicted using the UNAFold Web Server tool, and then the corresponding tertiary structure models were built using the RNA Composer tool and Discovery Studio 4.5 Client software. The resulted six tertiary structure models were docked with CAP respectively. By optimizing the docking conditions, multiple groups of docking outcomes were obtained, including the tertiary structure, its binding free energy, and the binding site. The results suggested that there may be multiple binding sites in the same tertiary structure, and the binding energy of the same tertiary structure as well as the proportion of multiple binding sites vary greatly. In addition, it was found that Autodock4 works well in analyzing the binding mode between screened aptamers with its defined target, but cannot be used to identify that whether an aptamer could bind well with other molecule with big structural difference from the target. The CAP aptamer was tailored according to the molecular docking results, and the potential binding sites with CAP were verified by a colloidal gold colorimetry assay. In conclusion, we propose a method to explore the binding patterns between aptamer and its targets by using multiple optimized docking data from different tertiary structures of the aptamer, which provides a theoretical basis for the study of the binding mode of aptamers and targets, as well as the optimization and modification of aptamers.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"750 ","pages":"Article 151387"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063531","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.bbrc.2025.151383
Deepika Dhillon, Monika Jain, Amit Kumar Singh, Jayaraman Muthukumaran
Cancer is the second foremost cause of fatalities associated with non-communicable diseases across the globe, affecting multiple organs and often necessitating costly treatments with adverse side effects. Apoptosis, the body's natural cell death process, plays a crucial role in the prevention of cancer, but it's often disrupted in cancer cells, allowing uncontrolled proliferation. Restoring apoptosis in cancer cells is one of the promising therapeutic strategies to curb tumor growth and enhance clinical outcomes. Bcl-B, an anti-apoptotic protein within the Bcl-2 family, interacts with Bax to mitigate apoptosis, indicating it as a druggable target for cancer therapy. There's a critical need for natural, cost-effective alternatives with minimal adverse effects to reduce morbidity rates of cancer patients. Plant-based immunoprotective medications, particularly from sustainable sources like known medicinal plants, offer substantial potential for cancer treatment. This study involves comprehensive in silico approaches (byte) to evaluate the inhibition potential of the phytochemicals derived from Withania somnifera against the anti-apoptotic Bcl-B protein. Research into Bcl-B's binding affinity with 80 phytochemicals from this plant aims to identify interaction sites for promising anticancer agents. This study's focus on Bcl-B protein highlights its potential in modulating apoptotic pathways and exploring novel anti-cancer therapeutics. Through comprehensive screening based on drug-likeness and pharmacokinetic properties, combined with in-house virtual screening, molecular docking, molecular dynamics simulations, and MM/PBSA-based binding free energy analysis, three promising candidate inhibitors—Withanolide L (IMPHY009438), Withanolide M (IMPHY003143), and Withanolide A (IMPHY000090)—were identified and prioritized. These candidates showed favorable estimated binding free energy values, along with desirable drug-likeness and pharmacokinetic profiles. The results demonstrated that the selected and prioritized phytochemicals, Withanolide L, Withanolide M, and Withanolide A display comparable efficacy to Obatoclax (CID: 11404337) and other known synthetic, semi-synthetic, and natural inhibitors of Bcl-2 family proteins. These findings establish a strong bench foundation for further experimental validation and bedside application, potentially offering an alternative natural approach to cancer therapy.
{"title":"Withania somnifera-derived phytochemicals as Bcl-B inhibitors in cancer therapy: A computational approach from byte to bench to bedside","authors":"Deepika Dhillon, Monika Jain, Amit Kumar Singh, Jayaraman Muthukumaran","doi":"10.1016/j.bbrc.2025.151383","DOIUrl":"10.1016/j.bbrc.2025.151383","url":null,"abstract":"<div><div>Cancer is the second foremost cause of fatalities associated with non-communicable diseases across the globe, affecting multiple organs and often necessitating costly treatments with adverse side effects. Apoptosis, the body's natural cell death process, plays a crucial role in the prevention of cancer, but it's often disrupted in cancer cells, allowing uncontrolled proliferation. Restoring apoptosis in cancer cells is one of the promising therapeutic strategies to curb tumor growth and enhance clinical outcomes. Bcl-B, an anti-apoptotic protein within the Bcl-2 family, interacts with Bax to mitigate apoptosis, indicating it as a druggable target for cancer therapy. There's a critical need for natural, cost-effective alternatives with minimal adverse effects to reduce morbidity rates of cancer patients. Plant-based immunoprotective medications, particularly from sustainable sources like known medicinal plants, offer substantial potential for cancer treatment. This study involves comprehensive <em>in silico</em> approaches (byte) to evaluate the inhibition potential of the phytochemicals derived from <em>Withania somnifera</em> against the anti-apoptotic Bcl-B protein<em>.</em> Research into Bcl-B's binding affinity with 80 phytochemicals from this plant aims to identify interaction sites for promising anticancer agents<em>.</em> This study's focus on Bcl-B protein highlights its potential in modulating apoptotic pathways and exploring novel anti-cancer therapeutics. Through comprehensive screening based on drug-likeness and pharmacokinetic properties, combined with <em>in-house</em> virtual screening, molecular docking, molecular dynamics simulations, and MM/PBSA-based binding free energy analysis, three promising candidate inhibitors—Withanolide L (IMPHY009438), Withanolide M (IMPHY003143), and Withanolide A (IMPHY000090)—were identified and prioritized. These candidates showed favorable estimated binding free energy values, along with desirable drug-likeness and pharmacokinetic profiles. The results demonstrated that the selected and prioritized phytochemicals, Withanolide L, Withanolide M, and Withanolide A display comparable efficacy to Obatoclax (CID: 11404337) and other known synthetic, semi-synthetic, and natural inhibitors of Bcl-2 family proteins. These findings establish a strong bench foundation for further experimental validation and bedside application, potentially offering an alternative natural approach to cancer therapy.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"750 ","pages":"Article 151383"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063535","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.bbrc.2025.151392
Sebastián F. Villar , Gerardo Ferrer-Sueta , Ana Denicola
Human peroxiredoxin 1 and peroxiredoxin 2 (HsPrx1 and HsPrx2), both cytosolic antioxidant enzymes share more than 90% sequence similitude, peroxide substrate specificity, reactivity, and an oligomeric ensemble of five homodimers forming a decamer. However, it is suggested that they serve different purposes in the cell. The question, whether the decamer-dimer equilibrium is relevant to the peroxidase activity and signaling functions has a long-standing history within the field, yet assessing its significance is still a challenge. We have studied the oligomerization dynamics of HsPrx1 and HsPrx2 in their dithiol and disulfide forms to find differences that could provide an explanation for their distinct functions. In this study, we performed analytic size exclusion chromatography (SEC) and fluorescence emission lifetime phasor analysis (FELPA) at different protein concentrations and quantified the relative fraction of the decamer species. We observed that reduced HsPrx2 forms stable decamers that do not fully dissociate, while HsPrx1 exhibits a highly cooperative transition from dimers to decamers with increasing concentration. Disulfide formation at the active site has a larger disruptive effect on the oligomerization equilibrium of HsPrx2 than that of HsPrx1. By performing kinetic measurements using FELPA, we observed that HsPrx2 goes from oxidized dimers to reduced decamers almost 20 times faster than HsPrx1 upon addition of DTT. Lastly, both SEC and FELPA results revealed that the mixture of reduced HsPrx1 and HsPrx2 yields hybrid decamers, that have not been looked for in vivo yet.
{"title":"Different oligomerization dynamics of reduced and oxidized human peroxiredoxin 1 and 2","authors":"Sebastián F. Villar , Gerardo Ferrer-Sueta , Ana Denicola","doi":"10.1016/j.bbrc.2025.151392","DOIUrl":"10.1016/j.bbrc.2025.151392","url":null,"abstract":"<div><div>Human peroxiredoxin 1 and peroxiredoxin 2 (<em>Hs</em>Prx1 and <em>Hs</em>Prx2), both cytosolic antioxidant enzymes share more than 90% sequence similitude, peroxide substrate specificity, reactivity, and an oligomeric ensemble of five homodimers forming a decamer. However, it is suggested that they serve different purposes in the cell. The question, whether the decamer-dimer equilibrium is relevant to the peroxidase activity and signaling functions has a long-standing history within the field, yet assessing its significance is still a challenge. We have studied the oligomerization dynamics of <em>Hs</em>Prx1 and <em>Hs</em>Prx2 in their dithiol and disulfide forms to find differences that could provide an explanation for their distinct functions. In this study, we performed analytic size exclusion chromatography (SEC) and fluorescence emission lifetime phasor analysis (FELPA) at different protein concentrations and quantified the relative fraction of the decamer species. We observed that reduced <em>Hs</em>Prx2 forms stable decamers that do not fully dissociate, while <em>Hs</em>Prx1 exhibits a highly cooperative transition from dimers to decamers with increasing concentration. Disulfide formation at the active site has a larger disruptive effect on the oligomerization equilibrium of <em>Hs</em>Prx2 than that of <em>Hs</em>Prx1. By performing kinetic measurements using FELPA, we observed that <em>Hs</em>Prx2 goes from oxidized dimers to reduced decamers almost 20 times faster than <em>Hs</em>Prx1 upon addition of DTT. Lastly, both SEC and FELPA results revealed that the mixture of reduced <em>Hs</em>Prx1 and <em>Hs</em>Prx2 yields hybrid decamers, that have not been looked for in vivo yet.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"750 ","pages":"Article 151392"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078554","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.bbrc.2025.151330
Sohyeon Kim, Hyun-Jung Kim
Identifying the molecules that control neural stem cell (NSC) fate would revolutionize treatment strategies for neurodegenerative diseases. Histone lysine demethylase 1A (KDM1A) demethylates the mono- and di-methyl groups of histone 3 lysine 4 (H3K4) and H3K9 and plays an essential role in NSC proliferation. In this study, we investigated the effects of Seclidemstat (SP-2577), a reversible KDM1A inhibitor, and tranylcypromine (TCP), a monoamine oxidase inhibitor and recently known as an irreversible histone lysine demethylase 1A inhibitor, on NSCs. SP-2577 and TCP increased glial fibrillary acidic protein expression (GFAP), decreased βIII-tubulin (TUBB3) expression, and phosphorylated signal transducer and activator of transcription 3 (STAT3) in rat NSCs. SP-2577 and TCP enhanced the transcription of Gfap and reduced Tubb3 transcription. Furthermore, SP-2577 increased the transcription levels of interleukin-6 and leukemia inhibitory factor, while TCP induced the transcription level of fibroblast growth factor 2. Therefore, we show that the KDM1A inhibitors, SP-2577 and TCP, induce astrocytogenesis in rat NSCs. These findings suggest that KDM1A is a target for regulating NSCs fate and provide insights into the molecular mechanisms underlying neurodevelopmental processes and epigenetics.
{"title":"Histone lysine demethylase 1A inhibitors, seclidemstat and tranylcypromine, induce astrocytogenesis in rat neural stem cells","authors":"Sohyeon Kim, Hyun-Jung Kim","doi":"10.1016/j.bbrc.2025.151330","DOIUrl":"10.1016/j.bbrc.2025.151330","url":null,"abstract":"<div><div>Identifying the molecules that control neural stem cell (NSC) fate would revolutionize treatment strategies for neurodegenerative diseases. Histone lysine demethylase 1A (KDM1A) demethylates the mono- and di-methyl groups of histone 3 lysine 4 (H3K4) and H3K9 and plays an essential role in NSC proliferation. In this study, we investigated the effects of Seclidemstat (SP-2577), a reversible KDM1A inhibitor, and tranylcypromine (TCP), a monoamine oxidase inhibitor and recently known as an irreversible histone lysine demethylase 1A inhibitor, on NSCs. SP-2577 and TCP increased glial fibrillary acidic protein expression (GFAP), decreased βIII-tubulin (TUBB3) expression, and phosphorylated signal transducer and activator of transcription 3 (STAT3) in rat NSCs. SP-2577 and TCP enhanced the transcription of <em>Gfap</em> and reduced <em>Tubb3</em> transcription. Furthermore, SP-2577 increased the transcription levels of interleukin-6 and leukemia inhibitory factor, while TCP induced the transcription level of fibroblast growth factor 2. Therefore, we show that the KDM1A inhibitors, SP-2577 and TCP, induce astrocytogenesis in rat NSCs. These findings suggest that KDM1A is a target for regulating NSCs fate and provide insights into the molecular mechanisms underlying neurodevelopmental processes and epigenetics.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"750 ","pages":"Article 151330"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121950","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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