Melaleuca alternifolia (Australian tea tree) sits at a rare intersection of ethnomedicine and modern pharmacology. Rooted in Bundjalung Aboriginal practice for respiratory, dermatologic, and wound care, its essential oil (TTO) has since been validated as a multi-target agent. We synthesize advances spanning cultivation ecology, chemistry, mechanisms, and translation. Chemotyped oils (ISO 4730) are dominated by terpinen-4-ol-supported by γ-/α-terpinene, 1,8-cineole, and selected sesquiterpenes-whose coordinated actions destabilize microbial membranes, impair energy metabolism, modulate redox and inflammatory pathways (PPAR-γ, Nrf2-ARE), and, in cancer models, trigger mitochondrial apoptosis and autophagy. Across pathogens, TTO displays antibacterial, antifungal, antiviral, and antiparasitic activity, including effects on drug-resistant biofilms and ectoparasites (e.g., Demodex, scabies, head lice). Inflammation and oxidative stress are dampened via NF-κB/MAPK restraint and antioxidant support, aligning with clinical signals in dermatology and wound care. Crucially, nanotechnology (nanoemulsions/nanoemulgels, chitosan-alginate hydrogels, lipid nanocarriers, electrospun fibers) converts volatile, irritancy-prone oil into a controllable payload with improved stability, targeted release, and safety, while enabling co-delivery with standard drugs for dose-sparing synergy. Remaining gaps include chemotype standardization, exposure-response definition at target sites, and adequately powered, indication-specific trials with patient-centered endpoints. We outline priorities for quality control, rational combinations, and engineered delivery, and note how data-driven tools (e.g., composition-activity modeling) can accelerate optimization. Altogether, TTO exemplifies how cultural knowledge, ecological stewardship, and formulation science can converge to yield a next-generation phytotherapeutic for anti-infective, wound, dermatologic, and emerging anticancer applications.
{"title":"Phytochemistry and pharmacology of Melaleuca alternifolia: Bridging aboriginal heritage with contemporary science.","authors":"Nader Ebrahimi, Hadiseh Shokouhi, Marzieh Omrani, Maryam Manzari Tavakoli, Andia Vojdani, Christine Carson, Parvaneh Mehrbod, Saeid Ghavami","doi":"10.1016/j.bbagen.2026.130917","DOIUrl":"https://doi.org/10.1016/j.bbagen.2026.130917","url":null,"abstract":"<p><p>Melaleuca alternifolia (Australian tea tree) sits at a rare intersection of ethnomedicine and modern pharmacology. Rooted in Bundjalung Aboriginal practice for respiratory, dermatologic, and wound care, its essential oil (TTO) has since been validated as a multi-target agent. We synthesize advances spanning cultivation ecology, chemistry, mechanisms, and translation. Chemotyped oils (ISO 4730) are dominated by terpinen-4-ol-supported by γ-/α-terpinene, 1,8-cineole, and selected sesquiterpenes-whose coordinated actions destabilize microbial membranes, impair energy metabolism, modulate redox and inflammatory pathways (PPAR-γ, Nrf2-ARE), and, in cancer models, trigger mitochondrial apoptosis and autophagy. Across pathogens, TTO displays antibacterial, antifungal, antiviral, and antiparasitic activity, including effects on drug-resistant biofilms and ectoparasites (e.g., Demodex, scabies, head lice). Inflammation and oxidative stress are dampened via NF-κB/MAPK restraint and antioxidant support, aligning with clinical signals in dermatology and wound care. Crucially, nanotechnology (nanoemulsions/nanoemulgels, chitosan-alginate hydrogels, lipid nanocarriers, electrospun fibers) converts volatile, irritancy-prone oil into a controllable payload with improved stability, targeted release, and safety, while enabling co-delivery with standard drugs for dose-sparing synergy. Remaining gaps include chemotype standardization, exposure-response definition at target sites, and adequately powered, indication-specific trials with patient-centered endpoints. We outline priorities for quality control, rational combinations, and engineered delivery, and note how data-driven tools (e.g., composition-activity modeling) can accelerate optimization. Altogether, TTO exemplifies how cultural knowledge, ecological stewardship, and formulation science can converge to yield a next-generation phytotherapeutic for anti-infective, wound, dermatologic, and emerging anticancer applications.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130917"},"PeriodicalIF":2.2,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In developing vertebrates, nutrient uptake by specialized epithelial cells is primarily mediated by endocytosis, a process driven by dynamic phosphoinositide remodeling that regulates vesicle formation and endosomal maturation. Voltage-sensing phosphatase (VSP), a unique membrane protein that couples changes in membrane potential to phosphoinositide hydrolysis, is expressed in zebrafish lysosome-rich enterocytes (LREs), which mediate endocytosis-dependent nutrient absorption during development. However, the molecular mechanisms by which zebrafish VSP (Dr-VSP) regulates endocytic membrane trafficking remain unclear. Here, we elucidate by confocal imaging that Dr-VSP localizes to subapical endomembranes and dynamically redistributes to the apical plasma membrane during nutrient uptake, where it promotes early vesicle formation and maintains proper endolysosomal organization. Loss of Dr-VSP reduces early endocytic vesicles and disrupts downstream recycling and lysosomal compartments, leading to defective nutrient absorption. Electrophysiological analyses showed that extracellular or luminal acidic pH suppresses Dr-VSP voltage sensing, consistent with its activity being confined to the apical plasma membrane where voltage, pH, and phosphoinositide conditions are favorable for activation. These findings indicate that Dr-VSP acts as a voltage- and pH-regulated phosphoinositide phosphatase during the early phase of endocytosis at the plasma membrane, preceding lysosomal digestion. This work defines a functional role for VSPs in epithelial nutrient uptake in vertebrate enterocytes and points to a novel electrochemical mechanism underlying membrane trafficking in vertebrates.
{"title":"Spatiotemporal regulation of endocytic membrane trafficking by voltage-sensing phosphatase (VSP) in zebrafish enterocytes.","authors":"Adisorn Ratanayotha, Natsuki Mizutani, Fumiko Takenaga, Takafumi Kawai, Yasushi Okamura","doi":"10.1016/j.bbagen.2026.130916","DOIUrl":"https://doi.org/10.1016/j.bbagen.2026.130916","url":null,"abstract":"<p><p>In developing vertebrates, nutrient uptake by specialized epithelial cells is primarily mediated by endocytosis, a process driven by dynamic phosphoinositide remodeling that regulates vesicle formation and endosomal maturation. Voltage-sensing phosphatase (VSP), a unique membrane protein that couples changes in membrane potential to phosphoinositide hydrolysis, is expressed in zebrafish lysosome-rich enterocytes (LREs), which mediate endocytosis-dependent nutrient absorption during development. However, the molecular mechanisms by which zebrafish VSP (Dr-VSP) regulates endocytic membrane trafficking remain unclear. Here, we elucidate by confocal imaging that Dr-VSP localizes to subapical endomembranes and dynamically redistributes to the apical plasma membrane during nutrient uptake, where it promotes early vesicle formation and maintains proper endolysosomal organization. Loss of Dr-VSP reduces early endocytic vesicles and disrupts downstream recycling and lysosomal compartments, leading to defective nutrient absorption. Electrophysiological analyses showed that extracellular or luminal acidic pH suppresses Dr-VSP voltage sensing, consistent with its activity being confined to the apical plasma membrane where voltage, pH, and phosphoinositide conditions are favorable for activation. These findings indicate that Dr-VSP acts as a voltage- and pH-regulated phosphoinositide phosphatase during the early phase of endocytosis at the plasma membrane, preceding lysosomal digestion. This work defines a functional role for VSPs in epithelial nutrient uptake in vertebrate enterocytes and points to a novel electrochemical mechanism underlying membrane trafficking in vertebrates.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130916"},"PeriodicalIF":2.2,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163870","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 : 2026-02-09DOI: 10.1016/j.bbagen.2026.130915
Steven J Karpowicz
Persulfide and hydrogen sulfide chemistry is relevant to the prevention of cellular oxidative damage. Thiotaurine is a poorly-studied precursor to the abundant biological molecule taurine and contains a labile sulfane sulfur. Here, reversible reactions of thiotaurine with glutathione or cysteine were investigated to observe formation of persulfides and hydrogen sulfide gas. Raman, Visible, and NMR spectroscopy were employed to characterize the reaction products and observe reaction kinetics. The reactions were verified through a kinetic competition experiment involving hydrogen peroxide. Data and kinetic models indicate initial transfer of the sulfane sulfur from thiotaurine to a free sulfide, followed by formation of disulfides and release of H2S gas. The findings identify thiotaurine as a candidate molecule involved in intracellular persulfide and H2S metabolism and suggest its cellular antioxidant behavior may be related to the transfer of its sulfane sulfur.
{"title":"Thiotaurine is a sulfane sulfur donor to the biological thiols glutathione and cysteine.","authors":"Steven J Karpowicz","doi":"10.1016/j.bbagen.2026.130915","DOIUrl":"https://doi.org/10.1016/j.bbagen.2026.130915","url":null,"abstract":"<p><p>Persulfide and hydrogen sulfide chemistry is relevant to the prevention of cellular oxidative damage. Thiotaurine is a poorly-studied precursor to the abundant biological molecule taurine and contains a labile sulfane sulfur. Here, reversible reactions of thiotaurine with glutathione or cysteine were investigated to observe formation of persulfides and hydrogen sulfide gas. Raman, Visible, and NMR spectroscopy were employed to characterize the reaction products and observe reaction kinetics. The reactions were verified through a kinetic competition experiment involving hydrogen peroxide. Data and kinetic models indicate initial transfer of the sulfane sulfur from thiotaurine to a free sulfide, followed by formation of disulfides and release of H<sub>2</sub>S gas. The findings identify thiotaurine as a candidate molecule involved in intracellular persulfide and H<sub>2</sub>S metabolism and suggest its cellular antioxidant behavior may be related to the transfer of its sulfane sulfur.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130915"},"PeriodicalIF":2.2,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163961","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}
Aberrant glycosylation is one of the key characteristics of cancer cells. High-mannose-type N-glycans are highly expressed in various types of cancer, making them potentially important therapeutic targets. As a basis for developing new therapeutic drugs targeting high-mannose glycans, we employed Pseudomonas fluorescens lectin (PFL) that specifically binds to high-mannose glycans as a model compound, and analyzed the cellular responses of MDA-MB-231 and T47D breast cancer cell lines. In both cell types, PFL induced the internalization and degradation of cancer-associated molecules such as epidermal growth factor receptor (EGFR), integrins, and immune checkpoint ligands via autophagy, ultimately leading to apoptotic cell death. In T47D cells, changes were observed in the cellular distribution and expression levels of hormone receptors and human epidermal growth factor receptor 2 (HER2) upon treatment with PFL, suggesting a possible compensatory response. Comprehensive analysis of cellular lipids revealed that lysophospholipids were dramatically increased by PFL treatment, regardless of breast cancer cell type. These changes may reflect the dynamic reorganization of lipid membranes associated with membrane traffic and autophagy. Time-lapse experiments using a redox sensor designed to localize to the cell membrane showed that cells transitioned to an oxidized state following PFL treatment. Furthermore, inflammatory substances such as interleukin 8 (IL-8) were significantly increased in MDA-MB-231 cells but not in T47D cells. The results provide insight into the responses and resistance of breast cancer cells to glycan-targeted therapies.
{"title":"Anticancer activity of Pseudomonas fluorescens lectin (PFL) targeting high-mannose glycans on breast cancer cells","authors":"Yuichiro Sato , Kohei Kawabata , Chiho Murakami , Yuta Hatori , Takanori Kubo , Yuya Ohtsuki , Hiroyuki Nishi , Akira Tokumura , Kinjiro Morimoto","doi":"10.1016/j.bbagen.2026.130914","DOIUrl":"10.1016/j.bbagen.2026.130914","url":null,"abstract":"<div><div>Aberrant glycosylation is one of the key characteristics of cancer cells. High-mannose-type N-glycans are highly expressed in various types of cancer, making them potentially important therapeutic targets. As a basis for developing new therapeutic drugs targeting high-mannose glycans, we employed <em>Pseudomonas fluorescens</em> lectin (PFL) that specifically binds to high-mannose glycans as a model compound, and analyzed the cellular responses of MDA-MB-231 and T47D breast cancer cell lines. In both cell types, PFL induced the internalization and degradation of cancer-associated molecules such as epidermal growth factor receptor (EGFR), integrins, and immune checkpoint ligands via autophagy, ultimately leading to apoptotic cell death. In T47D cells, changes were observed in the cellular distribution and expression levels of hormone receptors and human epidermal growth factor receptor 2 (HER2) upon treatment with PFL, suggesting a possible compensatory response. Comprehensive analysis of cellular lipids revealed that lysophospholipids were dramatically increased by PFL treatment, regardless of breast cancer cell type. These changes may reflect the dynamic reorganization of lipid membranes associated with membrane traffic and autophagy. Time-lapse experiments using a redox sensor designed to localize to the cell membrane showed that cells transitioned to an oxidized state following PFL treatment. Furthermore, inflammatory substances such as interleukin 8 (IL-8) were significantly increased in MDA-MB-231 cells but not in T47D cells. The results provide insight into the responses and resistance of breast cancer cells to glycan-targeted therapies.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 5","pages":"Article 130914"},"PeriodicalIF":2.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096750","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 : 2026-01-29DOI: 10.1016/j.bbagen.2026.130913
Thaís Cristino Rocha-Vieira , José Roberto Meyer-Fernandes
Compared with nontumor tissue, the tumor microenvironment has a higher concentration of extracellular ATP. Extracellular ATP is degraded by the cooperative action of CD39 and ecto-5′-nucleotidase (CD73), thus leading to increases in the concentrations of adenosine and phosphate. This cooperative action can convert a proinflammatory environment characterized by a high concentration of ATP into an anti-inflammatory environment characterized by a high concentration of adenosine. In addition to its role in immune suppression, adenosine induces migration, metastasis and angiogenesis in breast cancer. In breast cancer, extracellular Pi plays an important role in tumor progression by increasing metastatic capacity. Studies have demonstrated that ecto-5′-nucleotidases are associated with chemoresistance and immune suppression through adenosine generation. In addition, ecto-5′-nucleotidases play a role in activating the epithelial-mesenchymal transition. Therefore, ectonucleotidase activity may represent a therapeutic target for the treatment of breast cancer.
{"title":"Ectonucleotidases: Possible roles in the tumor microenvironment and influence on tumor progression in breast cancer","authors":"Thaís Cristino Rocha-Vieira , José Roberto Meyer-Fernandes","doi":"10.1016/j.bbagen.2026.130913","DOIUrl":"10.1016/j.bbagen.2026.130913","url":null,"abstract":"<div><div>Compared with nontumor tissue, the tumor microenvironment has a higher concentration of extracellular ATP. Extracellular ATP is degraded by the cooperative action of CD39 and ecto-5′-nucleotidase (CD73), thus leading to increases in the concentrations of adenosine and phosphate. This cooperative action can convert a proinflammatory environment characterized by a high concentration of ATP into an anti-inflammatory environment characterized by a high concentration of adenosine. In addition to its role in immune suppression, adenosine induces migration, metastasis and angiogenesis in breast cancer. In breast cancer, extracellular Pi plays an important role in tumor progression by increasing metastatic capacity. Studies have demonstrated that ecto-5′-nucleotidases are associated with chemoresistance and immune suppression through adenosine generation. In addition, ecto-5′-nucleotidases play a role in activating the epithelial-mesenchymal transition. Therefore, ectonucleotidase activity may represent a therapeutic target for the treatment of breast cancer.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130913"},"PeriodicalIF":2.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091824","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}
Clinical data indicate a positive association between obesity and DNA damage, which has been implicated in several pathological conditions. Obesity also increases the risk of the development and progression of cancers, including colon cancer. However, the underlying mechanisms linking obesity-induced alterations in the DNA damage response (DDR) to colon cancer remain largely unexplored. The present study aims to investigate the functional status of the cellular DNA damage response in an obese environment and its association with colon cancer. To address this, cells were cultured in media supplemented with serum collected from mice fed a normal-fat diet (ND) and a high-fat diet (HFD). Subsequently, the DNA damage response and associated phenotypic parameters were evaluated.
Experimental results revealed that cells cultured in HFD serum exhibited increased DNA damage along with reduced levels of DNA repair molecules, together with activation of the DDR, as indicated by elevated levels of pH2AX, P-p53Ser15, and pchk2 proteins. Moreover, cell growth assays demonstrated rapid proliferation of cells cultured in HFD serum. Furthermore, HFD-fed C57BL6/J mice administered with azoxymethane/dextran sodium sulfate (AOM/DSS) exhibited a higher incidence of colon polyps compared to ND-fed mice. Interestingly, in ATM knockout mice (ATM, a key DDR-related molecule), a higher occurrence of polyps was detected compared to ATM wild-type mice, suggesting a potential role of ATM in polyp formation. Thus, by perturbing DDR and DNA repair pathways and promoting cell survival, obesity creates a favorable environment for cell proliferation. Collectively, this pre-clinical study enhances our understanding of obesity-altered DDR and its association with cancer cell proliferation.
{"title":"Obese serum factors aggravate DNA damage, alter DNA damage response, and promote proliferation in colon cancer cells","authors":"Bhavana Deshmukh, Himanshi Yaduvanshi, Firoz Khan Bhati, Manoj Kumar Bhat","doi":"10.1016/j.bbagen.2026.130911","DOIUrl":"10.1016/j.bbagen.2026.130911","url":null,"abstract":"<div><div>Clinical data indicate a positive association between obesity and DNA damage, which has been implicated in several pathological conditions. Obesity also increases the risk of the development and progression of cancers, including colon cancer. However, the underlying mechanisms linking obesity-induced alterations in the DNA damage response (DDR) to colon cancer remain largely unexplored. The present study aims to investigate the functional status of the cellular DNA damage response in an obese environment and its association with colon cancer. To address this, cells were cultured in media supplemented with serum collected from mice fed a normal-fat diet (ND) and a high-fat diet (HFD). Subsequently, the DNA damage response and associated phenotypic parameters were evaluated.</div><div>Experimental results revealed that cells cultured in HFD serum exhibited increased DNA damage along with reduced levels of DNA repair molecules, together with activation of the DDR, as indicated by elevated levels of pH2AX, P-p53Ser15, and pchk2 proteins. Moreover, cell growth assays demonstrated rapid proliferation of cells cultured in HFD serum. Furthermore, HFD-fed C57BL6/J mice administered with azoxymethane/dextran sodium sulfate (AOM/DSS) exhibited a higher incidence of colon polyps compared to ND-fed mice. Interestingly, in ATM knockout mice (ATM, a key DDR-related molecule), a higher occurrence of polyps was detected compared to ATM wild-type mice, suggesting a potential role of ATM in polyp formation. Thus, by perturbing DDR and DNA repair pathways and promoting cell survival, obesity creates a favorable environment for cell proliferation. Collectively, this pre-clinical study enhances our understanding of obesity-altered DDR and its association with cancer cell proliferation.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130911"},"PeriodicalIF":2.2,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083540","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}
Pharmacological vitamin C (VC) infusion therapy has shown efficacy against various cancer types; however, there are few reports on its effects on fibrosarcoma. This study investigated the impact of high-dose ascorbic acid (AsA), the reduced form of VC, on human fibrosarcoma HT-1080 cells. High-dose AsA (2–5 mM) markedly decreased HT-1080 cell viability compared with normal fibroblasts, indicating cancer cell selectivity. In contrast, dehydroascorbic acid (DehAsA), the oxidized form of AsA, exhibited no cytotoxicity toward cancer cells. Studies using D-AsA and AsA transport inhibitors demonstrated that intracellular AsA transport was not required for cytotoxicity in HT-1080 cells. Our results showed that high-dose AsA induced extracellular H₂O₂ production and increased intracellular H₂O₂, reactive oxygen species (ROS), and Fe2+ levels in HT-1080 cells compared with normal fibroblasts, suggesting that strong oxidative stress triggers actin disruption, ATP depletion, DNA damage, and reduced DNA synthesis. Additionally, a 1-h AsA exposure produced a sustained inhibitory effect on cell proliferation lasting at least 72 h. Moreover, high-dose AsA inhibited HT-1080 cell invasion and adhesion, with increased intracellular ROS likely contributing to these effects. These results indicate that high-dose AsA generates extracellular H₂O₂ and subsequently induces cancer cell-specific oxidative damage due to differences in intracellular H₂O₂ and Fe2+ levels, which differ between normal fibroblasts and HT-1080 cells. These actions lead to cancer cell-selective toxicity and prolonged growth-suppressive effects induced by high-dose AsA.
{"title":"High-dose ascorbic acid prolongs the suppression of cell proliferation by enhancing intracellular oxidative stress–induced damage and inhibits invasion and adhesion in human fibrosarcoma HT-1080 cells","authors":"Yasukazu Saitoh , Yusuke Tanimura , Shun Ueda , Tomoya Furuhata , Manato Takeda , Kouichi Okawachi , Yusuke Fukukita","doi":"10.1016/j.bbagen.2026.130908","DOIUrl":"10.1016/j.bbagen.2026.130908","url":null,"abstract":"<div><div>Pharmacological vitamin C (VC) infusion therapy has shown efficacy against various cancer types; however, there are few reports on its effects on fibrosarcoma. This study investigated the impact of high-dose ascorbic acid (AsA), the reduced form of VC, on human fibrosarcoma HT-1080 cells. High-dose AsA (2–5 mM) markedly decreased HT-1080 cell viability compared with normal fibroblasts, indicating cancer cell selectivity. In contrast, dehydroascorbic acid (DehAsA), the oxidized form of AsA, exhibited no cytotoxicity toward cancer cells. Studies using D-AsA and AsA transport inhibitors demonstrated that intracellular AsA transport was not required for cytotoxicity in HT-1080 cells. Our results showed that high-dose AsA induced extracellular H₂O₂ production and increased intracellular H₂O₂, reactive oxygen species (ROS), and Fe<sup>2+</sup> levels in HT-1080 cells compared with normal fibroblasts, suggesting that strong oxidative stress triggers actin disruption, ATP depletion, DNA damage, and reduced DNA synthesis. Additionally, a 1-h AsA exposure produced a sustained inhibitory effect on cell proliferation lasting at least 72 h. Moreover, high-dose AsA inhibited HT-1080 cell invasion and adhesion, with increased intracellular ROS likely contributing to these effects. These results indicate that high-dose AsA generates extracellular H₂O₂ and subsequently induces cancer cell-specific oxidative damage due to differences in intracellular H₂O₂ and Fe<sup>2+</sup> levels, which differ between normal fibroblasts and HT-1080 cells. These actions lead to cancer cell-selective toxicity and prolonged growth-suppressive effects induced by high-dose AsA.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130908"},"PeriodicalIF":2.2,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050351","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}
G-quadruplex structures within the promoter regions of some oncogenes diminish transcriptional activity. The suppression and downregulation of Cyclooxygenase-2 (COX-2), which is encoded by the prostaglandin-endoperoxide synthase 2 (PTGS2) gene, could control the size of colorectal cancer tumors. This study aimed to investigate the impact of a mononuclear octahedral cobalt(III) Schiff base complex [CoL3] (L = 2-((allylimino)methyl)-6-methoxyphenol) on the G-quadruplex structures in the PTGS2 promoter region and to assess its downregulation effects in the human colorectal cancer cell line HT-29. At first, molecular docking was used to evaluate the binding of [CoL3] to the PTGS2 promoter region. Then, the potential and stabilization of G-quadruplex formation in the PTGS2 promoter motifs were investigated using circular dichroism (CD) spectroscopy, polyacrylamide gel electrophoresis, and polymerase chain reaction (PCR) stop assays. COX-2 expression was also assessed by real-time PCR and western blot. Molecular docking analysis indicates that [CoL3] has a potent interaction with the PTGS2 promoter region. Additionally, [CoL3] has an intense inhibitory effect on the PTGS2-PCR stop assay. The CD measurements confirmed the conformational property of G-quadruplex DNA structures induced by [CoL3]. Treatment of colorectal cancer cells with the [CoL3] resulted in a modest increase in PTGS2 expression by a mean factor of 1.69 (p < 0.05). Conversely, the expression of COX-2 proteins was downregulated significantly, with a mean protein intensity of 0.47 (p < 0.001). Therefore, [CoL3] induces G-quadruplex formation in the promoter region of PTGS2, which ultimately inhibits protein expression of COX-2. This means that [CoL3] can be an effective agent for colorectal cancer treatment.
{"title":"COX-2 downregulation via G-quadruplex structure induction in the PTGS2-promoter region by mononuclear octahedral cobalt(III) Schiff base complex [CoL3] in colorectal cancer cells","authors":"Abdolvahab Moshtaghian , Abasalt Hosseinzadeh Colagar , Ali Khaleghian , Tahereh Zahedi","doi":"10.1016/j.bbagen.2026.130909","DOIUrl":"10.1016/j.bbagen.2026.130909","url":null,"abstract":"<div><div>G-quadruplex structures within the promoter regions of some oncogenes diminish transcriptional activity. The suppression and downregulation of Cyclooxygenase-2 (COX-2), which is encoded by the prostaglandin-endoperoxide synthase 2 (<em>PTGS2</em>) gene, could control the size of colorectal cancer tumors. This study aimed to investigate the impact of a mononuclear octahedral cobalt(III) Schiff base complex [CoL<sub>3</sub>] (L = 2-((allylimino)methyl)-6-methoxyphenol) on the G-quadruplex structures in the <em>PTGS2</em> promoter region and to assess its downregulation effects in the human colorectal cancer cell line HT-29. At first, molecular docking was used to evaluate the binding of [CoL<sub>3</sub>] to the <em>PTGS</em>2 promoter region. Then, the potential and stabilization of G-quadruplex formation in the PTGS2 promoter motifs were investigated using circular dichroism (CD) spectroscopy, polyacrylamide gel electrophoresis, and polymerase chain reaction (PCR) stop assays. COX-2 expression was also assessed by real-time PCR and western blot. Molecular docking analysis indicates that [CoL<sub>3</sub>] has a potent interaction with the <em>PTGS2</em> promoter region. Additionally, [CoL<sub>3</sub>] has an intense inhibitory effect on the <em>PTGS2</em>-PCR stop assay. The CD measurements confirmed the conformational property of G-quadruplex DNA structures induced by [CoL<sub>3</sub>]. Treatment of colorectal cancer cells with the [CoL<sub>3</sub>] resulted in a modest increase in <em>PTGS2</em> expression by a mean factor of 1.69 (<em>p</em> < 0.05). Conversely, the expression of COX-2 proteins was downregulated significantly, with a mean protein intensity of 0.47 (<em>p</em> < 0.001). Therefore, [CoL<sub>3</sub>] induces G-quadruplex formation in the promoter region of <em>PTGS2</em>, which ultimately inhibits protein expression of COX-2. This means that [CoL<sub>3</sub>] can be an effective agent for colorectal cancer treatment.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130909"},"PeriodicalIF":2.2,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046064","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 : 2026-01-23DOI: 10.1016/j.bbagen.2026.130910
Jiajun Yin , Shiping Wang , Yang Liu
Background
TMED2, a p24 family member, has been implicated in the progression of multiple cancers. However, its function in thyroid cancer (THCA) is unclear and needs to be clarified.
Methods
TMED2 expression was first explored using single-cell datasets and the TCGA database, followed by validation in THCA tissues and cell lines by immunohistochemistry (IHC), western blot, and qRT-PCR. Survival analysis was performed to evaluate the correlation between TMED2 expression and patient survival. The impact of TMED2 on THCA cells was analyzed using CCK-8, EdU staining, wound healing, Transwell, and flow cytometry assays. The lipid droplet accumulation was detected using BODIPY staining. The expression of key enzymes involved in fatty acid (FA) synthesis was assessed using western blot assay. Rescue experiments were conducted to investigate the mechanism of TMED2. Finally, the role of TMED2 in vivo was assessed in a nude mouse model.
Results
TMED2 expression was significantly upregulated in THCA tissues and four cell lines and was closely related to worse outcomes. Functional experiments revealed that TMED2 enhanced proliferation, migration, invasion, and FA synthesis in THCA cells, while suppressing cell apoptosis. Mechanistically, TMED2 promoted tumor growth and FA synthesis in THCA by affecting the activation of mTORC1 signaling, which was also observed in a xenograft mouse model.
Conclusions
Our results demonstrated that TMED2 may function as an oncogene to support THCA growth by affecting mTORC1-mediated FA synthesis. These findings suggest that TMED2 could serve as a potential target for THCA treatment.
{"title":"TMED2 promotes thyroid cancer tumorigenesis by being involved in mTORC1-mediated fatty acid metabolism","authors":"Jiajun Yin , Shiping Wang , Yang Liu","doi":"10.1016/j.bbagen.2026.130910","DOIUrl":"10.1016/j.bbagen.2026.130910","url":null,"abstract":"<div><h3>Background</h3><div>TMED2, a p24 family member, has been implicated in the progression of multiple cancers. However, its function in thyroid cancer (THCA) is unclear and needs to be clarified.</div></div><div><h3>Methods</h3><div>TMED2 expression was first explored using single-cell datasets and the TCGA database, followed by validation in THCA tissues and cell lines by immunohistochemistry (IHC), western blot, and qRT-PCR. Survival analysis was performed to evaluate the correlation between TMED2 expression and patient survival. The impact of TMED2 on THCA cells was analyzed using CCK-8, EdU staining, wound healing, Transwell, and flow cytometry assays. The lipid droplet accumulation was detected using BODIPY staining. The expression of key enzymes involved in fatty acid (FA) synthesis was assessed using western blot assay. Rescue experiments were conducted to investigate the mechanism of TMED2. Finally, the role of TMED2 <em>in vivo</em> was assessed in a nude mouse model.</div></div><div><h3>Results</h3><div>TMED2 expression was significantly upregulated in THCA tissues and four cell lines and was closely related to worse outcomes. Functional experiments revealed that TMED2 enhanced proliferation, migration, invasion, and FA synthesis in THCA cells, while suppressing cell apoptosis. Mechanistically, TMED2 promoted tumor growth and FA synthesis in THCA by affecting the activation of mTORC1 signaling, which was also observed in a xenograft mouse model.</div></div><div><h3>Conclusions</h3><div>Our results demonstrated that TMED2 may function as an oncogene to support THCA growth by affecting mTORC1-mediated FA synthesis. These findings suggest that TMED2 could serve as a potential target for THCA treatment.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130910"},"PeriodicalIF":2.2,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046055","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}
α-Dystroglycan (α-DG) is a central component of the dystrophin-glycoprotein complex, with the characteristic O-mannosyl glycan modification, which binds to several extracellular matrix proteins such as laminin. Disruption in the synthesis of laminin-binding glycan on α-DG is related to muscular dystrophies. In addition, loss of this glycan is frequently observed in many cancers, including pancreatic ductal adenocarcinoma (PDAC), correlating with poor prognosis. However, the significance of this glycan in the pathology of cancer remains unclear. This study aimed to clarify the biological significance of laminin-binding O-mannosyl glycan on α-DG in PDAC cells. Since a tumor-derived cancer cell line consists of cells with diverse characteristics, we first obtained several single-cell-derived clones using MIA PaCa-2, a commonly used undifferentiated PDAC cell line, and found that the laminin-binding glycan modification level on α-DG differs among the various clones. The glycan modification level correlated well with the mRNA expression level of LARGE1, the enzyme that synthesizes the laminin-binding structure on the glycan. We analyzed several PDAC cell properties, such as cellular morphology, proliferation and migration/invasion abilities, and examined their correlation with the glycan modification. We found that a high level of laminin-binding O-mannosyl glycan modification on α-DG correlated with the elongated cell morphology, high invasion ability, and low membrane blebbing activity, and vice versa. Furthermore, manipulation of the laminin-binding O-mannosyl glycan synthesis confirmed that this glycan partially contributed to these properties. Overall, this study provides valuable insights into the roles of the laminin-binding glycan on α-DG in PDAC.
{"title":"Heterogeneous expression of the laminin-binding O-mannosyl glycan on α-dystroglycan in pancreatic cancer cell line MIA PaCa-2 and the correlation with cell properties","authors":"Rieko Imae , Yuuki Shichi , Satoshi Ninagawa , Toshiyuki Ishiwata , Hiroshi Manya","doi":"10.1016/j.bbagen.2026.130907","DOIUrl":"10.1016/j.bbagen.2026.130907","url":null,"abstract":"<div><div>α-Dystroglycan (α-DG) is a central component of the dystrophin-glycoprotein complex, with the characteristic O-mannosyl glycan modification, which binds to several extracellular matrix proteins such as laminin. Disruption in the synthesis of laminin-binding glycan on α-DG is related to muscular dystrophies. In addition, loss of this glycan is frequently observed in many cancers, including pancreatic ductal adenocarcinoma (PDAC), correlating with poor prognosis. However, the significance of this glycan in the pathology of cancer remains unclear. This study aimed to clarify the biological significance of laminin-binding O-mannosyl glycan on α-DG in PDAC cells. Since a tumor-derived cancer cell line consists of cells with diverse characteristics, we first obtained several single-cell-derived clones using MIA PaCa-2, a commonly used undifferentiated PDAC cell line, and found that the laminin-binding glycan modification level on α-DG differs among the various clones. The glycan modification level correlated well with the mRNA expression level of LARGE1, the enzyme that synthesizes the laminin-binding structure on the glycan. We analyzed several PDAC cell properties, such as cellular morphology, proliferation and migration/invasion abilities, and examined their correlation with the glycan modification. We found that a high level of laminin-binding O-mannosyl glycan modification on α-DG correlated with the elongated cell morphology, high invasion ability, and low membrane blebbing activity, and vice versa. Furthermore, manipulation of the laminin-binding O-mannosyl glycan synthesis confirmed that this glycan partially contributed to these properties. Overall, this study provides valuable insights into the roles of the laminin-binding glycan on α-DG in PDAC.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130907"},"PeriodicalIF":2.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997142","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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