Pub Date : 2026-04-23Epub Date: 2026-02-19DOI: 10.1016/j.bbrc.2026.153504
Zelin Pan , Kaili Deng , Zhe Sun
Cytidine triphosphate synthase (CTPS), the rate-limiting enzyme in de novo CTP synthesis, forms filamentous structures known as cytoophidia, which are evolutionarily conserved across species and cell types. These dynamic structures are regulated by cellular metabolic states, stress, and post-translational modifications. Cytoophidia are believed to play a vital role in regulating nucleotide biosynthesis, ensuring cellular homeostasis, and responding to metabolic stress through the modulation of CTPS activity. In cancer cells, where the demand for nucleotides is heightened, cytoophidia may be essential for supporting proliferation and survival. This review delves into the growing understanding of cytoophidia, highlighting their significance in cancer biology and potential as therapeutic targets. Understanding how cytoophidia regulate the balance between CTPS stabilization and degradation could provide valuable insights into cancer metabolism, offering novel therapeutic opportunities. Targeting the mechanisms that govern cytoophidia formation presents a potential strategy for cancer therapy.
{"title":"Cytoophidia: Implications and opportunities for cancer treatment","authors":"Zelin Pan , Kaili Deng , Zhe Sun","doi":"10.1016/j.bbrc.2026.153504","DOIUrl":"10.1016/j.bbrc.2026.153504","url":null,"abstract":"<div><div>Cytidine triphosphate synthase (CTPS), the rate-limiting enzyme in de novo CTP synthesis, forms filamentous structures known as cytoophidia, which are evolutionarily conserved across species and cell types. These dynamic structures are regulated by cellular metabolic states, stress, and post-translational modifications. Cytoophidia are believed to play a vital role in regulating nucleotide biosynthesis, ensuring cellular homeostasis, and responding to metabolic stress through the modulation of CTPS activity. In cancer cells, where the demand for nucleotides is heightened, cytoophidia may be essential for supporting proliferation and survival. This review delves into the growing understanding of cytoophidia, highlighting their significance in cancer biology and potential as therapeutic targets. Understanding how cytoophidia regulate the balance between CTPS stabilization and degradation could provide valuable insights into cancer metabolism, offering novel therapeutic opportunities. Targeting the mechanisms that govern cytoophidia formation presents a potential strategy for cancer therapy.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153504"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316184","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 : 2026-04-23Epub Date: 2026-02-21DOI: 10.1016/j.bbrc.2026.153512
Huiyi Wang , Jing Wu , Zhendong Huang , Zhengkun Yang , Jiayi Ding , Xiaoxuan Wang , Zhengguo Cao
Aims
Given the high prevalence of periodontitis and potential for undetected primary hyperparathyroidism (pHPT) to exacerbate periodontal damage, managing pHPT in advanced periodontitis (stages III/IV) is critical. The causal link between pHPT and periodontitis remains unclear. This study aims to investigate the causal effect and mechanisms between hyperparathyroidism and periodontitis.
Methods
A two-sample Mendelian randomization study used genome-wide association studies (GWAS) summary data to explore the causal link between hyperparathyroidism and periodontitis, employing single nucleotide polymorphisms (SNPs) as instrumental variables and methods like MR-Egger regression and Weighted median for robust results. PTH levels were detected on samples from both healthy and periodontitis-affected gingival tissues and gingival crevicular fluids. We assessed the impact of PTH on periodontal inflammation through treating gingival fibroblasts with PTH and detecting endoplasmic reticulum stress-related markers. Transcriptomics and metabolomics analyses were integrated to explore genetic pathways related to PTH.
Results
Hyperparathyroidism increased the risk of periodontitis, but analyses of periodontitis on hyperparathyroidism showed no reverse causality. PTH levels increased in gingival tissues and gingival crevicular fluid. Multi-omics analysis revealed significant gene and metabolite enrichment in calcium signaling and parathyroid hormone pathways. Since calcium ions are mainly from the endoplasmic reticulum, we focused on endoplasmic reticulum stress and found its effect on lessening PTH-induced periodontal inflammation.
Conclusions
This study suggests that periodontitis may serve as a warning sign for pHPT, highlighting the importance of screening for hyperparathyroidism in periodontitis patients. The principal molecules involved in the endoplasmic reticulum stress pathway present promising therapeutic targets for improving periodontal health in patients with hyperparathyroidism.
{"title":"Hyperparathyroidism drives periodontitis progression via parathyroid hormone-induced endoplasmic reticulum stress","authors":"Huiyi Wang , Jing Wu , Zhendong Huang , Zhengkun Yang , Jiayi Ding , Xiaoxuan Wang , Zhengguo Cao","doi":"10.1016/j.bbrc.2026.153512","DOIUrl":"10.1016/j.bbrc.2026.153512","url":null,"abstract":"<div><h3>Aims</h3><div>Given the high prevalence of periodontitis and potential for undetected primary hyperparathyroidism (pHPT) to exacerbate periodontal damage, managing pHPT in advanced periodontitis (stages III/IV) is critical. The causal link between pHPT and periodontitis remains unclear. This study aims to investigate the causal effect and mechanisms between hyperparathyroidism and periodontitis.</div></div><div><h3>Methods</h3><div>A two-sample Mendelian randomization study used genome-wide association studies (GWAS) summary data to explore the causal link between hyperparathyroidism and periodontitis, employing single nucleotide polymorphisms (SNPs) as instrumental variables and methods like MR-Egger regression and Weighted median for robust results. PTH levels were detected on samples from both healthy and periodontitis-affected gingival tissues and gingival crevicular fluids. We assessed the impact of PTH on periodontal inflammation through treating gingival fibroblasts with PTH and detecting endoplasmic reticulum stress-related markers. Transcriptomics and metabolomics analyses were integrated to explore genetic pathways related to PTH.</div></div><div><h3>Results</h3><div>Hyperparathyroidism increased the risk of periodontitis, but analyses of periodontitis on hyperparathyroidism showed no reverse causality. PTH levels increased in gingival tissues and gingival crevicular fluid. Multi-omics analysis revealed significant gene and metabolite enrichment in calcium signaling and parathyroid hormone pathways. Since calcium ions are mainly from the endoplasmic reticulum, we focused on endoplasmic reticulum stress and found its effect on lessening PTH-induced periodontal inflammation.</div></div><div><h3>Conclusions</h3><div>This study suggests that periodontitis may serve as a warning sign for pHPT, highlighting the importance of screening for hyperparathyroidism in periodontitis patients. The principal molecules involved in the endoplasmic reticulum stress pathway present promising therapeutic targets for improving periodontal health in patients with hyperparathyroidism.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153512"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343500","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 : 2026-04-23Epub Date: 2026-02-24DOI: 10.1016/j.bbrc.2026.153498
Nada H. Hussein , Mahadi Hasan , Renata Akhmetzianova , Hai Yu , Susumu Kohno , Takiko Daikoku , Akira Orimo , Chiaki Takahashi
Cancer associated fibroblasts (CAFs) play pivotal roles in modulating behaviors of tumor cells through various mechanisms. Here we analyzed a pair of fibroblastic cells derived from stromal tissue of breast cancer (BC-CAFs) or corresponding normal mammary microenvironment (NMFs). We found that the reversion-inducing cysteine-rich protein with Kazal motif (RECK) was highly expressed only in NMFs. Conditioned media derived from BC-CAFs enhanced epithelial-mesenchymal transition (EMT) in breast cancer cells significantly stronger than NMFs. Similarly, BC-CAFs induced EMT in co-injected breast cancer cells when xenografted into immune-compromised mice. These activities of BC-CAFs were significantly suppressed by RECK overexpression. BC-CAFs exhibited higher rate of active/latent TGF-β1 and active/pro-MMP-2. Induction of RECK in BC-CAFs significantly antagonized EMT induction with diminished activation of TGF-β1 and pro-MMP-2. Inversely, depletion of RECK in NMFs promoted EMT with enhancement of TGF-β1 and pro-MMP2 activation. BC-CAFs express higher level of histone deacetylase 1/2 (HDAC-1/2). Multiple HDAC inhibitors induced RECK in BC-CAFs with concomitant decrease in TGF-β 1and pro-MMP2 activation and ability to induce EMT. BC-CAFs exhibited higher histone acetylation in the promoter of RECK. These findings suggest that RECK ectopic expression in BC-CAFs suppresses TGF-β1 maturation by inhibiting pro-MMP-2 activation thereby attenuates EMT and that RECK promoter deacetylation occurs in fibroblasts associated with developing breast cancer. HDAC inhibitors may exhibit therapeutic efficacy in breast cancer by inducing RECK in BC-CAFs.
{"title":"RECK attenuates CAF-mediated promotion of epithelial-mesenchymal transition in breast cancer","authors":"Nada H. Hussein , Mahadi Hasan , Renata Akhmetzianova , Hai Yu , Susumu Kohno , Takiko Daikoku , Akira Orimo , Chiaki Takahashi","doi":"10.1016/j.bbrc.2026.153498","DOIUrl":"10.1016/j.bbrc.2026.153498","url":null,"abstract":"<div><div>Cancer associated fibroblasts (CAFs) play pivotal roles in modulating behaviors of tumor cells through various mechanisms. Here we analyzed a pair of fibroblastic cells derived from stromal tissue of breast cancer (BC-CAFs) or corresponding normal mammary microenvironment (NMFs). We found that the reversion-inducing cysteine-rich protein with Kazal motif (RECK) was highly expressed only in NMFs. Conditioned media derived from BC-CAFs enhanced epithelial-mesenchymal transition (EMT) in breast cancer cells significantly stronger than NMFs. Similarly, BC-CAFs induced EMT in co-injected breast cancer cells when xenografted into immune-compromised mice. These activities of BC-CAFs were significantly suppressed by RECK overexpression. BC-CAFs exhibited higher rate of active/latent TGF-β1 and active/pro-MMP-2. Induction of RECK in BC-CAFs significantly antagonized EMT induction with diminished activation of TGF-β1 and pro-MMP-2. Inversely, depletion of RECK in NMFs promoted EMT with enhancement of TGF-β1 and pro-MMP2 activation. BC-CAFs express higher level of histone deacetylase 1/2 (HDAC-1/2). Multiple HDAC inhibitors induced RECK in BC-CAFs with concomitant decrease in TGF-β 1and pro-MMP2 activation and ability to induce EMT. BC-CAFs exhibited higher histone acetylation in the promoter of RECK. These findings suggest that RECK ectopic expression in BC-CAFs suppresses TGF-β1 maturation by inhibiting pro-MMP-2 activation thereby attenuates EMT and that RECK promoter deacetylation occurs in fibroblasts associated with developing breast cancer. HDAC inhibitors may exhibit therapeutic efficacy in breast cancer by inducing RECK in BC-CAFs.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153498"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347132","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 : 2026-04-23Epub Date: 2026-02-26DOI: 10.1016/j.bbrc.2026.153537
Roman Dekhtiarenko , Katarina Polcicova , Zuzana Sevcikova Tomaskova
Cardiac arrhythmias rank among the leading causes of death worldwide. They frequently develop during ischemia/reperfusion, when fluctuations in oxygen and nutrient supply occur. Reperfusion can elevate levels of oxygen radicals, and both metabolic and oxidative stress have been shown to trigger arrhythmias by inducing cyclic changes in mitochondrial membrane potential. These fluctuations are mediated by chloride channels believed to correspond to the CLIC5 isoform of intracellular chloride channels. The cardioprotective effects have been observed following administration of 4-chlorodiazepam (4Cl-DZP), a specific ligand of the mitochondrial translocator protein TSPO, as well as after treatment with a non-specific anion channel inhibitor. Although 4Cl-DZP is thought to influence chloride channel activity indirectly through TSPO, the details of this interaction remain unclear. CLIC5 has been localized to the inner mitochondrial membrane. Based on the comparison of single-channel properties, it may represent a candidate for the molecular identity of the centum-pS channel. The potential physical association between CLIC5 and TSPO was investigated. To assess the spatial proximity of CLIC5 and TSPO, we performed Förster resonance energy transfer (FRET) measurements in immunolabeled cardiomyoblasts using acceptor photobleaching configuration. The observed FRET efficiency between CLIC5 and TSPO was 24%, comparable to the 28% efficiency measured in the positive control and substantially higher than the 7% efficiency observed in the negative control. These findings support the hypothesis that, if CLIC5 indeed constitutes the centum-pS channel, TSPO is positioned in sufficiently close proximity to modulate its activity.
{"title":"Translocator protein in touch with mitochondrial chloride intracellular channel CLIC5","authors":"Roman Dekhtiarenko , Katarina Polcicova , Zuzana Sevcikova Tomaskova","doi":"10.1016/j.bbrc.2026.153537","DOIUrl":"10.1016/j.bbrc.2026.153537","url":null,"abstract":"<div><div>Cardiac arrhythmias rank among the leading causes of death worldwide. They frequently develop during ischemia/reperfusion, when fluctuations in oxygen and nutrient supply occur. Reperfusion can elevate levels of oxygen radicals, and both metabolic and oxidative stress have been shown to trigger arrhythmias by inducing cyclic changes in mitochondrial membrane potential. These fluctuations are mediated by chloride channels believed to correspond to the CLIC5 isoform of intracellular chloride channels. The cardioprotective effects have been observed following administration of 4-chlorodiazepam (4Cl-DZP), a specific ligand of the mitochondrial translocator protein TSPO, as well as after treatment with a non-specific anion channel inhibitor. Although 4Cl-DZP is thought to influence chloride channel activity indirectly through TSPO, the details of this interaction remain unclear. CLIC5 has been localized to the inner mitochondrial membrane. Based on the comparison of single-channel properties, it may represent a candidate for the molecular identity of the centum-pS channel. The potential physical association between CLIC5 and TSPO was investigated. To assess the spatial proximity of CLIC5 and TSPO, we performed Förster resonance energy transfer (FRET) measurements in immunolabeled cardiomyoblasts using acceptor photobleaching configuration. The observed FRET efficiency between CLIC5 and TSPO was 24%, comparable to the 28% efficiency measured in the positive control and substantially higher than the 7% efficiency observed in the negative control. These findings support the hypothesis that, if CLIC5 indeed constitutes the centum-pS channel, TSPO is positioned in sufficiently close proximity to modulate its activity.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153537"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324084","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 : 2026-04-23Epub Date: 2026-02-20DOI: 10.1016/j.bbrc.2026.153459
Koh-ei Toyoshima , Ayako Tsuchiya , Miho Ogawa , Miki Takase , Tarou Irié , Masayuki Yanagisawa , Richard H. Kaszynski , Hiroshi Fujimaki , Kyoko Baba , Takayuki Sugimoto , Akira Takeda , Akio Sato , Takashi Tsuji
Organ morphogenesis is essential for not only integrated organ functions in the body but also the determination of adult-tissue stem cells and their niche. Only hair follicle organs can cyclically regenerate in the variable bulbous germinative region as a form of programmed organ regeneration in adults. Here, we identified a cell population, hair follicle organ-intrinsic mesenchymal cells, with PDGFRα+/Sca1+/CD34high+ mesenchymal cells, from the boundary zone of the epithelial stem cell niche by using the organ germ method, which plays essential roles in entering and promoting the downgrowth phase of the hair cycle. The bioengineered hair follicle germ reconstituted from bulge region-derived epithelial stem cells, dermal papillae and mesenchymal cells has full functions, including downgrowth, full-size hair follicle regeneration and the hair cycle, both in in vitro artificial skin and after intracutaneous skin transplantation. This study provides significant contributions to the basic and medical science of adult organ-inductive potential stem cells and their niches in organ morphogenesis and the adult hair cycle.
{"title":"Fully functional hair follicle organ regeneration using organ-inductive potential stem cells with an accessory mesenchymal cell population in an in vitro culture system","authors":"Koh-ei Toyoshima , Ayako Tsuchiya , Miho Ogawa , Miki Takase , Tarou Irié , Masayuki Yanagisawa , Richard H. Kaszynski , Hiroshi Fujimaki , Kyoko Baba , Takayuki Sugimoto , Akira Takeda , Akio Sato , Takashi Tsuji","doi":"10.1016/j.bbrc.2026.153459","DOIUrl":"10.1016/j.bbrc.2026.153459","url":null,"abstract":"<div><div>Organ morphogenesis is essential for not only integrated organ functions in the body but also the determination of adult-tissue stem cells and their niche. Only hair follicle organs can cyclically regenerate in the variable bulbous germinative region as a form of programmed organ regeneration in adults. Here, we identified a cell population, hair follicle organ-intrinsic mesenchymal cells, with PDGFRα<sup>+</sup>/Sca1<sup>+</sup>/CD34<sup>high+</sup> mesenchymal cells, from the boundary zone of the epithelial stem cell niche by using the organ germ method, which plays essential roles in entering and promoting the downgrowth phase of the hair cycle. The bioengineered hair follicle germ reconstituted from bulge region-derived epithelial stem cells, dermal papillae and mesenchymal cells has full functions, including downgrowth, full-size hair follicle regeneration and the hair cycle, both in <em>in vitro</em> artificial skin and after intracutaneous skin transplantation. This study provides significant contributions to the basic and medical science of adult organ-inductive potential stem cells and their niches in organ morphogenesis and the adult hair cycle.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153459"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321250","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 : 2026-04-23Epub Date: 2026-02-17DOI: 10.1016/j.bbrc.2026.153490
Jiping Huang , Shaomei Zhao , Jining Huang , Guocheng Yu , Lian Liu
Purpose
This study aimed to investigate the protective effect of epalrestat (EPS) and the molecular mechanisms that underlie its treatment of retinal excitotoxicity.
Methods
The corresponding targets of drug and disease were obtained from relevant databases, respectively. By constructing and analyzing connected networks, the targets, primary molecular function, biological processes, and signaling pathways associated with EPS were found. The binding affinity between EPS and potential targets was confirmed by molecular docking. Establishing an excitotoxicity model with glutamate to further evaluate network pharmacology results by gathering samples from R28 cells and measuring inflammatory factor levels, cell viability, oxidative stress indicators, and Nrf2/HO-1 signaling pathway expression.
Results
138 targets, including the NFE2L2 and HMOX1 that encode HO-1 and Nrf2, were shown to overlap between drug and disease by network pharmacology analysis. Molecular docking results revealed that EPS exerts therapeutic effects through multiple targets like Nrf2 and HO-1. In vitro experiments have shown that EPS reversed the effects of glutamate-induced apoptosis, which included a decrease in superoxide dismutase (SOD) and an increase in intracellular reactive oxygen species (ROS), malondialdehyde (MDA), TNF-α, IL-1β, and IL-6, by regulating the Nrf2/HO-1 signaling. Furthermore, by reducing glutamate-induced cell damage, the Nrf2 inhibitor ML385 further supports the important roles of Nrf2/HO-1 signaling in R28 cell antioxidant and anti-inflammatory responses.
Conclusions
EPS inhibits retinal excitotoxicity by acting as an antioxidant and anti-inflammatory through the Nrf2/HO-1 signaling pathway. EPS may have some clinical benefits in reducing retinal excitotoxicity-related retinopathy.
{"title":"Protection mechanism of epalrestat on glutamate-induced retinal excitotoxicity model based on network pharmacology","authors":"Jiping Huang , Shaomei Zhao , Jining Huang , Guocheng Yu , Lian Liu","doi":"10.1016/j.bbrc.2026.153490","DOIUrl":"10.1016/j.bbrc.2026.153490","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to investigate the protective effect of epalrestat (EPS) and the molecular mechanisms that underlie its treatment of retinal excitotoxicity.</div></div><div><h3>Methods</h3><div>The corresponding targets of drug and disease were obtained from relevant databases, respectively. By constructing and analyzing connected networks, the targets, primary molecular function, biological processes, and signaling pathways associated with EPS were found. The binding affinity between EPS and potential targets was confirmed by molecular docking. Establishing an excitotoxicity model with glutamate to further evaluate network pharmacology results by gathering samples from R28 cells and measuring inflammatory factor levels, cell viability, oxidative stress indicators, and Nrf2/HO-1 signaling pathway expression.</div></div><div><h3>Results</h3><div>138 targets, including the NFE2L2 and HMOX1 that encode HO-1 and Nrf2, were shown to overlap between drug and disease by network pharmacology analysis. Molecular docking results revealed that EPS exerts therapeutic effects through multiple targets like Nrf2 and HO-1. In vitro experiments have shown that EPS reversed the effects of glutamate-induced apoptosis, which included a decrease in superoxide dismutase (SOD) and an increase in intracellular reactive oxygen species (ROS), malondialdehyde (MDA), TNF-α, IL-1β, and IL-6, by regulating the Nrf2/HO-1 signaling. Furthermore, by reducing glutamate-induced cell damage, the Nrf2 inhibitor ML385 further supports the important roles of Nrf2/HO-1 signaling in R28 cell antioxidant and anti-inflammatory responses.</div></div><div><h3>Conclusions</h3><div>EPS inhibits retinal excitotoxicity by acting as an antioxidant and anti-inflammatory through the Nrf2/HO-1 signaling pathway. EPS may have some clinical benefits in reducing retinal excitotoxicity-related retinopathy.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153490"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347096","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}
Triple-negative breast cancer (TNBC) represents one of the most aggressive breast cancer subtypes, lacking effective targeted therapies and relying primarily on chemotherapy. In this study, we investigated the cytotoxic and molecular effects of doxorubicin (DOX) and methyl divanillate (DMV), alone or in combination, in three-dimensional spheroid models derived from MDA-MB-231 (claudin-low) and HCC70 (basal-like) TNBC cell lines. Combined DOX/DMV treatment significantly reduced spheroid viability and was associated with increased reactive oxygen species (ROS) accumulation and thiol depletion, thereby indicating redox imbalance and cytoskeletal disruption. Immunofluorescence further confirmed actin filament disorganization and nuclear instability under combined therapy. Integrated qPCR and proteomic analyses revealed lineage-dependent modulation of apoptotic signaling in MDA-MB-231 spheroids, DOX/DMV broadly suppressed apoptosis-associated proteins, whereas in HCC70 spheroids, the combination upregulated key intrinsic apoptotic regulators, including caspases and mitochondrial stress-related proteins. Furthermore, gene expression analysis, gelatin zymography, and proteomic profiling demonstrated that DOX and DMV modulated metalloproteinase (MMP) activity and cytoskeletal remodeling, with combination therapy promoting MMP9 suppression and widespread downregulation of actin cytoskeleton regulators in MDA-MB-231 spheroids, while inducing cytoskeletal reinforcement–associated profiles in HCC70 spheroids. Transgelin-2 expression also exhibited divergent patterns between the cell lines at both transcript and protein levels. Collectively, our findings indicate that DOX/DMV combination therapy exerts synergistic interaction, as determined by Combination Index analysis (CI = 0.3 for MDA-MB-231 spheroids and CI = 0.8 for HCC70 spheroids), resulting in enhanced cytotoxicity associated with oxidative stress, apoptotic pathway modulation, and cytoskeletal remodeling in a subtype-dependent manner. These results underscore the potential of DMV as a redox-modulating adjuvant to enhance chemotherapy efficacy in TNBC, while highlighting the importance of tumor subtype context in determining therapeutic responses.
{"title":"Methyl divanillate enhances doxorubicin efficacy in TNBC cell lines through redox imbalance and apoptotic reprogramming","authors":"Adriano de Souza Pessoa , Flávia Godoy Iano , Mariana Liessa Rovis Sanches , Emanuelle Pangoni de Carvalho , Ana Lígia Pagnan , Larissa Tercília Grizzo Thomassian , Talita Mendes Oliveira Ventura , Marília Afonso Rabelo Buzalaf , Valdecir Farias Ximenes , Rodrigo Cardoso de Oliveira","doi":"10.1016/j.bbrc.2026.153532","DOIUrl":"10.1016/j.bbrc.2026.153532","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) represents one of the most aggressive breast cancer subtypes, lacking effective targeted therapies and relying primarily on chemotherapy. In this study, we investigated the cytotoxic and molecular effects of doxorubicin (DOX) and methyl divanillate (DMV), alone or in combination, in three-dimensional spheroid models derived from MDA-MB-231 (claudin-low) and HCC70 (basal-like) TNBC cell lines. Combined DOX/DMV treatment significantly reduced spheroid viability and was associated with increased reactive oxygen species (ROS) accumulation and thiol depletion, thereby indicating redox imbalance and cytoskeletal disruption. Immunofluorescence further confirmed actin filament disorganization and nuclear instability under combined therapy. Integrated qPCR and proteomic analyses revealed lineage-dependent modulation of apoptotic signaling in MDA-MB-231 spheroids, DOX/DMV broadly suppressed apoptosis-associated proteins, whereas in HCC70 spheroids, the combination upregulated key intrinsic apoptotic regulators, including caspases and mitochondrial stress-related proteins. Furthermore, gene expression analysis, gelatin zymography, and proteomic profiling demonstrated that DOX and DMV modulated metalloproteinase (MMP) activity and cytoskeletal remodeling, with combination therapy promoting MMP9 suppression and widespread downregulation of actin cytoskeleton regulators in MDA-MB-231 spheroids, while inducing cytoskeletal reinforcement–associated profiles in HCC70 spheroids. Transgelin-2 expression also exhibited divergent patterns between the cell lines at both transcript and protein levels. Collectively, our findings indicate that DOX/DMV combination therapy exerts synergistic interaction, as determined by Combination Index analysis (CI = 0.3 for MDA-MB-231 spheroids and CI = 0.8 for HCC70 spheroids), resulting in enhanced cytotoxicity associated with oxidative stress, apoptotic pathway modulation, and cytoskeletal remodeling in a subtype-dependent manner. These results underscore the potential of DMV as a redox-modulating adjuvant to enhance chemotherapy efficacy in TNBC, while highlighting the importance of tumor subtype context in determining therapeutic responses.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153532"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347098","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 : 2026-04-23Epub Date: 2026-02-26DOI: 10.1016/j.bbrc.2026.153531
Xiao Luan , Yang Liu , Xiaoqian Zhang , Xiangrong Sun , Feifei Guo , Mi Wang
Aims
Obesity is associated with binge eating and abnormal activation of the reward pathway. Hypothalamic neuropeptides such as orexin-A and μ-opioid receptor signaling are closely involved in feeding behavior and reward processing; however, the interaction between orexin-A and μ-opioid receptor signaling in palatable food seeking remains unclear.
Materials and methods
We used fluorogold retrograde tracing to examine neural projection between the perifornical region (PeF) and the ventral tegmental area (VTA). Immunohistochemical staining was performed to assess the distribution of orexin-A receptor 1 (OX1-R) and tyrosine hydroxylase (TH) neurons in the VTA. Subsequently, drugs were administered into the VTA to investigate the interactions between orexin-A and μ-opioid receptor antagonist naltrexone (NTX) in regulating palatable food seeking and the firing frequency of VTA dopamine (DA) neurons.
Key findings
Fluorogold-labeled orexin-A neurons were observed in the PeF, and co-localization of OX1R and TH neurons was detected in the VTA. Furthermore, electrical stimulation (ES) of the PeF or administration of orexin-A into the VTA increased the expression of c-Fos in TH-positive neurons, providing an anatomical basis for this study. Microinjection of orexin-A into the VTA promoted palatable food seeking in rats, an effect that was completely blocked by pre-administration of the OX1R antagonist SB-334867. In addition, orexin-A and NTX were found to modulate the firing frequency of VTA DA neurons, suggesting that orexin-A and μ-opioid receptor signaling may regulate palatable food seeking through their actions on VTA DA neurons.
Significance
This study sheds light on the interaction between orexin-A and the μ-opioid system in regulating palatable food seeking and the firing frequency of VTA DA neurons.
{"title":"Orexin-A signaling modulates dopamine neurons and palatable food seeking: potential involvement of μ-opioid receptor signaling pathway","authors":"Xiao Luan , Yang Liu , Xiaoqian Zhang , Xiangrong Sun , Feifei Guo , Mi Wang","doi":"10.1016/j.bbrc.2026.153531","DOIUrl":"10.1016/j.bbrc.2026.153531","url":null,"abstract":"<div><h3>Aims</h3><div>Obesity is associated with binge eating and abnormal activation of the reward pathway. Hypothalamic neuropeptides such as orexin-A and μ-opioid receptor signaling are closely involved in feeding behavior and reward processing; however, the interaction between orexin-A and μ-opioid receptor signaling in palatable food seeking remains unclear.</div></div><div><h3>Materials and methods</h3><div>We used fluorogold retrograde tracing to examine neural projection between the perifornical region (PeF) and the ventral tegmental area (VTA). Immunohistochemical staining was performed to assess the distribution of orexin-A receptor 1 (OX1-R) and tyrosine hydroxylase (TH) neurons in the VTA. Subsequently, drugs were administered into the VTA to investigate the interactions between orexin-A and μ-opioid receptor antagonist naltrexone (NTX) in regulating palatable food seeking and the firing frequency of VTA dopamine (DA) neurons.</div></div><div><h3>Key findings</h3><div>Fluorogold-labeled orexin-A neurons were observed in the PeF, and co-localization of OX1R and TH neurons was detected in the VTA. Furthermore, electrical stimulation (ES) of the PeF or administration of orexin-A into the VTA increased the expression of c-Fos in TH-positive neurons, providing an anatomical basis for this study. Microinjection of orexin-A into the VTA promoted palatable food seeking in rats, an effect that was completely blocked by pre-administration of the OX1R antagonist SB-334867. In addition, orexin-A and NTX were found to modulate the firing frequency of VTA DA neurons, suggesting that orexin-A and μ-opioid receptor signaling may regulate palatable food seeking through their actions on VTA DA neurons.</div></div><div><h3>Significance</h3><div>This study sheds light on the interaction between orexin-A and the μ-opioid system in regulating palatable food seeking and the firing frequency of VTA DA neurons.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153531"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321255","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}
The tumor microenvironment (TME) exerts a pivotal influence on malignant phenotypes, including invasion, metastasis, immune evasion, and therapeutic resistance, thereby dictating clinical outcomes and patient prognosis. Consequently, a comprehensive elucidation of TME dynamics is of paramount importance. To address this, the development of in vitro tumor models capable of faithfully recapitulating its inherent complexity is indispensable. In this study, we engineered millimeter-scale, high-density 3D tumor constructs that recapitulate the intricate architectural and functional hallmarks of the in vivo TME. Within this biomimetic platform, reciprocal crosstalk with cancer cells induced the differentiation of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). Furthermore, we successfully modeled divergent immunophenotypes, characterized as "hot" and "cold" tumors, and integrated a hierarchical vascular network comprising venous and capillary-like structures. Collectively, this construct accurately mirrors the in vivo TME, providing a robust platform for modeling complex tumor ecosystems and offering substantial potential to catalyze advancements in cancer research and drug discovery.
{"title":"Millimeter-scale, high-density three-dimensional constructs recapitulate hot and cold tumor microenvironment","authors":"Kazuki Yokota, Nobutaka Yasuma, Peizheng Wu, Masataka Hakamada, Mamoru Mabuchi","doi":"10.1016/j.bbrc.2026.153527","DOIUrl":"10.1016/j.bbrc.2026.153527","url":null,"abstract":"<div><div>The tumor microenvironment (TME) exerts a pivotal influence on malignant phenotypes, including invasion, metastasis, immune evasion, and therapeutic resistance, thereby dictating clinical outcomes and patient prognosis. Consequently, a comprehensive elucidation of TME dynamics is of paramount importance. To address this, the development of in vitro tumor models capable of faithfully recapitulating its inherent complexity is indispensable. In this study, we engineered millimeter-scale, high-density 3D tumor constructs that recapitulate the intricate architectural and functional hallmarks of the in vivo TME. Within this biomimetic platform, reciprocal crosstalk with cancer cells induced the differentiation of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). Furthermore, we successfully modeled divergent immunophenotypes, characterized as \"hot\" and \"cold\" tumors, and integrated a hierarchical vascular network comprising venous and capillary-like structures. Collectively, this construct accurately mirrors the in vivo TME, providing a robust platform for modeling complex tumor ecosystems and offering substantial potential to catalyze advancements in cancer research and drug discovery.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153527"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316259","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 : 2026-04-23Epub Date: 2026-02-27DOI: 10.1016/j.bbrc.2026.153457
Jungao Zhu , Xiaoqin Huang , Chuanchuan Li , Weixian Liu , Xiaoqing Zhong
Osteoporosis is a highly prevalent metabolic bone disorder characterized by an imbalance in bone remodeling, primarily due to excessive osteoclast-mediated bone resorption. The present study systematically investigates the protective effects of genistein, a naturally occurring soy isoflavone, against osteoporosis by targeting osteoclast differentiation and autophagy, as well we the underlying mechanism. Using RANKL-stimulated RAW264.7 cells as an in vitro model, we found that genistein treatment significantly and dose-dependently inhibited osteoclast formation and autophagic activity, which was evidenced by reduced tartrate-resistant acid phosphatase (TRAP) activity, fewer autophagic vacuoles observed under transmission electron microscopy, decreased protein levels of LC3-II/I and Beclin1, and increased expression of p62. Mechanistic studies revealed that genistein upregulates the deubiquitinase CYLD, which stabilizes p62 through deubiquitylation, leading to inhibition of the RANKL signaling pathway. Importantly, the anti-osteoclastogenic effects of genistein were markedly attenuated upon CYLD or p62 knockdown or upon induction of autophagy with rapamycin. In an ovariectomized (OVX) rat model of postmenopausal osteoporosis, genistein administration (5 or 10 mg/kg/day) effectively ameliorated bone loss, as confirmed by micro-CT analyses showing improvements in bone mineral density (BMD), bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular separation (Tb.Sp). Consistent with in vitro findings, genistein reduced osteoclast numbers and modulated autophagy markers in femoral tissues. Collectively, these results demonstrate that genistein mitigates osteoporosis by suppressing osteoclast differentiation and autophagy through regulating the CYLD/p62/RANKL axis, highlighting its promising potential as a natural therapeutic agent for osteoporosis treatment.
{"title":"Genistein alleviates Osteoporosis by inhibiting the differentiation and autophagy of osteoclasts via regulating the CYLD/p62/RANKL axis","authors":"Jungao Zhu , Xiaoqin Huang , Chuanchuan Li , Weixian Liu , Xiaoqing Zhong","doi":"10.1016/j.bbrc.2026.153457","DOIUrl":"10.1016/j.bbrc.2026.153457","url":null,"abstract":"<div><div>Osteoporosis is a highly prevalent metabolic bone disorder characterized by an imbalance in bone remodeling, primarily due to excessive osteoclast-mediated bone resorption. The present study systematically investigates the protective effects of genistein, a naturally occurring soy isoflavone, against osteoporosis by targeting osteoclast differentiation and autophagy, as well we the underlying mechanism. Using RANKL-stimulated RAW264.7 cells as an in vitro model, we found that genistein treatment significantly and dose-dependently inhibited osteoclast formation and autophagic activity, which was evidenced by reduced tartrate-resistant acid phosphatase (TRAP) activity, fewer autophagic vacuoles observed under transmission electron microscopy, decreased protein levels of LC3-II/I and Beclin1, and increased expression of p62. Mechanistic studies revealed that genistein upregulates the deubiquitinase CYLD, which stabilizes p62 through deubiquitylation, leading to inhibition of the RANKL signaling pathway. Importantly, the anti-osteoclastogenic effects of genistein were markedly attenuated upon CYLD or p62 knockdown or upon induction of autophagy with rapamycin. In an ovariectomized (OVX) rat model of postmenopausal osteoporosis, genistein administration (5 or 10 mg/kg/day) effectively ameliorated bone loss, as confirmed by micro-CT analyses showing improvements in bone mineral density (BMD), bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular separation (Tb.Sp). Consistent with in vitro findings, genistein reduced osteoclast numbers and modulated autophagy markers in femoral tissues. Collectively, these results demonstrate that genistein mitigates osteoporosis by suppressing osteoclast differentiation and autophagy through regulating the CYLD/p62/RANKL axis, highlighting its promising potential as a natural therapeutic agent for osteoporosis treatment.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"810 ","pages":"Article 153457"},"PeriodicalIF":2.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324611","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号