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Search Results (2,211)

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Keywords = ER-stress

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20 pages, 7055 KiB  
Article
Cardiopulmonary Bypass-Induced IL-17A Aggravates Caspase-12-Dependent Neuronal Apoptosis Through the Act1-IRE1-JNK1 Pathway
by Ruixue Zhao, Yajun Ma, Shujuan Li and Junfa Li
Biomolecules 2025, 15(8), 1134; https://doi.org/10.3390/biom15081134 - 6 Aug 2025
Abstract
Cardiopulmonary bypass (CPB) is associated with significant neurological complications, yet the mechanisms underlying brain injury remain unclear. This study investigated the role of interleukin-17A (IL-17A) in exacerbating CPB-induced neuronal apoptosis and identified vulnerable brain regions. Utilizing a rat CPB model and an oxygen–glucose [...] Read more.
Cardiopulmonary bypass (CPB) is associated with significant neurological complications, yet the mechanisms underlying brain injury remain unclear. This study investigated the role of interleukin-17A (IL-17A) in exacerbating CPB-induced neuronal apoptosis and identified vulnerable brain regions. Utilizing a rat CPB model and an oxygen–glucose deprivation/reoxygenation (OGD/R) cellular model, we demonstrated that IL-17A levels were markedly elevated in the hippocampus post-CPB, correlating with endoplasmic reticulum stress (ERS)-mediated apoptosis. Transcriptomic analysis revealed the enrichment of IL-17 signaling and apoptosis-related pathways. IL-17A-Neutralizing monoclonal antibody (mAb) and the ERS inhibitor 4-phenylbutyric acid (4-PBA) significantly attenuated neurological deficits and hippocampal neuronal damage. Mechanistically, IL-17A activated the Act1-IRE1-JNK1 axis, wherein heat shock protein 90 (Hsp90) competitively regulated Act1-IRE1 interactions. Co-immunoprecipitation confirmed the enhanced Hsp90-Act1 binding post-CPB, promoting IRE1 phosphorylation and downstream caspase-12 activation. In vitro, IL-17A exacerbated OGD/R-induced apoptosis via IRE1-JNK1 signaling, reversible by IRE1 inhibition. These findings identify the hippocampus as a key vulnerable region and delineate a novel IL-17A/Act1-IRE1-JNK1 pathway driving ERS-dependent apoptosis. Targeting IL-17A or Hsp90-mediated chaperone switching represents a promising therapeutic strategy for CPB-associated neuroprotection. This study provides critical insights into the molecular crosstalk between systemic inflammation and neuronal stress responses during cardiac surgery. Full article
(This article belongs to the Section Molecular Medicine)
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22 pages, 4653 KiB  
Review
Curcumin as a Dual Modulator of Pyroptosis: Mechanistic Insights and Therapeutic Potential
by Dong Oh Moon
Int. J. Mol. Sci. 2025, 26(15), 7590; https://doi.org/10.3390/ijms26157590 - 6 Aug 2025
Abstract
Curcumin, a polyphenolic compound derived from Curcuma longa, has drawn significant attention for its pleiotropic pharmacological activities, including anti-inflammatory and anticancer effects. Pyroptosis, an inflammatory form of programmed cell death mediated by inflammasome activation and gasdermin cleavage, has emerged as a critical [...] Read more.
Curcumin, a polyphenolic compound derived from Curcuma longa, has drawn significant attention for its pleiotropic pharmacological activities, including anti-inflammatory and anticancer effects. Pyroptosis, an inflammatory form of programmed cell death mediated by inflammasome activation and gasdermin cleavage, has emerged as a critical target in both chronic inflammatory diseases and cancer therapy. This review comprehensively explores the dual roles of curcumin in the regulation of NLRP3 inflammasome-mediated pyroptosis. Curcumin exerts inhibitory effects by suppressing NF-κB signaling, attenuating mitochondrial reactive oxygen species (ROS) and ER stress, preventing potassium efflux, and disrupting inflammasome complex assembly. Conversely, in certain cancer contexts, curcumin promotes pyroptosis by stabilizing NLRP3 through the inhibition of Smurf2-mediated ubiquitination. Molecular docking studies support curcumin’s direct binding to several pyroptosis-associated proteins, including NLRP3, AMPK, caspase-1, and Smurf2. These context-dependent regulatory effects underscore the therapeutic potential of curcumin as both an inflammasome suppressor in inflammatory diseases and a pyroptosis inducer in cancer. Full article
(This article belongs to the Collection Latest Review Papers in Bioactives and Nutraceuticals)
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13 pages, 1534 KiB  
Article
Analysis of Endoplasmic Reticulum Stress Proteins in Spermatogenic Cells After Paclitaxel Administration
by Suna Karadeniz Saygılı, Meryem Cansu Sahin, Fulya Yukcu and Senem Sanli
Curr. Issues Mol. Biol. 2025, 47(8), 620; https://doi.org/10.3390/cimb47080620 - 5 Aug 2025
Viewed by 81
Abstract
Background/Objectives: The aim of this research is to analyze the effect of paclitaxel on endoplasmic reticulum (ER) stress in spermatogenic cells. Methods: In the study, spermatogonium (GC1) and spermatocyte (GC2) cell lines were used. The IC50 dose of paclitaxel was calculated using an [...] Read more.
Background/Objectives: The aim of this research is to analyze the effect of paclitaxel on endoplasmic reticulum (ER) stress in spermatogenic cells. Methods: In the study, spermatogonium (GC1) and spermatocyte (GC2) cell lines were used. The IC50 dose of paclitaxel was calculated using an MTT assay. Each cell line was separated into two different groups: control (GC1-C, GC2-C) and paclitaxel-treated (GC1-P, GC2-P). The control cells were incubated under standard culture conditions. The paclitaxel group cells were incubated in culture medium containing the paclitaxel IC50 dose for 24 h. After the experiments, all groups were stained with GRP78, p-PERK, and p-eIF2α antibodies using semi-quantitative immunocytochemistry. Results: Paclitaxel showed cytotoxicity. In the experimental model of the paclitaxel-treated cells, all the markers showed elevated levels of immunoreactivity, indicating ER stress. Conclusions: Paclitaxel administration triggered ER stress in spermatogenic cells. Studies of ER-related stress mechanisms in spermatogenic cells with further advanced molecular analyses will be important for therapeutic strategies. Full article
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24 pages, 1861 KiB  
Review
Protective Effect of Melatonin Against Bisphenol A Toxicity
by Seong Soo Joo and Yeong-Min Yoo
Int. J. Mol. Sci. 2025, 26(15), 7526; https://doi.org/10.3390/ijms26157526 - 4 Aug 2025
Viewed by 189
Abstract
Bisphenol A (BPA), a prevalent endocrine-disrupting chemical, is widely found in various consumer products and poses significant health risks, particularly through hormone receptor interactions, oxidative stress, and mitochondrial dysfunction. BPA exposure is associated with reproductive, metabolic, and neurodevelopmental disorders. Melatonin, a neurohormone with [...] Read more.
Bisphenol A (BPA), a prevalent endocrine-disrupting chemical, is widely found in various consumer products and poses significant health risks, particularly through hormone receptor interactions, oxidative stress, and mitochondrial dysfunction. BPA exposure is associated with reproductive, metabolic, and neurodevelopmental disorders. Melatonin, a neurohormone with strong antioxidant and anti-inflammatory properties, has emerged as a potential therapeutic agent to counteract the toxic effects of BPA. This review consolidates recent findings from in vitro and animal/preclinical studies, highlighting melatonin’s protective mechanisms against BPA-induced toxicity. These include its capacity to reduce oxidative stress, restore mitochondrial function, modulate inflammatory responses, and protect against DNA damage. In animal models, melatonin also mitigates reproductive toxicity, enhances fertility parameters, and reduces histopathological damage. Melatonin’s ability to regulate endoplasmic reticulum (ER) stress and cell death pathways underscores its multifaceted protective role. Despite promising preclinical results, human clinical trials are needed to validate these findings and establish optimal dosages, treatment durations, and safety profiles. This review discusses the wide range of potential uses of melatonin for treating BPA toxicity and suggests directions for future research. Full article
(This article belongs to the Section Molecular Toxicology)
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27 pages, 2005 KiB  
Article
Glyoxalase 1 Inducer, trans-Resveratrol and Hesperetin–Dietary Supplement with Multi-Modal Health Benefits
by Mingzhan Xue, Naila Rabbani and Paul J. Thornalley
Antioxidants 2025, 14(8), 956; https://doi.org/10.3390/antiox14080956 (registering DOI) - 4 Aug 2025
Viewed by 208
Abstract
A dietary supplement, trans-resveratrol and hesperetin (tRES+HESP)—also known as GlucoRegulate—induces increased expression of glyoxalase 1 (Glo1) by activation of transcription factor Nrf2, countering accumulation of the reactive dicarbonyl glycating agent, methylglyoxal. tRES+HESP corrected insulin resistance and decreased fasting and postprandial plasma glucose [...] Read more.
A dietary supplement, trans-resveratrol and hesperetin (tRES+HESP)—also known as GlucoRegulate—induces increased expression of glyoxalase 1 (Glo1) by activation of transcription factor Nrf2, countering accumulation of the reactive dicarbonyl glycating agent, methylglyoxal. tRES+HESP corrected insulin resistance and decreased fasting and postprandial plasma glucose and low-grade inflammation in overweight and obese subjects in a clinical trial. The aim of this study was to explore, for the first time, health-beneficial gene expression other than Glo1 induced by tRES+HESP in human endothelial cells and fibroblasts in primary culture and HepG2 hepatoma cell line and activity of cis-resveratrol (cRES) as a Glo1 inducer. We measured antioxidant response element-linked gene expression in these cells in response to 5 µM tRES+HESP by the NanoString method. tRES+HESP increases gene expression linked to the prevention of dicarbonyl stress, lipid peroxidation, oxidative stress, proteotoxicity and hyperglycemia-linked glycolytic overload. Downstream benefits were improved regulation of glucose and lipid metabolism and decreased inflammation, extracellular matrix remodeling and senescence markers. The median effective concentration of tRES was ninefold lower than cRES in the Glo1 inducer luciferase reporter assay. The GlucoRegulate supplement provides a new treatment option for the prevention of type 2 diabetes and metabolic dysfunction–associated steatotic liver disease and supports healthy aging. Full article
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10 pages, 1191 KiB  
Article
RNA Sequencing on Muscle Biopsies from Exertional Rhabdomyolysis Patients Revealed Down-Regulation of Mitochondrial Function and Enhancement of Extracellular Matrix Composition
by Mingqiang Ren, Luke P. Michaelson, Ognoon Mungunsukh, Peter Bedocs, Liam Friel, Kristen Cofer, Carolyn E. Dartt, Nyamkhishig Sambuughin and Francis G. O’Connor
Genes 2025, 16(8), 930; https://doi.org/10.3390/genes16080930 (registering DOI) - 2 Aug 2025
Viewed by 189
Abstract
Background/Objective: Exertional rhabdomyolysis (ER) is primarily driven by mechanical stress on muscles during strenuous or unaccustomed exercise, often exacerbated by environmental factors like heat and dehydration. While the general cellular pathway involving energy depletion and calcium overload is understood in horse ER models, [...] Read more.
Background/Objective: Exertional rhabdomyolysis (ER) is primarily driven by mechanical stress on muscles during strenuous or unaccustomed exercise, often exacerbated by environmental factors like heat and dehydration. While the general cellular pathway involving energy depletion and calcium overload is understood in horse ER models, the underlying mechanisms specific to the ER are not universally known within humans. This study aimed to evaluate whether patients with ER exhibited transcriptional signatures that were significantly different from those of healthy individuals. Methods: This study utilized RNA sequencing on skeletal muscle samples from 19 human patients with ER history, collected at a minimum of six months after the most recent ER event, and eight healthy controls to investigate the transcriptomic landscape of ER. To identify any alterations in biological processes between the case and control groups, functional pathway analyses were conducted. Results: Functional pathway enrichment analyses of differentially expressed genes revealed strong suppression of mitochondrial function. This suppression included the “aerobic electron transport chain” and “oxidative phosphorylation” pathways, indicating impaired energy production. Conversely, there was an upregulation of genes associated with adhesion and extracellular matrix-related pathways, indicating active restoration of muscle function in ER cases. Conclusions: The study demonstrated that muscle tissue exhibited signs of suppressed mitochondrial function and increased extracellular matrix development. Both of these facilitate muscle recovery within several months after an ER episode. Full article
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33 pages, 2423 KiB  
Review
Chaperone-Mediated Responses and Mitochondrial–Endoplasmic Reticulum Coupling: Emerging Insight into Alzheimer’s Disease
by Manish Kumar Singh, Minghao Fu, Sunhee Han, Jyotsna S. Ranbhise, Wonchae Choe, Sung Soo Kim and Insug Kang
Cells 2025, 14(15), 1179; https://doi.org/10.3390/cells14151179 - 31 Jul 2025
Viewed by 474
Abstract
Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the [...] Read more.
Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. Full article
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18 pages, 5168 KiB  
Article
Arabidopsis Antiporter Genes as Targets of NO Signalling: Phylogenetic, Structural, and Expression Analysis
by Rabia Amir, Zuhra Qayyum, Sajeel Hussain, Byung-Wook Yun, Adil Hussain and Bong-Gyu Mun
Int. J. Mol. Sci. 2025, 26(15), 7195; https://doi.org/10.3390/ijms26157195 - 25 Jul 2025
Viewed by 196
Abstract
Nitric oxide is a gaseous signalling molecule produced by plants. Slight changes in endogenous NO levels have significant biochemical and physiological consequences. We investigated the structural and functional properties of NO-responsive antiporter genes in Arabidopsis thaliana. Phylogenetic analysis of 50 antiporter genes [...] Read more.
Nitric oxide is a gaseous signalling molecule produced by plants. Slight changes in endogenous NO levels have significant biochemical and physiological consequences. We investigated the structural and functional properties of NO-responsive antiporter genes in Arabidopsis thaliana. Phylogenetic analysis of 50 antiporter genes classified them into four subgroups based on the presence of NHX and CPA domains and the evolutionary similarity of the protein sequences. Antiporters were found scattered across the five chromosomes with unique physico-chemical properties and subcellular localisation in the plasma membrane, nucleus, chloroplasts, and vacuole. Furthermore, we performed QPCR analysis of eight different antiporter genes after infiltrating the plants with 1 mM CySNO (S-nitroso-L-cysteine), a nitric oxide donor, in WT and the loss-of-function atgsnor1-3 (disruptive S-nitrosoglutathione reductase 1 activity) plants. The AT1G79400 (CHX2), AT2G38170 (RCI4), and AT5G17400 (ER-ANT1) showed a significant increase in their expression in response to CySNO infiltration. However, their expression in atgsnor1-3 plants was found to be lower than in the WT plants, indicating a significant redundancy in the response of these genes to 1 mM levels of CySNO and physiological levels of SNOs in atgsnor1-3. On the other hand, a significant reduction in the expression of AT1G16380 (CHX1), AT2G47600 (MHX1), AT3G13320 (CAX2), and AT5G11800 (KEA6) was observed in WT plants after CySNO infiltration as well as in the leaves of atgsnor1-3 plants. Our study identified three NO-responsive antiporter genes in Arabidopsis, indicating their roles in stress responsiveness and ion homeostasis that could be used for further validation of their roles in NO signalling in plants. Full article
(This article belongs to the Special Issue Nitric Oxide Signalling in Plants)
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23 pages, 2161 KiB  
Review
Recent Advances in Engineering the Unfolded Protein Response in Recombinant Chinese Hamster Ovary Cell Lines
by Dyllan Rives, Tara Richbourg, Sierra Gurtler, Julia Martone and Mark A. Blenner
Int. J. Mol. Sci. 2025, 26(15), 7189; https://doi.org/10.3390/ijms26157189 - 25 Jul 2025
Viewed by 342
Abstract
Chinese hamster ovary (CHO) cells are the most common protein production platform for glycosylated biopharmaceuticals due to their relatively efficient secretion systems, post-translational modification (PTM) machinery, and quality control mechanisms. However, high productivity and titer demands can overburden these processes. In particular, the [...] Read more.
Chinese hamster ovary (CHO) cells are the most common protein production platform for glycosylated biopharmaceuticals due to their relatively efficient secretion systems, post-translational modification (PTM) machinery, and quality control mechanisms. However, high productivity and titer demands can overburden these processes. In particular, the endoplasmic reticulum (ER) can become overwhelmed with misfolded proteins, triggering the unfolded protein response (UPR) as evidence of ER stress. The UPR increases the expression of multiple genes/proteins, which are beneficial to protein folding and secretion. However, if the stressed ER cannot return to a state of homeostasis, a prolonged UPR results in apoptosis. Because ER stress poses a substantial bottleneck for secreting protein therapeutics, CHO cells are both selected for and engineered to improve high-quality protein production through optimized UPR and ER stress management. This is vital for optimizing industrial CHO cell fermentation. This review begins with an overview of common ER-stress related markers. Next, the optimal UPR profile of high-producing CHO cells is discussed followed by the context-dependency of a UPR profile for any given recombinant CHO cell line. Recent efforts to control and engineer ER stress-related responses in CHO cell lines through the use of various bioprocess operations and activation/inhibition strategies are elucidated. Finally, this review concludes with a discussion on future directions for engineering the CHO cell UPR. Full article
(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of the UPR and Cell Stress)
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17 pages, 7068 KiB  
Article
Effect of Ni-Based Buttering on the Microstructure and Mechanical Properties of a Bimetallic API 5L X-52/AISI 316L-Si Welded Joint
by Luis Ángel Lázaro-Lobato, Gildardo Gutiérrez-Vargas, Francisco Fernando Curiel-López, Víctor Hugo López-Morelos, María del Carmen Ramírez-López, Julio Cesar Verduzco-Juárez and José Jaime Taha-Tijerina
Metals 2025, 15(8), 824; https://doi.org/10.3390/met15080824 - 23 Jul 2025
Viewed by 317
Abstract
The microstructure and mechanical properties of welded joints of API 5L X-52 steel plates cladded with AISI 316L-Si austenitic stainless steel were evaluated. The gas metal arc welding process with pulsed arc (GMAW-P) and controlled arc oscillation were used to join the bimetallic [...] Read more.
The microstructure and mechanical properties of welded joints of API 5L X-52 steel plates cladded with AISI 316L-Si austenitic stainless steel were evaluated. The gas metal arc welding process with pulsed arc (GMAW-P) and controlled arc oscillation were used to join the bimetallic plates. After the root welding pass, buttering with an ERNiCrMo-3 filler wire was performed and multi-pass welding followed using an ER70S-6 electrode. The results obtained by optical and scanning electron microscopy indicated that the shielding atmosphere, welding parameters, and electric arc oscillation enabled good arc stability and proper molten metal transfer from the filler wire to the sidewalls of the joint during welding. Vickers microhardness (HV) and tensile tests were performed for correlating microstructural and mechanical properties. The mixture of ERNiCrMo-3 and ER70S-6 filler materials presented fine interlocked grains with a honeycomb network shape of the Ni–Fe mixture with Ni-rich grain boundaries and a cellular-dendritic and equiaxed solidification. Variation of microhardness at the weld metal (WM) in the middle zone of the bimetallic welded joints (BWJ) is associated with the manipulation of the welding parameters, promoting precipitation of carbides in the austenitic matrix and formation of martensite during solidification of the weld pool and cooling of the WM. The BWJ exhibited a mechanical strength of 380 and 520 MPa for the yield stress and ultimate tensile strength, respectively. These values are close to those of the as-received API 5L X-52 steel. Full article
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11 pages, 231 KiB  
Article
Tempol Induces Oxidative Stress, ER Stress and Apoptosis via MAPK/Akt/mTOR Pathway Suppression in HT29 (Colon) and CRL-1739 (Gastric) Cancer Cell Lines
by Gorkem Ozdemir and Halil Mahir Kaplan
Curr. Issues Mol. Biol. 2025, 47(7), 574; https://doi.org/10.3390/cimb47070574 - 21 Jul 2025
Viewed by 270
Abstract
Tempol is a synthetic antioxidant that shows promise in preclinical cancer studies by inhibiting growth and inducing apoptosis. Given that the Mitogen-Activated Protein Kinase (MAPK) and Protein Kinase B/Mammalian Target of Rapamycin (Akt/mTOR) signaling pathways are frequently dysregulated in gastric and colon cancers [...] Read more.
Tempol is a synthetic antioxidant that shows promise in preclinical cancer studies by inhibiting growth and inducing apoptosis. Given that the Mitogen-Activated Protein Kinase (MAPK) and Protein Kinase B/Mammalian Target of Rapamycin (Akt/mTOR) signaling pathways are frequently dysregulated in gastric and colon cancers and contribute to their progression, we investigated Tempol’s anti-cancer potential in HT29 (colon) and CRL-1739 (gastric) cancer cells. Cells were treated with 2 mM Tempol for 48 h, with untreated cells as controls. We evaluated apoptosis (Bax, cleaved caspase-3, and Bcl-2), key signaling pathway activity (p-ERK, p-JNK, p-AKT, and p-mTOR), and levels of stress- and apoptosis-related proteins (WEE1, GADD153, GRP78, and AIF). Tempol significantly increased pro-apoptotic Bax and cleaved caspase-3 (p < 0.0001) and decreased anti-apoptotic Bcl-2 (p < 0.0001) in both cell lines. Furthermore, Tempol markedly reduced the activity of p-ERK, p-JNK, p-AKT, and p-mTOR (p < 0.0001) and significantly increased the protein levels of WEE1, GADD153, GRP78, and AIF (p < 0.0001). Tempol treatment also led to a significant increase in total oxidant status and a decrease in total antioxidant status. In conclusion, our findings suggest that Tempol exhibits its anti-cancer activity through multiple interconnected mechanisms, primarily inducing apoptosis and oxidative stress, while concurrently suppressing pro-survival signaling pathways. These results highlight Tempol’s potential as a therapeutic agent for gastric and colon cancers. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
21 pages, 3526 KiB  
Article
Prenatal Bisphenol A Exposure Impairs Fetal Heart Development: Molecular and Structural Alterations with Sex-Specific Differences
by Alessandro Marrone, Anna De Bartolo, Vittoria Rago, Francesco Conforti, Lidia Urlandini, Tommaso Angelone, Rosa Mazza, Maurizio Mandalà and Carmine Rocca
Antioxidants 2025, 14(7), 863; https://doi.org/10.3390/antiox14070863 - 14 Jul 2025
Viewed by 439
Abstract
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, with increasing evidence suggesting that their origins may lie in prenatal life. Endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), have been implicated in the alteration of fetal programming mechanisms that [...] Read more.
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, with increasing evidence suggesting that their origins may lie in prenatal life. Endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), have been implicated in the alteration of fetal programming mechanisms that cause a predisposition to long-term cardiovascular vulnerability. However, the impact of prenatal endocrine disruption on fetal heart development and its sex-specific nature remains incompletely understood. This study investigates the molecular and structural effects of low-dose prenatal BPA exposure on fetal rat hearts. Our results reveal that BPA disrupts estrogen receptor (ER) signaling in a sex-dependent manner, with distinct alterations in ERα, ERβ, and GPER expression. BPA exposure also triggers significant inflammation, oxidative stress, and ferroptosis; this is evidenced by elevated NF-κB, IL-1β, TNF-α, and NLRP3 inflammasome activation, as well as impaired antioxidant defenses (SOD1, SOD2, CAT, and SELENOT), increased lipid peroxidation (MDA) and protein oxidation, decreased GPX4, and increased ACSL4 levels. These alterations are accompanied by increased markers of cardiac distension (ANP, BNP), extracellular matrix remodeling mediators, and pro-fibrotic regulators (Col1A1, Col3A1, TGF-β, and CTGF), with a more pronounced response in males. Histological analyses corroborated these molecular findings, revealing structural alterations as well as glycogen depletion in male fetal hearts, consistent with altered cardiac morphogenesis and metabolic stress. These effects were milder in females, reinforcing the notion of sex-specific vulnerability. Moreover, prenatal BPA exposure affected myocardial fiber architecture and vascular remodeling in a sex-dependent manner, as evidenced by reduced expression of desmin alongside increased levels of CD34 and Ki67. Overall, our findings provide novel insights into the crucial role of prenatal endocrine disruption during fetal heart development and its contribution to the early origins of CVD, underscoring the urgent need for targeted preventive strategies and further research into the functional impact of BPA-induced alterations on postnatal cardiac function and long-term disease susceptibility. Full article
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16 pages, 3493 KiB  
Article
Molecular Mechanisms of Aminoglycoside-Induced Ototoxicity in Murine Auditory Cells: Implications for Otoprotective Drug Development
by Cheng-Yu Hsieh, Jia-Ni Lin, Yi-Fan Chou, Chuan-Jen Hsu, Peir-Rong Chen, Yu-Hsuan Wen, Chen-Chi Wu and Chuan-Hung Sun
Int. J. Mol. Sci. 2025, 26(14), 6720; https://doi.org/10.3390/ijms26146720 - 13 Jul 2025
Viewed by 347
Abstract
Aminoglycoside antibiotics are critical in clinical use for treating severe infections, but they can occasionally cause irreversible sensorineural hearing loss. To establish a rational pathway for otoprotectant discovery, we provide an integrated, three-tier methodology—comprising cell-model selection, transcriptomic analysis, and a gentamicin–Texas Red (GTTR) [...] Read more.
Aminoglycoside antibiotics are critical in clinical use for treating severe infections, but they can occasionally cause irreversible sensorineural hearing loss. To establish a rational pathway for otoprotectant discovery, we provide an integrated, three-tier methodology—comprising cell-model selection, transcriptomic analysis, and a gentamicin–Texas Red (GTTR) uptake assay—to guide the development of otoprotective strategies. We first utilized two murine auditory cell lines—UB/OC-2 and HEI-OC1. We focused on TMC1 and OCT2 and further explored the underlying mechanisms of ototoxicity. UB/OC-2 exhibited a higher sensitivity to gentamicin, which correlated with elevated OCT2 expression confirmed via RT-PCR and Western blot. Transcriptomic analysis revealed upregulation of PI3K-Akt, calcium, and GPCR-related stress pathways in gentamicin-treated HEI-OC1 cells. Protein-level analysis further confirmed that gentamicin suppressed phosphorylated Akt while upregulating ER stress markers (GRP78, CHOP) and apoptotic proteins (cleaved caspase 3, PARP). Co-treatment with PI3K inhibitors (LY294002, wortmannin) further suppressed Akt phosphorylation, supporting the role of PI3K-Akt signaling in auditory cells. To visualize drug entry, we used GTTR to evaluate its applicability as a fluorescence-based uptake assay in these cell lines, which were previously employed mainly in cochlear explants. Sodium thiosulfate (STS) and N-acetylcysteine (NAC) significantly decreased GTTR uptake, suggesting a protective effect against gentamicin-induced hair cell damage. In conclusion, our findings showed a complex ototoxic cascade involving OCT2- and TMC1-mediated drug uptake, calcium imbalance, ER stress, and disruption of PI3K-Akt survival signaling. We believe that UB/OC-2 cells serve as a practical in vitro model for mechanistic investigations and screening of otoprotective compounds. Additionally, GTTR may be a simple, effective method for evaluating protective interventions in auditory cell lines. Overall, this study provides molecular-level insights into aminoglycoside-induced ototoxicity and introduces a platform for protective strategies. Full article
(This article belongs to the Special Issue Hearing Loss: Molecular Biological Insights)
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26 pages, 3018 KiB  
Article
High Glucose in Diabetic Hyperglycemia Perturbs Lymphocyte SERCA-Regulated Ca2+ Stores with Accompanying ER Stress and Signaling Dysfunction
by Md Nasim Uddin, James L. Graham, Peter J. Havel, Roshanak Rahimian and David W. Thomas
Biomolecules 2025, 15(7), 987; https://doi.org/10.3390/biom15070987 - 11 Jul 2025
Viewed by 521
Abstract
It is well recognized that patients with type 2 diabetes mellitus (T2DM) exhibit significant impairment of immune function resulting in a higher frequency of infections. We hypothesize in this study that a likely contributor to immune dysfunction in T2DM is alteration of T [...] Read more.
It is well recognized that patients with type 2 diabetes mellitus (T2DM) exhibit significant impairment of immune function resulting in a higher frequency of infections. We hypothesize in this study that a likely contributor to immune dysfunction in T2DM is alteration of T lymphocyte signaling functions induced by chronic hyperglycemia. In this study we have utilized the established UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat model of human T2DM to investigate whether progressive hyperglycemia diminishes T cell receptor (TCR)-releasable endoplasmic reticulum (ER) Ca2+ stores, an essential early antigen-stimulated signal driving T cell activation. Furthermore, results from this study demonstrate that chronic hyperglycemia markedly alters the expression profile of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ ion pumps, which are the major enzymatic ion transporters maintaining replenished TCR-sensitive Ca2+ pools. We conducted companion experiments using Jurkat T lymphocytes exposed to high glucose which allowed finer resolution of early disruptions to ER Ca2+ store integrity and greater clarity on SERCA isoform-specific roles in diabetes-induced Ca2+ signal dysregulation. In summary, these experiments suggest that hyperglycemia in T2DM drives an ER stress state manifesting in reduced expression of the SERCA pumps, erosion of ER Ca2+ stores and culminating in T cell and immune dysfunction. Full article
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17 pages, 1736 KiB  
Article
The Adjuvant Effect of Hyperbaric Oxygenation for Loxosceles rufescens Bite: A Case Series
by Simona Mrakic-Sposta, Alessandra Vezzoli, Carmela Graci, Maristella Gussoni, Attilio Cimmino, Cinzia Dellanoce, Enrico Maria Camporesi, Giovanni Sesana and Gerardo Bosco
Metabolites 2025, 15(7), 470; https://doi.org/10.3390/metabo15070470 - 10 Jul 2025
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Abstract
Background. The venom of Loxoscelesrufescens (L.r.), also known as the violin and/or brown spider, contains a wide variety of proteins and can induce a complex, intense, and uncontrolled inflammatory response, hemolysis, thrombocytopenia, dermo-necrosis, and renal failure. Studies have postulated the efficacy of [...] Read more.
Background. The venom of Loxoscelesrufescens (L.r.), also known as the violin and/or brown spider, contains a wide variety of proteins and can induce a complex, intense, and uncontrolled inflammatory response, hemolysis, thrombocytopenia, dermo-necrosis, and renal failure. Studies have postulated the efficacy of hyperbaric oxygen therapy (HBOT) for Loxosceles bites. However, data describing the use and beneficial effects of HBO are, to date, relatively scarce. Only a few cases of Loxosceles bites in Northern Italy have been documented, and there is no laboratory test available for the diagnosis. Objectives. We present seven cases (aged 54.5 ± 4.2 years) of patients who presented to the emergency room (E.R.) of Niguarda Hospital in Milan from March to October 2022. Methods. Blood and urine samples were collected and biomarkers of oxidative stress (OxS) (reactive oxygen species (ROS), total antioxidant capacity (TAC), lipid peroxidation (8iso-PFG2α), DNA damage (8-OH-dG)), inflammation (IL-6, IL-1β, TNF-α, sICAM1), and renal function (creatinine, neopterin, uric acid) before (T0), during (T1, T2), and after (1–2 wk T3–T4; 1 month T5) the HBOT treatment (US Navy Treatment Table 15 protocol) were studied. Results. At T0, patients showed a significant unbalance of OxS; high levels of ROS, 8-isoPGF2α, and inflammatory status (IL-6, TNF-α; sICAM); and a low level of antioxidant capacity. At the end of HBOT (T2), a significant reduction in Oxy-inflammation levels over time—8-iso −26%, 8-OH-dG −9%, IL-6 −71%, IL-1bβ −12%, TNF-α −13%, and sICAM1 −17%—associated with clinical improvement was shown. Conclusions. These reductions, along with those in renal function markers, mirrored the observed improvement in the evolution of the skin lesion and the patients’ self-reported general wellness and pain. In conclusion, HBOT should be considered a valuable therapeutic tool after L.r. bites. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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