Lysophosphatidic acid (LPA) receptor-mediated signaling contributes to the pathogenesis of cancer. The tumor microenvironment (TME), composed of cancer cells and surrounding stromal cells, plays a key role in promoting malignant traits, including resistance to anticancer drugs. In this study, we investigated the roles of LPA receptor-1 (LPA1) and LPA2 in colon cancer DLD-1 cell functions modulated by 3T3 fibroblasts chronically exposed to chemotherapy. 3T3 cells were treated long-term with fluorouracil (5-FU), irinotecan (CPT-11), or cisplatin (CDDP) to generate 3T3–5FU, 3T3-CPT11, and 3T3-CDDP cells, respectively. Co-culture with anticancer drug-treated 3T3 cells altered LPA receptor expression in DLD-1 cells, characterized by reduced LPAR1 and elevated LPAR2 levels, compared with co-culture with untreated fibroblasts (n = 3 independent experiments). Under these conditions, LPA stimulation enhanced DLD-1 cell proliferation and motility. Pharmacological modulation of LPA signaling further supported receptor-specific effects: the LPA1 antagonist AM966 and the LPA2 agonist GRI-977143 promoted DLD-1 cell growth, while AM966 suppressed and GRI-977143 enhanced cell motility in co-culture with drug-treated fibroblasts. These findings suggest that chemotherapy-conditioned fibroblasts reshape LPA receptor-dependent signaling in colon cancer cells, suggesting potential therapeutic relevance of distinct roles for LPA1 and LPA2 within the drug-modified TME.
{"title":"Anticancer drug-treated fibroblasts modulate colon cancer cell behavior through lysophosphatidic acid (LPA) receptor-mediated signaling","authors":"Mao Yamamoto, Narumi Yashiro, Yuka Kusumoto, Shion Nagano, Moemi Tamura, Nanami Shimomura, Toshifumi Tsujiuchi","doi":"10.1016/j.acthis.2026.152325","DOIUrl":"10.1016/j.acthis.2026.152325","url":null,"abstract":"<div><div>Lysophosphatidic acid (LPA) receptor-mediated signaling contributes to the pathogenesis of cancer. The tumor microenvironment (TME), composed of cancer cells and surrounding stromal cells, plays a key role in promoting malignant traits, including resistance to anticancer drugs. In this study, we investigated the roles of LPA receptor-1 (LPA<sub>1</sub>) and LPA<sub>2</sub> in colon cancer DLD-1 cell functions modulated by 3T3 fibroblasts chronically exposed to chemotherapy. 3T3 cells were treated long-term with fluorouracil (5-FU), irinotecan (CPT-11), or cisplatin (CDDP) to generate 3T3–5FU, 3T3-CPT11, and 3T3-CDDP cells, respectively. Co-culture with anticancer drug-treated 3T3 cells altered LPA receptor expression in DLD-1 cells, characterized by reduced <em>LPAR1</em> and elevated <em>LPAR2</em> levels, compared with co-culture with untreated fibroblasts (n = 3 independent experiments). Under these conditions, LPA stimulation enhanced DLD-1 cell proliferation and motility. Pharmacological modulation of LPA signaling further supported receptor-specific effects: the LPA<sub>1</sub> antagonist AM966 and the LPA<sub>2</sub> agonist GRI-977143 promoted DLD-1 cell growth, while AM966 suppressed and GRI-977143 enhanced cell motility in co-culture with drug-treated fibroblasts. These findings suggest that chemotherapy-conditioned fibroblasts reshape LPA receptor-dependent signaling in colon cancer cells<strong>,</strong> suggesting potential therapeutic relevance of distinct roles for LPA<sub>1</sub> and LPA<sub>2</sub> within the drug-modified TME.</div></div>","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"128 2","pages":"Article 152325"},"PeriodicalIF":2.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2026-01-19DOI: 10.1016/j.acthis.2026.152323
Genlai Du , Diyu Wang , Qingqian Chen , Jiaqi Zhang , Jiaru Sun , Qizhi Shuai , Li Li , Xun Huang , Quanyou Zhang , Shaowei Wang , Qin Zhang , Chongwei Chen , Ruyi Shi
Osteoarthritis (OA) is a degenerative joint disease characterized by an increasing prevalence and complex pathogenesis. Despite significant research efforts, understanding its mechanisms and developing effective treatments remain challenging. The development of in vitro models that accurately mimic the native articular microenvironment while preserving chondrocyte phenotype is crucial for advancing OA research. In this study, we constructed an Alginate-Hyaluronic Acid-Type I Collagen (Alg-HA-Col) composite hydrogel through physical mixing and chemical cross-linking. This composite matrix exhibited exceptional stability over 28 days under simulated physiological conditions. Neonatal murine chondrocytes encapsulated within Alg-HA-Col hydrogels for 28 days maintained their phenotype better than those cultured in monolayer, as evidenced by higher expression levels of SOX9, type II collagen, and aggrecan. Furthermore, by adjusting the component ratios, the stiffness of Alg-HA-Col hydrogels could mimic the stiffness of the pericellular matrix (PCM) in both physiological and pathological states, referred to as Firm and Soft. Chondrocytes cultured in Alg-HA-Col hydrogels with varying stiffness showed decreased expression of marker proteins, increased cellular mortality, and elevated inflammatory factor expression as stiffness decreased. Therefore, Alg-HA-Col hydrogels with tunable stiffness effectively simulated the physiological and pathological states of cartilage, providing an ideal three-dimensional (3D) matrix for chondrocyte culture. Additionally, this model's long-term culture stability offers potential applications in osteoarthritis drug therapy and cartilage tissue engineering.
骨关节炎（OA）是一种发病率越来越高、发病机制复杂的退行性关节疾病。尽管进行了大量的研究，但了解其机制和开发有效的治疗方法仍然具有挑战性。在保留软骨细胞表型的同时，开发能够准确模拟天然关节微环境的体外模型对于推进OA研究至关重要。在本研究中，我们通过物理混合和化学交联构建了海藻酸盐-透明质酸- I型胶原蛋白（algi - ha - col）复合水凝胶。在模拟生理条件下，该复合基质在28天内表现出优异的稳定性。在Alg-HA-Col水凝胶中包裹28天的新生小鼠软骨细胞比单层培养的小鼠保持了更好的表型，SOX9、II型胶原和聚集蛋白的表达水平更高。此外，通过调整组分比例，Alg-HA-Col水凝胶的硬度可以模拟细胞周围基质（PCM）在生理和病理状态下的硬度，称为硬和软。在不同硬度的Alg-HA-Col水凝胶中培养的软骨细胞显示，随着硬度的降低，标记蛋白的表达降低，细胞死亡率增加，炎症因子的表达升高。因此，具有可调刚度的al - ha - col水凝胶可以有效地模拟软骨的生理和病理状态，为软骨细胞培养提供了理想的三维（3D）基质。此外，该模型的长期培养稳定性为骨关节炎药物治疗和软骨组织工程提供了潜在的应用。
{"title":"Stiffness-tunable alginate-hyaluronic acid-collagen hydrogel mimics chondrocyte microenvironment for osteoarthritis pathophysiological modeling","authors":"Genlai Du , Diyu Wang , Qingqian Chen , Jiaqi Zhang , Jiaru Sun , Qizhi Shuai , Li Li , Xun Huang , Quanyou Zhang , Shaowei Wang , Qin Zhang , Chongwei Chen , Ruyi Shi","doi":"10.1016/j.acthis.2026.152323","DOIUrl":"10.1016/j.acthis.2026.152323","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a degenerative joint disease characterized by an increasing prevalence and complex pathogenesis. Despite significant research efforts, understanding its mechanisms and developing effective treatments remain challenging. The development of <em>in vitro</em> models that accurately mimic the native articular microenvironment while preserving chondrocyte phenotype is crucial for advancing OA research. In this study, we constructed an Alginate-Hyaluronic Acid-Type I Collagen (Alg-HA-Col) composite hydrogel through physical mixing and chemical cross-linking. This composite matrix exhibited exceptional stability over 28 days under simulated physiological conditions. Neonatal murine chondrocytes encapsulated within Alg-HA-Col hydrogels for 28 days maintained their phenotype better than those cultured in monolayer, as evidenced by higher expression levels of SOX9, type II collagen, and aggrecan. Furthermore, by adjusting the component ratios, the stiffness of Alg-HA-Col hydrogels could mimic the stiffness of the pericellular matrix (PCM) in both physiological and pathological states, referred to as Firm and Soft. Chondrocytes cultured in Alg-HA-Col hydrogels with varying stiffness showed decreased expression of marker proteins, increased cellular mortality, and elevated inflammatory factor expression as stiffness decreased. Therefore, Alg-HA-Col hydrogels with tunable stiffness effectively simulated the physiological and pathological states of cartilage, providing an ideal three-dimensional (3D) matrix for chondrocyte culture. Additionally, this model's long-term culture stability offers potential applications in osteoarthritis drug therapy and cartilage tissue engineering.</div></div>","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"128 2","pages":"Article 152323"},"PeriodicalIF":2.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145993577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2026-02-12DOI: 10.1016/j.acthis.2026.152327
Eli Heber Martins dos Anjos, Maria Luiza Silveira Mello , Benedicto de Campos Vidal
Tenocytes migrating from cultured rat tendon explants have been shown to aggregate and gradually align in parallel rows with the tendon’s long axis as the explant culture period extends to 12 days, leading to structure remodeling of collagen bundles. It is well established that tendon architecture and mechanical load influence fibroblast phenotypes. In this study, we examined cells derived from tenocytes that migrated from tendon explants cultured for 8 and 12 days to determine whether their chromatin supraorganization differed based on their varying organization. Image analysis and immunofluorescence were used to assess features indicative of chromatin transcriptional expression or repression activities. While no differences occurred in Feulgen-DNA amounts, DNA methylation markers, or distribution of acetylated H3K9 when comparing cells derived from 8- and 12-day tendon cultures, we observed differences in light absorbance, fractal dimension, and concentration of stained chromatin at the image periphery (margination). Increased levels of the trimethylated H3K27 and decreased levels of 5-hydroxymethylcytosine (both repressive markers) in cells derived from the 12-day tendon explants provide evidence of chromatin condensation at that time. Elevated levels of the translational activating markers H3K4me2 and H3K4me3 in cells derived from tenocytes that extensively aligned in parallel rows in the explants during the extended tendon culture period, may suggest acquired or enhanced expression of specific gene sets, despite the concurrent indication of greater overall chromatin compaction. Further assays are needed to explore whether these findings correlate with a differential potential of tenocyte-derived cells for extracellular matrix synthesis and their implication in practical bioengineering applications.
{"title":"Nuclear image changes in cells originating from tenocytes that migrated from tendon explants","authors":"Eli Heber Martins dos Anjos, Maria Luiza Silveira Mello , Benedicto de Campos Vidal","doi":"10.1016/j.acthis.2026.152327","DOIUrl":"10.1016/j.acthis.2026.152327","url":null,"abstract":"<div><div>Tenocytes migrating from cultured rat tendon explants have been shown to aggregate and gradually align in parallel rows with the tendon’s long axis as the explant culture period extends to 12 days, leading to structure remodeling of collagen bundles. It is well established that tendon architecture and mechanical load influence fibroblast phenotypes. In this study, we examined cells derived from tenocytes that migrated from tendon explants cultured for 8 and 12 days to determine whether their chromatin supraorganization differed based on their varying organization. Image analysis and immunofluorescence were used to assess features indicative of chromatin transcriptional expression or repression activities. While no differences occurred in Feulgen-DNA amounts, DNA methylation markers, or distribution of acetylated H3K9 when comparing cells derived from 8- and 12-day tendon cultures, we observed differences in light absorbance, fractal dimension, and concentration of stained chromatin at the image periphery (margination). Increased levels of the trimethylated H3K27 and decreased levels of 5-hydroxymethylcytosine (both repressive markers) in cells derived from the 12-day tendon explants provide evidence of chromatin condensation at that time. Elevated levels of the translational activating markers H3K4me2 and H3K4me3 in cells derived from tenocytes that extensively aligned in parallel rows in the explants during the extended tendon culture period, may suggest acquired or enhanced expression of specific gene sets, despite the concurrent indication of greater overall chromatin compaction. Further assays are needed to explore whether these findings correlate with a differential potential of tenocyte-derived cells for extracellular matrix synthesis and their implication in practical bioengineering applications.</div></div>","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"128 2","pages":"Article 152327"},"PeriodicalIF":2.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146184847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2026-01-30DOI: 10.1016/j.acthis.2026.152324
Dalia Shaaban , Alyssa Seerley , Lilia Crew , Clairissa Kaylor , Sayre McElroy , Emma Guter , June Pounder , Andrea Grindeland Panter
There are significant risks in clinical, diagnostic, and research settings to those who investigate prion diseases, due to the difficult nature of inactivating prion proteins with standard decontamination methods. Formic acid treatment has been shown to be effective for decontaminating infectious prions and commonly used in biosafety practice to prevent occupational exposure. However, the impact of formic acid protocols on the morphology of tissue samples has not been adequately documented. The goal of this study is to examine morphologic effects of formic acid treatment on central nervous system tissue, using mouse model brain hemisphere tissues that exhibit varying degrees of neurodegeneration as a model. This study included normal, non-diseased wild-type tissues and a 5xFAD model, which recapitulates aspects of Alzheimer’s Disease (AD). A model exhibiting Chronic Wasting Disease (CWD), a prion disease of deer and elk, was also used to analyze the effects of formic acid on tissues with spongiform changes. Tissues from both formic acid and untreated control treatment groups were embedded in paraffin, sectioned, stained, and imaged microscopically. Anatomical regions were analyzed and evaluated quantitatively to determine the width, area, and structural integrity of the tissue between treatment groups. Our findings demonstrated that while formic acid has been previously reported to effectively inactivate prions, it compromised the morphology of mouse brain tissues. Furthermore, the effects of formic acid were not distributed equally between regions of the brain. Age did not play a role in the morphologic changes seen in the formic acid treatment group. Interestingly, the presence of neurodegeneration in the tissues did not appear to exacerbate the effects of morphological changes post-formic acid treatment. These results emphasize the need to explore alternative prion inactivation methods that ensure the safety and reliability of handling prion-infected tissues without compromising the integrity of tissues.
{"title":"The impact of formic acid treatment on brain tissues for prion inactivation","authors":"Dalia Shaaban , Alyssa Seerley , Lilia Crew , Clairissa Kaylor , Sayre McElroy , Emma Guter , June Pounder , Andrea Grindeland Panter","doi":"10.1016/j.acthis.2026.152324","DOIUrl":"10.1016/j.acthis.2026.152324","url":null,"abstract":"<div><div>There are significant risks in clinical, diagnostic, and research settings to those who investigate prion diseases, due to the difficult nature of inactivating prion proteins with standard decontamination methods. Formic acid treatment has been shown to be effective for decontaminating infectious prions and commonly used in biosafety practice to prevent occupational exposure. However, the impact of formic acid protocols on the morphology of tissue samples has not been adequately documented. The goal of this study is to examine morphologic effects of formic acid treatment on central nervous system tissue, using mouse model brain hemisphere tissues that exhibit varying degrees of neurodegeneration as a model. This study included normal, non-diseased wild-type tissues and a 5xFAD model, which recapitulates aspects of Alzheimer’s Disease (AD). A model exhibiting Chronic Wasting Disease (CWD), a prion disease of deer and elk, was also used to analyze the effects of formic acid on tissues with spongiform changes. Tissues from both formic acid and untreated control treatment groups were embedded in paraffin, sectioned, stained, and imaged microscopically. Anatomical regions were analyzed and evaluated quantitatively to determine the width, area, and structural integrity of the tissue between treatment groups. Our findings demonstrated that while formic acid has been previously reported to effectively inactivate prions, it compromised the morphology of mouse brain tissues. Furthermore, the effects of formic acid were not distributed equally between regions of the brain. Age did not play a role in the morphologic changes seen in the formic acid treatment group. Interestingly, the presence of neurodegeneration in the tissues did not appear to exacerbate the effects of morphological changes post-formic acid treatment. These results emphasize the need to explore alternative prion inactivation methods that ensure the safety and reliability of handling prion-infected tissues without compromising the integrity of tissues.</div></div>","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"128 2","pages":"Article 152324"},"PeriodicalIF":2.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2026-01-29DOI: 10.1016/j.acthis.2026.152326
Rajesh Prasad Jayaswal
{"title":"Commentary on: “Cellular landscape of reactive and neoplastic human lymph nodes in 3D” by Diederich et al.”","authors":"Rajesh Prasad Jayaswal","doi":"10.1016/j.acthis.2026.152326","DOIUrl":"10.1016/j.acthis.2026.152326","url":null,"abstract":"","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"128 2","pages":"Article 152326"},"PeriodicalIF":2.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Saussurea lappa, a plant used in traditional medicine, has shown promise in cancer treatment This study aimed to evaluate the therapeutic efficacy of Saussurea lappa nanoparticles using immunohistochemical analysis in a benzo[a]pyrene-induced mouse model of oral squamous cell carcinoma (OSCC). The investigation focused on the expression of markers related to apoptosis (Bax, Caspase-3, BCL-2), inflammation (TNF-α), proliferation (Ki-67), and tumor suppression (p53).
Methods
A true experimental design was employed using male Mus musculus mice. OSCC was induced via exposure to benzo[a]pyrene. Following induction, mice were treated perorally with Saussurea lappa nanoparticles at doses of 50, 100, and 200 mg/kg body weight, while the control group received CMC-Na. Buccal mucosa samples were collected for immunohistochemical analysis, assessing dose-dependent effects of Saussurea lappa nanoparticles on the expression of Bax, Caspase-3, BCL-2, TNF-α, Ki-67 and p53.
Result
Saussurea lappa nanoparticles demonstrated dose-dependent therapeutic effects in the OSCC mouse model. They significantly upregulated Bax, Caspase-3, TNF-α, and p53, while downregulating BCL-2 and Ki-67expression. The highest dose (200 mg/kg) showed the most pronounced effects, indicating enhanced apoptosis, reduced proliferation, and modulation of the inflammatory environment.
Conclusion
These findings suggest that Saussurea lappa nanoparticles, particularly at a dose of 200 mg/kg BW, effectively promote apoptosis, inhibit cell proliferation, and suppress anti-apoptotic pathways. This highlights their potential as a promising therapeutic candidate for the treatment of oral mucosal malignancies.
{"title":"An immunohistochemical study of Saussurea lappa nanoparticle on transformed cells in mice induced with benzo[a]pyrene for oral squamous cell carcinoma","authors":"Theresia Indah Budhy , Ira Arundina , Anis Irmawati , Cheng Hwee Ming , Meircurius Dwi Condro Surboyo , Azzahra Salsabila Adira Moelyanto , Pandu Dewanata , Naqiya Saqifa","doi":"10.1016/j.acthis.2025.152312","DOIUrl":"10.1016/j.acthis.2025.152312","url":null,"abstract":"<div><h3>Background</h3><div><em>Saussurea lappa</em>, a plant used in traditional medicine, has shown promise in cancer treatment This study aimed to evaluate the therapeutic efficacy of <em>Saussurea lappa</em> nanoparticles using immunohistochemical analysis in a benzo[<em>a</em>]pyrene-induced mouse model of oral squamous cell carcinoma (OSCC). The investigation focused on the expression of markers related to apoptosis (Bax, Caspase-3, BCL-2), inflammation (TNF-α), proliferation (Ki-67), and tumor suppression (p53).</div></div><div><h3>Methods</h3><div>A true experimental design was employed using male <em>Mus musculus</em> mice. OSCC was induced via exposure to benzo[<em>a</em>]pyrene. Following induction, mice were treated perorally with <em>Saussurea lappa</em> nanoparticles at doses of 50, 100, and 200 mg/kg body weight, while the control group received CMC-Na. Buccal mucosa samples were collected for immunohistochemical analysis, assessing dose-dependent effects of <em>Saussurea lappa</em> nanoparticles on the expression of Bax, Caspase-3, BCL-2, TNF-α, Ki-67 and p53.</div></div><div><h3>Result</h3><div><em>Saussurea lappa</em> nanoparticles demonstrated dose-dependent therapeutic effects in the OSCC mouse model. They significantly upregulated Bax, Caspase-3, TNF-α, and p53, while downregulating BCL-2 and Ki-67expression. The highest dose (200 mg/kg) showed the most pronounced effects, indicating enhanced apoptosis, reduced proliferation, and modulation of the inflammatory environment.</div></div><div><h3>Conclusion</h3><div>These findings suggest that <em>Saussurea lappa</em> nanoparticles, particularly at a dose of 200 mg/kg BW, effectively promote apoptosis, inhibit cell proliferation, and suppress anti-apoptotic pathways. This highlights their potential as a promising therapeutic candidate for the treatment of oral mucosal malignancies.</div></div>","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"128 1","pages":"Article 152312"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145825600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hypoxia plays a crucial role in driving tumor progression by altering cellular signaling pathways. Lysophosphatidic acid (LPA) receptor signaling regulates malignant properties in cancer cells, including motility and chemoresistance. This study aimed to compare the cellular functions of gastric cancer AGS cells under cobalt chloride (CoCl2)-induced hypoxia and true hypoxia (1 % O2), with a focus on the role of LPA receptor signaling in mediating these responses. Treatment with CoCl2 (200 μM) elevated LPAR1 and LPAR3 expression while reducing LPAR2 expression, resulting in enhanced cell motility. CoCl2 also increased AGS cell viability in response to cisplatin (CDDP) in the presence of LPA. These effects were suppressed by LW6, an inhibitor of HIF-1α, indicating HIF-1α involvement. Furthermore, AGS cel motility and CDDP resistance were enhanced by AM966 (LPA1 antagonist), GRI-977143 (LPA2 agonist), and (2S)-OMPT (LPA3 agonist), suggesting that LPA2 and LPA3 promote, while LPA1 suppresses, these cellular functions under CoCl2-induced hypoxia. In contrast, under 1 % O2 conditions, LPAR1 and LPAR3 expression levels were downregulated, while LPAR2 expression remained unchanged. AGS cells cultured at 1 % O2 showed increased motility but reduced viability in response to CDDP. LW6 further inhibited viability under these conditions. Our results demonstrate that LPA receptor signaling is differentially regulated under CoCl2-induced and true hypoxia, contributing to distinct outcomes in cell motility and drug response. This suggests that LPA receptor signaling is a potential target for controlling hypoxia-induced malignant transformation in gastric cancer cells.
{"title":"Distinct roles of lysophosphatidic acid (LPA) receptor signaling in regulating gastric cancer cell functions under chemical versus physiological hypoxia","authors":"Narumi Yashiro, Mao Yamamoto, Yuka Kusumoto, Shion Nagano, Moemi Tamura, Nanami Shimomura, Miwa Takai, Toshifumi Tsujiuchi","doi":"10.1016/j.acthis.2025.152299","DOIUrl":"10.1016/j.acthis.2025.152299","url":null,"abstract":"<div><div>Hypoxia plays a crucial role in driving tumor progression by altering cellular signaling pathways. Lysophosphatidic acid (LPA) receptor signaling regulates malignant properties in cancer cells, including motility and chemoresistance. This study aimed to compare the cellular functions of gastric cancer AGS cells under cobalt chloride (CoCl<sub>2</sub>)-induced hypoxia and true hypoxia (1 % O<sub>2</sub>), with a focus on the role of LPA receptor signaling in mediating these responses. Treatment with CoCl<sub>2</sub> (200 μM) elevated <em>LPAR1</em> and <em>LPAR3</em> expression while reducing <em>LPAR2</em> expression, resulting in enhanced cell motility. CoCl<sub>2</sub> also increased AGS cell viability in response to cisplatin (CDDP) in the presence of LPA. These effects were suppressed by LW6, an inhibitor of HIF-1α, indicating HIF-1α involvement. Furthermore, AGS cel motility and CDDP resistance were enhanced by AM966 (LPA<sub>1</sub> antagonist), GRI-977143 (LPA<sub>2</sub> agonist), and (2S)-OMPT (LPA<sub>3</sub> agonist), suggesting that LPA<sub>2</sub> and LPA<sub>3</sub> promote, while LPA<sub>1</sub> suppresses, these cellular functions under CoCl<sub>2</sub>-induced hypoxia. In contrast, under 1 % O<sub>2</sub> conditions, <em>LPAR1</em> and <em>LPAR3</em> expression levels were downregulated, while <em>LPAR2</em> expression remained unchanged. AGS cells cultured at 1 % O<sub>2</sub> showed increased motility but reduced viability in response to CDDP. LW6 further inhibited viability under these conditions. Our results demonstrate that LPA receptor signaling is differentially regulated under CoCl<sub>2</sub>-induced and true hypoxia, contributing to distinct outcomes in cell motility and drug response. This suggests that LPA receptor signaling is a potential target for controlling hypoxia-induced malignant transformation in gastric cancer cells.</div></div>","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"128 1","pages":"Article 152299"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ezrin, a dynamic member of the Ezrin-Radixin-Moesin (ERM) family, plays a crucial role in orchestrating fundamental cellular functions, including membrane-cytoskeleton interactions, signal transduction, cell adhesion, migration, and immune regulation. Due to its broad functional repertoire, Ezrin has been increasingly recognized for its involvement in the pathogenesis of numerous human diseases, ranging from cancers and neurodegenerative disorders to renal and i conditions. In the central nervous system, Ezrin contributes to neurological homeostasis by preserving blood–brain barrier (BBB) integrity, modulating neuroinflammatory responses, and supporting synaptic plasticity and neuronal viability. Over the past few decades, scientific interest in Ezrin has grown significantly, as reflected by a marked increase in publications detailing its physiological and pathological roles. This review provides a comprehensive and uniquely alphabetized overview of Ezrin associations with a wide array of diseases, making it the first of its kind to catalog Ezrin biological relevance from A to Z. We examine its structural and biochemical characteristics, underscoring its potential as a diagnostic and prognostic biomarker, as well as an emerging therapeutic target. By addressing critical knowledge gaps, this review highlights Ezrin central role at the intersection of cancer biology, immunology, and neurotherapeutics.
{"title":"From membranes to medicine: Emerging insights into Ezrin’s Role in human disease — A comprehensive overview","authors":"Himanshu Kumar , Kanika Vashisht , Shavinder Kumari , Rimpi Arora , Pratima Ashawat , Mahendra Singh Ashawat , Shiv Kumar Kushawaha","doi":"10.1016/j.acthis.2025.152314","DOIUrl":"10.1016/j.acthis.2025.152314","url":null,"abstract":"<div><div>Ezrin, a dynamic member of the Ezrin-Radixin-Moesin (ERM) family, plays a crucial role in orchestrating fundamental cellular functions, including membrane-cytoskeleton interactions, signal transduction, cell adhesion, migration, and immune regulation. Due to its broad functional repertoire, Ezrin has been increasingly recognized for its involvement in the pathogenesis of numerous human diseases, ranging from cancers and neurodegenerative disorders to renal and i conditions. In the central nervous system, Ezrin contributes to neurological homeostasis by preserving blood–brain barrier (BBB) integrity, modulating neuroinflammatory responses, and supporting synaptic plasticity and neuronal viability. Over the past few decades, scientific interest in Ezrin has grown significantly, as reflected by a marked increase in publications detailing its physiological and pathological roles. This review provides a comprehensive and uniquely alphabetized overview of Ezrin associations with a wide array of diseases, making it the first of its kind to catalog Ezrin biological relevance from A to Z. We examine its structural and biochemical characteristics, underscoring its potential as a diagnostic and prognostic biomarker, as well as an emerging therapeutic target. By addressing critical knowledge gaps, this review highlights Ezrin central role at the intersection of cancer biology, immunology, and neurotherapeutics.</div></div>","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"128 1","pages":"Article 152314"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-27DOI: 10.1016/j.acthis.2025.152311
Shiyou Dai , Chen Liang , Xiao Fan , Wenting Li , Lei Zhao
The utilization of hydrogels in bone defect repair applications faces numerous challenges, while carbon dioxide (CO2) demonstrates potential beneficial effects in bone healing processes. Based on this, the current study proposes a novel approach, namely, the deployment of a hydrogel scaffold laden with CO2-controlled release material to promote bone defect repair, successfully proving its beneficial impact. By combining Poly-L-lactic Acid (PLLA), Gelatin Methacryloyl (GelMA), Nano-Hydroxyapatite (nHA), and Ammonium Bicarbonate (NH₄HCO₃) into a composite material, CO₂ may be produced in a 37°C PBS environment, primarily due to the decomposition of NH₄HCO₃. Additionally, the material can be thermosensitive, and the application of near-infrared (NIR) light may further enhance the CO₂ release by increasing the temperature locally, facilitating the decomposition of NH₄HCO₃. Bone marrow stromal cells (BMSCs) were cultured on the composite hydrogel to evaluate cell proliferation and osteogenic differentiation in vitro, while a rat cranial bone defect model was employed to assess in vivo bone regeneration. The research results indicate that this composite material significantly promotes BMSC cell proliferation and osteogenic differentiation and successfully accelerates bone healing in a rat cranial bone defect model. The substantiated insights and empirical evidence proffered herein lay a robust foundation for subsequent explorations in this vanguard domain of research.
{"title":"Enhancing bone regeneration: The role of short fiber reinforced hydrogel with CO2-controlled release on the osteogenic differentiation of bone marrow mesenchymal stem cells","authors":"Shiyou Dai , Chen Liang , Xiao Fan , Wenting Li , Lei Zhao","doi":"10.1016/j.acthis.2025.152311","DOIUrl":"10.1016/j.acthis.2025.152311","url":null,"abstract":"<div><div>The utilization of hydrogels in bone defect repair applications faces numerous challenges, while carbon dioxide (CO<sub>2</sub>) demonstrates potential beneficial effects in bone healing processes. Based on this, the current study proposes a novel approach, namely, the deployment of a hydrogel scaffold laden with CO<sub>2</sub>-controlled release material to promote bone defect repair, successfully proving its beneficial impact. By combining Poly-<span>L</span>-lactic Acid (PLLA), Gelatin Methacryloyl (GelMA), Nano-Hydroxyapatite (nHA), and Ammonium Bicarbonate (NH₄HCO₃) into a composite material, CO₂ may be produced in a 37°C PBS environment, primarily due to the decomposition of NH₄HCO₃. Additionally, the material can be thermosensitive, and the application of near-infrared (NIR) light may further enhance the CO₂ release by increasing the temperature locally, facilitating the decomposition of NH₄HCO₃. Bone marrow stromal cells (BMSCs) were cultured on the composite hydrogel to evaluate cell proliferation and osteogenic differentiation in vitro, while a rat cranial bone defect model was employed to assess in vivo bone regeneration. The research results indicate that this composite material significantly promotes BMSC cell proliferation and osteogenic differentiation and successfully accelerates bone healing in a rat cranial bone defect model. The substantiated insights and empirical evidence proffered herein lay a robust foundation for subsequent explorations in this vanguard domain of research.</div></div>","PeriodicalId":6961,"journal":{"name":"Acta histochemica","volume":"128 1","pages":"Article 152311"},"PeriodicalIF":2.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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