Pub Date : 2025-07-19DOI: 10.1016/j.yexmp.2025.104987
Xiaolu Zhu , Zheng Wang , Yuanping Shi , Shuang Yao , Fengliang He , Xiuli Cong , Fang Teng
For mesenchymal stem cell (MSC) therapy to be effective, the vascular system may be used to deliver and steer the cells to the target tissue. However, the expanded MSCs in petri dishes typically exhibit limited deformability and commonly excluded by the capillary networks when homing to the downstream organs via microcirculation. Here, we propose to utilize specially designed 3D dextran hydrogels and tuning the microscopic heterogeneity of hydrogel composition to make the administrated cells mechanically comply with the structure and mechanics of the capillary. The deformability of cells cultured in petri dishes, microcosmically homogeneous (HOM), and heterogeneous (HET) dextran hydrogels was investigated in vitro by measuring cell moduli through atomic force microscope (AFM), analyzing the expression of cytoskeletal protein via flow cytometry and fluorescent imaging. The in vitro experimental results demonstrate a progressive increase in cell deformability from 2D dishes, to HOM-hydrogel derived cells, and then to HET-hydrogel derived cells. The in vivo mouse experiment indicates the cells could deform accordingly and pass through easily with reduced resistance inside the mouse organs. It is suggested that the main destination of hMSC microcirculation could be selected between the spleen and liver of mice, by tuning cell mechanics that depends on the stimulus from HOM or HET hydrogel, which lays a potential foundation for the mechanically modified MSC therapy targeting organ lesions.
{"title":"Modulating cellular deformability via 3D dextran hydrogel cultivation to regulate the microcirculation of mesenchymal stem cells in murine spleen and liver","authors":"Xiaolu Zhu , Zheng Wang , Yuanping Shi , Shuang Yao , Fengliang He , Xiuli Cong , Fang Teng","doi":"10.1016/j.yexmp.2025.104987","DOIUrl":"10.1016/j.yexmp.2025.104987","url":null,"abstract":"<div><div>For mesenchymal stem cell (MSC) therapy to be effective, the vascular system may be used to deliver and steer the cells to the target tissue. However, the expanded MSCs in petri dishes typically exhibit limited deformability and commonly excluded by the capillary networks when homing to the downstream organs via microcirculation. Here, we propose to utilize specially designed 3D dextran hydrogels and tuning the microscopic heterogeneity of hydrogel composition to make the administrated cells mechanically comply with the structure and mechanics of the capillary. The deformability of cells cultured in petri dishes, microcosmically homogeneous (HOM), and heterogeneous (HET) dextran hydrogels was investigated in vitro by measuring cell moduli through atomic force microscope (AFM), analyzing the expression of cytoskeletal protein via flow cytometry and fluorescent imaging. The in vitro experimental results demonstrate a progressive increase in cell deformability from 2D dishes, to HOM-hydrogel derived cells, and then to HET-hydrogel derived cells. The in vivo mouse experiment indicates the cells could deform accordingly and pass through easily with reduced resistance inside the mouse organs. It is suggested that the main destination of hMSC microcirculation could be selected between the spleen and liver of mice, by tuning cell mechanics that depends on the stimulus from HOM or HET hydrogel, which lays a potential foundation for the mechanically modified MSC therapy targeting organ lesions.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104987"},"PeriodicalIF":2.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-16DOI: 10.1016/j.yexmp.2025.104977
Dayene S. Gomes , Bruna Visniauskas , Prasad V.G. Katakam , Rosilane Taveira-da-Silva , Jennifer Lowe , Zoe Vallotton , Minolfa C. Prieto , Lucienne S. Lara
Salt-inducible kinase (SIK) is a serine/threonine kinase that acts as an intracellular Na+ sensor, playing a role in salt-sensitive hypertension. We aimed to evaluate the therapeutic potential of YKL-05-099, a selective SIK inhibitor, in protecting kidney function and attenuating salt-sensitive hypertension. Male adult C57BL/6 J mice were randomly assigned to either a normal sodium (0.5 % NaCl; NS) or high‑sodium diet (4 % NaCl; HS) and further divided into two subgroups – receiving either intraperitoneal injection of saline or SIK inhibitor (SIKi; YKL-05-099, 20 mg/Kg/day). Blood pressure was measured by radiotelemetry for 15 days. On days 7 and 14, mice were placed in metabolic cages for 24 h urine collection. At the end of the treatment, blood and kidneys were collected for renal function assessment, and the renal cortex was extracted for biochemical analysis. HS intake led to a salt-sensitive hypertension model, as seen by increased systolic blood pressure (SPB), kidney damage and impairment in renal function. In the HS, SIKi treatment blocked the elevated SIK activity in the renal cortex, preventing kidney damage, proteinuria, and increased SBP. The Na+ balance was positive due, partly, to a higher (Na++K+)-ATPase activity in the HS. SIKi treatment exerted an anti-inflammatory effect by attenuating HS-dependent macrophage infiltration and ROS production and decreasing the metalloprotease activity. Consequently, the kidney damage biomarker monocyte chemotactic protein type 1 excretion was enhanced. In conclusion, SIK inhibition rescued HS mice from salt-sensitive hypertension and kidney insufficiency by blocking inflammation, metalloprotease activity, and oxidative stress.
Significance
Salt-sensitive hypertension is a major contributor to chronic kidney disease and cardiovascular morbidity worldwide. Despite its prevalence, the underlying mechanisms linking high salt intake to renal injury remain incompletely understood, and targeted therapies are lacking. This study identifies salt-inducible kinase (SIK) as a key mediator of salt-induced renal dysfunction and systemic hypertension. By using a selective SIK inhibitor (YKL-05-099), we demonstrate that pharmacological inhibition of SIK effectively prevents kidney damage, inflammation, oxidative stress, and high blood pressure in a preclinical model of salt-sensitive hypertension. These findings highlight SIK as a promising therapeutic target for preserving renal function and managing salt-induced hypertension, paving the way for novel interventions in salt-related cardiovascular and renal diseases.
{"title":"Treatment with YKL-05-099, a salt inducible kinase (SIK) inhibitor, attenuates salt-sensitive hypertension: The molecular outcomes of SIK in the kidney","authors":"Dayene S. Gomes , Bruna Visniauskas , Prasad V.G. Katakam , Rosilane Taveira-da-Silva , Jennifer Lowe , Zoe Vallotton , Minolfa C. Prieto , Lucienne S. Lara","doi":"10.1016/j.yexmp.2025.104977","DOIUrl":"10.1016/j.yexmp.2025.104977","url":null,"abstract":"<div><div>Salt-inducible kinase (SIK) is a serine/threonine kinase that acts as an intracellular Na<sup>+</sup> sensor, playing a role in salt-sensitive hypertension. We aimed to evaluate the therapeutic potential of YKL-05-099, a selective SIK inhibitor, in protecting kidney function and attenuating salt-sensitive hypertension. Male adult C57BL/6 J mice were randomly assigned to either a normal sodium (0.5 % NaCl; NS) or high‑sodium diet (4 % NaCl; HS) and further divided into two subgroups – receiving either intraperitoneal injection of saline or SIK inhibitor (SIKi; YKL-05-099, 20 mg/Kg/day). Blood pressure was measured by radiotelemetry for 15 days. On days 7 and 14, mice were placed in metabolic cages for 24 h urine collection. At the end of the treatment, blood and kidneys were collected for renal function assessment, and the renal cortex was extracted for biochemical analysis. HS intake led to a salt-sensitive hypertension model, as seen by increased systolic blood pressure (SPB), kidney damage and impairment in renal function. In the HS, SIKi treatment blocked the elevated SIK activity in the renal cortex, preventing kidney damage, proteinuria, and increased SBP. The Na<sup>+</sup> balance was positive due, partly, to a higher (Na<sup>+</sup>+K<sup>+</sup>)-ATPase activity in the HS. SIKi treatment exerted an anti-inflammatory effect by attenuating HS-dependent macrophage infiltration and ROS production and decreasing the metalloprotease activity. Consequently, the kidney damage biomarker monocyte chemotactic protein type 1 excretion was enhanced. In conclusion, SIK inhibition rescued HS mice from salt-sensitive hypertension and kidney insufficiency by blocking inflammation, metalloprotease activity, and oxidative stress.</div></div><div><h3>Significance</h3><div>Salt-sensitive hypertension is a major contributor to chronic kidney disease and cardiovascular morbidity worldwide. Despite its prevalence, the underlying mechanisms linking high salt intake to renal injury remain incompletely understood, and targeted therapies are lacking. This study identifies salt-inducible kinase (SIK) as a key mediator of salt-induced renal dysfunction and systemic hypertension. By using a selective SIK inhibitor (YKL-05-099), we demonstrate that pharmacological inhibition of SIK effectively prevents kidney damage, inflammation, oxidative stress, and high blood pressure in a preclinical model of salt-sensitive hypertension. These findings highlight SIK as a promising therapeutic target for preserving renal function and managing salt-induced hypertension, paving the way for novel interventions in salt-related cardiovascular and renal diseases.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104977"},"PeriodicalIF":2.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Small intestinal mucosal injuries are observed during treatment with enteric-coated, low-dose aspirin (LDA) through uncertain mechanism(s). Because aspirin (acetylsalicylic acid, ASA) is an acetylated form of the highly cytotoxic salicylic acid (SA), we hypothesized that SA deacetylated by esterases in the small intestine directly causes mucosal injuries. This study explored the mechanism(s) of ASA deacetylation to SA in the small intestinal environment.
Methods
ASA was added to the x, and deacetylation of added ASA and cell damage were evaluated. To explore the ASA deacetylation mechanism(s) in the intestinal environment, ASA was incubated with different pH phosphate buffers (4.01–9.10), pancreatic enzymes, homogenates of pancreas and IEC-6 cell, and caecum bacterial suspension (CBS). ASA and CBS were co-injected into the murine duodenum, and small intestinal damage was evaluated after an hour by histological observation.
Results
Intestinal cell damage was caused dependently on the deacetylation rate of added ASA to SA in the cell and culture media. In vitro, almost ASA was not deacetylated by incubation with different pH buffer, pancreatic enzymes, or IEC-6 cell homogenate, but deacetylation of ASA was significantly promoted with CBS. ASA deacetylation by bacterial esterases(s) was confirmed by adding an esterase-specific inhibitor, potassium fluoride. Furthermore, severe injuries throughout the entire murine small intestine were found after co-injection of ASA and CBS, but not after ASA alone.
Conclusions
Enteric-coated, LDA-induced mucosal injuries in the small intestine are mainly caused by direct cytotoxicity of SA deacetylated by enterobacterial esterase in the small intestine.
{"title":"Small intestinal bacteria accelerate aspirin-induced small intestinal injuries","authors":"Fumio Kakizaki , Teruo Miyazaki , Hajime Ueda , Junichi Iwamoto , Akira Honda , Tadashi Ikegami","doi":"10.1016/j.yexmp.2025.104984","DOIUrl":"10.1016/j.yexmp.2025.104984","url":null,"abstract":"<div><h3>Background</h3><div>Small intestinal mucosal injuries are observed during treatment with enteric-coated, low-dose aspirin (LDA) through uncertain mechanism(s). Because aspirin (acetylsalicylic acid, ASA) is an acetylated form of the highly cytotoxic salicylic acid (SA), we hypothesized that SA deacetylated by esterases in the small intestine directly causes mucosal injuries. This study explored the mechanism(s) of ASA deacetylation to SA in the small intestinal environment.</div></div><div><h3>Methods</h3><div>ASA was added to the x, and deacetylation of added ASA and cell damage were evaluated. To explore the ASA deacetylation mechanism(s) in the intestinal environment, ASA was incubated with different pH phosphate buffers (4.01–9.10), pancreatic enzymes, homogenates of pancreas and IEC-6 cell, and caecum bacterial suspension (CBS). ASA and CBS were co-injected into the murine duodenum, and small intestinal damage was evaluated after an hour by histological observation.</div></div><div><h3>Results</h3><div>Intestinal cell damage was caused dependently on the deacetylation rate of added ASA to SA in the cell and culture media. In vitro, almost ASA was not deacetylated by incubation with different pH buffer, pancreatic enzymes, or IEC-6 cell homogenate, but deacetylation of ASA was significantly promoted with CBS. ASA deacetylation by bacterial esterases(s) was confirmed by adding an esterase-specific inhibitor, potassium fluoride. Furthermore, severe injuries throughout the entire murine small intestine were found after co-injection of ASA and CBS, but not after ASA alone.</div></div><div><h3>Conclusions</h3><div>Enteric-coated, LDA-induced mucosal injuries in the small intestine are mainly caused by direct cytotoxicity of SA deacetylated by enterobacterial esterase in the small intestine.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104984"},"PeriodicalIF":2.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-14DOI: 10.1016/j.yexmp.2025.104982
Qingqing Wang , Wenxue Ma
Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment (TME), significantly influencing cancer progression and therapeutic responses. TAMs polarize into M1 or M2 phenotypes, exerting distinct functional roles. M1-type macrophages promote inflammation and tumor cell destruction, whereas M2-type macrophages facilitate immune suppression, angiogenesis, and metastasis. However, inconsistencies and mischaracterizations in the literature regarding TAM classification have led to confusion in the field, potentially impeding the development of effective macrophage-targeted immunotherapies. This commentary highlights the need for clear and standardized nomenclature, clarifies the functional distinctions between M1- and M2- type TAMs, and explores the signaling pathways and environmental factors driving their polarization. We also discuss emerging TAM subtypes and the therapeutic significance of accurate classification, including macrophage reprogramming strategies. Standardizing terminology and addressing misconceptions will be critical to advancing macrophage-based immunotherapies and improving clinical outcomes in cancer treatment.
{"title":"Revisiting TAM polarization: beyond M1- and M2-type TAM toward clinical precision in macrophage-targeted therapy","authors":"Qingqing Wang , Wenxue Ma","doi":"10.1016/j.yexmp.2025.104982","DOIUrl":"10.1016/j.yexmp.2025.104982","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment (TME), significantly influencing cancer progression and therapeutic responses. TAMs polarize into M1 or M2 phenotypes, exerting distinct functional roles. M1-type macrophages promote inflammation and tumor cell destruction, whereas M2-type macrophages facilitate immune suppression, angiogenesis, and metastasis. However, inconsistencies and mischaracterizations in the literature regarding TAM classification have led to confusion in the field, potentially impeding the development of effective macrophage-targeted immunotherapies. This commentary highlights the need for clear and standardized nomenclature, clarifies the functional distinctions between M1- and M2- type TAMs, and explores the signaling pathways and environmental factors driving their polarization. We also discuss emerging TAM subtypes and the therapeutic significance of accurate classification, including macrophage reprogramming strategies. Standardizing terminology and addressing misconceptions will be critical to advancing macrophage-based immunotherapies and improving clinical outcomes in cancer treatment.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104982"},"PeriodicalIF":2.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1016/j.yexmp.2025.104983
Xiaoyun Zhang , Yingyu Wang , Xinyi Guo , Yu Xiao , Weiguo Wan , Hejian Zou , Xue Yang
Fibrosis is a common pathological feature of most chronic diseases progressing to the end stage, with its specific pathogenesis still unclear and lacking effective therapeutic approaches. Mitochondria are essential organelles responsible for energy production and the maintenance of cellular homeostasis. Increasing evidence indicates that mitochondrial dysfunction is closely associated with the onset and progression of fibrotic diseases. In this review, we explore the relationship between mitophagy, oxidative stress, mitochondrial dynamics, mtDNA release, and progression of fibrosis from the perspective of mitochondrial dysfunction. Furthermore, we summarized the latest research advances of mitochondrial dysfunction in lung, liver, kidney and skin fibrosis, and provided an overview of the potential therapeutic use of mesenchymal stem cell-derived exosomes in the treatment of fibrotic diseases by improving mitochondrial function, aiming to deepen the understanding of mitochondrial dysfunction in the pathogenesis of fibrotic diseases and provide new insights into targeting mitochondria in the treatment of fibrotic diseases.
{"title":"Mitochondrial dysfunction in fibrotic diseases: Research progress and MSC-exos therapy","authors":"Xiaoyun Zhang , Yingyu Wang , Xinyi Guo , Yu Xiao , Weiguo Wan , Hejian Zou , Xue Yang","doi":"10.1016/j.yexmp.2025.104983","DOIUrl":"10.1016/j.yexmp.2025.104983","url":null,"abstract":"<div><div>Fibrosis is a common pathological feature of most chronic diseases progressing to the end stage, with its specific pathogenesis still unclear and lacking effective therapeutic approaches. Mitochondria are essential organelles responsible for energy production and the maintenance of cellular homeostasis. Increasing evidence indicates that mitochondrial dysfunction is closely associated with the onset and progression of fibrotic diseases. In this review, we explore the relationship between mitophagy, oxidative stress, mitochondrial dynamics, mtDNA release, and progression of fibrosis from the perspective of mitochondrial dysfunction. Furthermore, we summarized the latest research advances of mitochondrial dysfunction in lung, liver, kidney and skin fibrosis, and provided an overview of the potential therapeutic use of mesenchymal stem cell-derived exosomes in the treatment of fibrotic diseases by improving mitochondrial function, aiming to deepen the understanding of mitochondrial dysfunction in the pathogenesis of fibrotic diseases and provide new insights into targeting mitochondria in the treatment of fibrotic diseases.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104983"},"PeriodicalIF":2.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ineffective erythropoiesis, the main cause of anemia in β-thalassemia disease, is characterized by dramatic expansion of erythroblasts and increased erythroblast cell death. The absence or reduction of β-globin chains causes an accumulation of excess α-globin chains and generates cytotoxic reactive oxidant species, resulting in erythroblast cell death. Metabolism provides energy, building blocks for macromolecule synthesis, and cofactors for antioxidative defense systems. We hypothesized that β-thalassemia erythroblasts might alter their metabolism to cope with increased proliferation and cellular stress. Herein, transcriptomic analysis of basophilic and polychromatic erythroblasts isolated from bone marrow obtained from β-thalassemia/HbE patients showed the global up-regulation of metabolic genes in glycolysis, TCA cycle, pentose phosphate pathway, ATP, and fatty acid synthesis pathway. The expression of metabolic genes during terminal erythropoiesis was further determined by PCR array and RT-qPCR in erythroblast culture obtained from β-thalassemia/HbE patients with mild and severe symptoms. The increased expression of enolase1, isocitrate dehydrogenase 1, and bisphosphoglycerate mutase was observed in mild cases compared to severe patients, suggesting that mild patients might modulate metabolic flux for cellular stress defense mechanisms, reducing disease severity. Moreover, the role of BPGM in regulating erythroid differentiation was demonstrated in K562 cells. Inhibition of BPGM promotes cell differentiation in K562 cells. Understanding metabolic reprogramming in thalassemia erythropoiesis opens new therapeutic approaches for β-thalassemia/HbE treatment. Further research is needed to explore how metabolism affects ineffective erythropoiesis and supports thalassemic erythroblasts' high proliferation and oxidative stress defense.
{"title":"Metabolic reprogramming during ineffective erythropoiesis in β-thalassemia/HbE disease","authors":"Chanyanat Sukhuma , Donny Nauphar , Khanita Nuamsee , Wasinee Kheansaard , Kittiphong Paiboonsukwong , Alisa Wilantho , Chumpol Ngamphiw , Pornthip Chaichompoo , Sissades Tongsima , Saovaros Svasti , Phatchariya Phannasil","doi":"10.1016/j.yexmp.2025.104980","DOIUrl":"10.1016/j.yexmp.2025.104980","url":null,"abstract":"<div><div>Ineffective erythropoiesis, the main cause of anemia in β-thalassemia disease, is characterized by dramatic expansion of erythroblasts and increased erythroblast cell death. The absence or reduction of β-globin chains causes an accumulation of excess α-globin chains and generates cytotoxic reactive oxidant species, resulting in erythroblast cell death. Metabolism provides energy, building blocks for macromolecule synthesis, and cofactors for antioxidative defense systems. We hypothesized that β-thalassemia erythroblasts might alter their metabolism to cope with increased proliferation and cellular stress. Herein, transcriptomic analysis of basophilic and polychromatic erythroblasts isolated from bone marrow obtained from β-thalassemia/HbE patients showed the global up-regulation of metabolic genes in glycolysis, TCA cycle, pentose phosphate pathway, ATP, and fatty acid synthesis pathway. The expression of metabolic genes during terminal erythropoiesis was further determined by PCR array and RT-qPCR in erythroblast culture obtained from β-thalassemia/HbE patients with mild and severe symptoms. The increased expression of enolase1, isocitrate dehydrogenase 1, and bisphosphoglycerate mutase was observed in mild cases compared to severe patients, suggesting that mild patients might modulate metabolic flux for cellular stress defense mechanisms, reducing disease severity. Moreover, the role of BPGM in regulating erythroid differentiation was demonstrated in K562 cells. Inhibition of BPGM promotes cell differentiation in K562 cells. Understanding metabolic reprogramming in thalassemia erythropoiesis opens new therapeutic approaches for β-thalassemia/HbE treatment. Further research is needed to explore how metabolism affects ineffective erythropoiesis and supports thalassemic erythroblasts' high proliferation and oxidative stress defense.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104980"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-27DOI: 10.1016/j.yexmp.2025.104978
Beverly A. Teicher , Thomas S. Dexheimer , Li Chen , Thomas Silvers , Eric M. Jones , Nathan P. Coussens , J. Paul Eder , James H. Doroshow
The potential of novobiocin, recently identified to be a DNA POLѲ inhibitor, to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells, tumor-bearing mice and in Phase 1 clinical trial in combination with cyclophosphamide or cisplatin. Genetic alterations which may increase or decrease POLѲ inhibitor effects have been elucidated. Thirty patient-derived tumor cell lines with known BRCA, ATM, ATR, POLѲ, XRCC1, PALB2, PARP1, LIG3 alterations as well as know gLOH% and MSI status were screened in a mct-spheroid assay (tumor cells, endothelial cells, mesenchymal stem cells) with a POLѲ inhibitor, novobiocin, ART-558, and RP6685, alone or in simultaneous combination with a FDA-approved or investigational anticancer small molecule with a 7-day exposure and a CellTiter-Glo 3D luminescence endpoint. As single agents, the POLѲ inhibitors had little or no cytotoxicity. In simultaneous combination with ART-558, talazoparib produced greater-than-additive cytotoxicity at the highest concentrations of the POLѲ inhibitors in the 922,993–354-T-J3-PDC endometrial serous carcinoma mct-spheroids. Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922,993–354-T-J3 mct-spheroids. The combination of POLѲ inhibitors ART-558 and RP6685, and the Chk1/2 inhibitor prexasertib produced up to 1 log increase in cytotoxicity in the 922,993–354-T-J3 mct-spheroids. Regions of potentiation were evident in the 922,993–354-T-J3-PDC endometrial carcinoma survival surface plots at the highest concentration of paclitaxel tested, while regions of potentiation were evident in the paclitaxel mid-concentrations of the 299,254–011-R-J1-PDC melanoma mct-spheroids survival surface plots as determined by the Bliss independence calculation. DNA POLѲ is recruited to DNA double-strand breaks as a component of repair. POLѲ allosteric inhibitors, novobiocin, ART558 and RP-6685, have entered clinical trial. The current study explores the cytotoxicity of POLѲ inhibitors in combination with anticancer drugs and investigational agents in patient-derived cell lines grown as mct-spheroids.
{"title":"Polymerase Ѳ inhibitors combinations with approved and investigational agents in patient-derived tumor multi-cell type (mct) spheroids","authors":"Beverly A. Teicher , Thomas S. Dexheimer , Li Chen , Thomas Silvers , Eric M. Jones , Nathan P. Coussens , J. Paul Eder , James H. Doroshow","doi":"10.1016/j.yexmp.2025.104978","DOIUrl":"10.1016/j.yexmp.2025.104978","url":null,"abstract":"<div><div>The potential of novobiocin, recently identified to be a DNA POLѲ inhibitor, to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells, tumor-bearing mice and in Phase 1 clinical trial in combination with cyclophosphamide or cisplatin. Genetic alterations which may increase or decrease POLѲ inhibitor effects have been elucidated. Thirty patient-derived tumor cell lines with known BRCA, ATM, ATR, POLѲ, XRCC1, PALB2, PARP1, LIG3 alterations as well as know gLOH% and MSI status were screened in a mct-spheroid assay (tumor cells, endothelial cells, mesenchymal stem cells) with a POLѲ inhibitor, novobiocin, ART-558, and RP6685, alone or in simultaneous combination with a FDA-approved or investigational anticancer small molecule with a 7-day exposure and a CellTiter-Glo 3D luminescence endpoint. As single agents, the POLѲ inhibitors had little or no cytotoxicity. In simultaneous combination with ART-558, talazoparib produced greater-than-additive cytotoxicity at the highest concentrations of the POLѲ inhibitors in the 922,993–354-T-J3-PDC endometrial serous carcinoma mct-spheroids. Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922,993–354-T-J3 mct-spheroids. The combination of POLѲ inhibitors ART-558 and RP6685, and the Chk1/2 inhibitor prexasertib produced up to 1 log increase in cytotoxicity in the 922,993–354-T-J3 mct-spheroids. Regions of potentiation were evident in the 922,993–354-T-J3-PDC endometrial carcinoma survival surface plots at the highest concentration of paclitaxel tested, while regions of potentiation were evident in the paclitaxel mid-concentrations of the 299,254–011-R-J1-PDC melanoma mct-spheroids survival surface plots as determined by the Bliss independence calculation. DNA POLѲ is recruited to DNA double-strand breaks as a component of repair. POLѲ allosteric inhibitors, novobiocin, ART558 and RP-6685, have entered clinical trial. The current study explores the cytotoxicity of POLѲ inhibitors in combination with anticancer drugs and investigational agents in patient-derived cell lines grown as mct-spheroids.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104978"},"PeriodicalIF":2.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A simple suspension method, wherein tablets and capsules are disintegrated in warm water (55 °C), is increasingly used in clinical settings. Previously, we demonstrated that probiotic strains were reduced or below limit of detection in a simultaneous simple suspension of probiotic preparations and metronidazole or fidaxomicin. This study investigated its effectiveness in mice with C. difficile infection (CDI).
Methods
Clostridium butyricum products and antibiotics used in this study were the Miya-BM tablet (CBM), metronidazole (Flagyl 250-mg oral tablet), and fidaxomicin (Dafclir 200-mg tablet). Non-infected mice received a simple suspension of CBM and antibiotics simultaneously to assess probiotic viability in the feces. Additionally, C. difficile counts and cytokine production were investigated in CDI-infected mice treated with these suspensions.
Results
C. butyricum was detectable in the feces of non-infected mice receiving simultaneous suspensions of CBM and antibiotics. In CDI-infected mice, simultaneous suspensions significantly reduced C. difficile colony counts in feces compared to CBM or antibiotics alone. Furthermore, suspensions downregulated tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10 levels, while upregulating interferon-γ (IFN-γ) levels in colon tissues, indicating reduced inflammation and an enhanced immune response.
Conclusions
This study using mice demonstrates the effectiveness of simultaneous simple suspensions of CBM and antibiotics in treating CDI. This approach significantly reduces C. difficile counts, modulates cytokine levels, and maintains probiotic viability, potentially making it a viable option for administration via gastric tubes in clinical settings.
{"title":"Effect of Clostridium butyricum and antibiotics using simultaneous simple suspension in mice with Clostridioides difficile infection","authors":"Hideo Kato , Mao Hagihara , Chihiro Shiraishi , Yuki Asai , Hiroshige Mikamo , Takuya Iwamoto","doi":"10.1016/j.yexmp.2025.104979","DOIUrl":"10.1016/j.yexmp.2025.104979","url":null,"abstract":"<div><h3>Background</h3><div>A simple suspension method, wherein tablets and capsules are disintegrated in warm water (55 °C), is increasingly used in clinical settings. Previously, we demonstrated that probiotic strains were reduced or below limit of detection in a simultaneous simple suspension of probiotic preparations and metronidazole or fidaxomicin. This study investigated its effectiveness in mice with <em>C. difficile</em> infection (CDI).</div></div><div><h3>Methods</h3><div><em>Clostridium butyricum</em> products and antibiotics used in this study were the Miya-BM tablet (CBM), metronidazole (Flagyl 250-mg oral tablet), and fidaxomicin (Dafclir 200-mg tablet). Non-infected mice received a simple suspension of CBM and antibiotics simultaneously to assess probiotic viability in the feces. Additionally, <em>C. difficile</em> counts and cytokine production were investigated in CDI-infected mice treated with these suspensions.</div></div><div><h3>Results</h3><div><em>C. butyricum</em> was detectable in the feces of non-infected mice receiving simultaneous suspensions of CBM and antibiotics. In CDI-infected mice, simultaneous suspensions significantly reduced <em>C. difficile</em> colony counts in feces compared to CBM or antibiotics alone. Furthermore, suspensions downregulated tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10 levels, while upregulating interferon-γ (IFN-γ) levels in colon tissues, indicating reduced inflammation and an enhanced immune response.</div></div><div><h3>Conclusions</h3><div>This study using mice demonstrates the effectiveness of simultaneous simple suspensions of CBM and antibiotics in treating CDI. This approach significantly reduces <em>C. difficile</em> counts, modulates cytokine levels, and maintains probiotic viability, potentially making it a viable option for administration via gastric tubes in clinical settings.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104979"},"PeriodicalIF":2.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-04-03DOI: 10.1016/j.yexmp.2025.104962
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