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Search Results (1,207)

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17 pages, 1485 KiB  
Article
Selective Inhibition of Vascular Smooth Muscle Cell Function by COVID-19 Antiviral Drugs: Impact of Heme Oxygenase-1
by Kelly J. Peyton, Giovanna L. Durante and William Durante
Antioxidants 2025, 14(8), 945; https://doi.org/10.3390/antiox14080945 (registering DOI) - 31 Jul 2025
Viewed by 41
Abstract
Coronavirus disease 2019 (COVID-19) causes cardiovascular complications, which contributes to the high mortality rate of the disease. Emerging evidence indicates that aberrant vascular smooth muscle cell (SMC) function is a key driver of vascular disease in COVID-19. While antivirals alleviate the symptoms of [...] Read more.
Coronavirus disease 2019 (COVID-19) causes cardiovascular complications, which contributes to the high mortality rate of the disease. Emerging evidence indicates that aberrant vascular smooth muscle cell (SMC) function is a key driver of vascular disease in COVID-19. While antivirals alleviate the symptoms of COVID-19, it is not known whether these drugs directly affect SMCs. Accordingly, the present study investigated the ability of three approved COVID-19 antiviral drugs to influence SMC function. Treatment of SMCs with remdesivir (RDV), but not molnupiravir or nirmatrelvir, inhibited cell proliferation, DNA synthesis, and migration without affecting cell viability. RDV also stimulated an increase in heme oxygenase-1 (HO-1) expression that was not observed with molnupiravir or nirmatrelvir. The induction of HO-1 by RDV was abolished by mutating the antioxidant responsive element of the promoter, overexpressing dominant-negative NF-E2-related factor-2 (Nrf2), or treating cells with an antioxidant. Finally, silencing HO-1 partly rescued the proliferative and migratory response of RDV-treated SMCs, and this was reversed by carbon monoxide and bilirubin. In conclusion, the induction of HO-1 via the oxidant-sensitive Nrf2 signaling pathway contributes to the antiproliferative and antimigratory actions of RDV by generating carbon monoxide and bilirubin. These pleiotropic actions of RDV may prevent occlusive vascular disease in COVID-19. Full article
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17 pages, 1160 KiB  
Article
Enhanced Antioxidant and Antiproliferative Activities of Apple and Korean Green Chili Pepper Extracts Cultivated with Mineral Supplementation
by Ji-Sun Lim, Mi-Hee Yu, Dong Kyu Choi, Hae Won Kim, Seung-Hwan Park, Sin-Il Sin and Jong-Sang Kim
Foods 2025, 14(15), 2685; https://doi.org/10.3390/foods14152685 - 30 Jul 2025
Viewed by 153
Abstract
Apples and Korean green chili peppers are rich in phytochemicals and recognized for their diverse bioactive properties. Given the potential to enhance these beneficial compounds, this study investigated the effects of mineral supplementation during cultivation on the antioxidant and antiproliferative activities of extracts [...] Read more.
Apples and Korean green chili peppers are rich in phytochemicals and recognized for their diverse bioactive properties. Given the potential to enhance these beneficial compounds, this study investigated the effects of mineral supplementation during cultivation on the antioxidant and antiproliferative activities of extracts from both crops. Mineral-enriched cultivation significantly increased the total phenolic and flavonoid contents in both crops, which was accompanied by enhanced DPPH and ABTS radical scavenging activities. Moreover, the mineral-supplemented extracts of Korean green chili pepper activated the Nrf2 signaling pathway and upregulated downstream antioxidant enzymes, including heme oxygenase-1 (HO-1), γ-glutamylcysteine ligase (GCL), and glutathione peroxidase (GPx). Notably, the mineral-supplemented Korean green chili pepper extract significantly suppressed the proliferation of human colorectal cancer cells. These findings suggest that mineral supplementation during cultivation may improve the functional quality of apples and Korean green chili peppers, supporting their potential application in cancer prevention and complementary therapeutic strategies. Full article
(This article belongs to the Special Issue Bioactive Phenolic Compounds from Agri-Food and Its Wastes)
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20 pages, 2015 KiB  
Article
Origanum majorana Extracts: A Preliminary Comparative Study on Phytochemical Profiles and Bioactive Properties of Valuable Fraction and By-Product
by Simone Bianchi, Rosaria Acquaviva, Claudia Di Giacomo, Laura Siracusa, Leeyah Issop-Merlen, Roberto Motterlini, Roberta Foresti, Donata Condorelli and Giuseppe Antonio Malfa
Plants 2025, 14(15), 2264; https://doi.org/10.3390/plants14152264 - 23 Jul 2025
Viewed by 280
Abstract
Origanum majorana L. (O. majorana) (Lamiaceae) is an aromatic Mediterranean plant widely used in food, cosmetics, and traditional medicine due to its aroma and rich content of bioactive compounds. While its leaves and flowers are commonly utilized, lignified stems are often [...] Read more.
Origanum majorana L. (O. majorana) (Lamiaceae) is an aromatic Mediterranean plant widely used in food, cosmetics, and traditional medicine due to its aroma and rich content of bioactive compounds. While its leaves and flowers are commonly utilized, lignified stems are often discarded. This study compared hydroalcoholic extracts from the leaves and flowers (valuable fraction, VF) and stems (by-product, BP). Phytochemical analysis revealed qualitatively similar profiles, identifying 20 phenolic compounds, with Rosmarinic acid and Salvianolic acid B as the most and second most abundant, respectively. Antioxidant activity was evaluated in vitro using DPPH (IC50 [µg/mL]: VF 30.11 ± 3.46; BP 31.72 ± 1.46), H2O2 (IC50 [µg/mL]: VF 103.09 ± 4.97; BP 119.55 ± 10.58), and O2•− (IC50 [µg/mL]: VF 0.71 ± 0.062; BP 0.79 ± 0.070). Both extracts (20 µg/mL) fully restored oxidative balance in hemin-stressed AC16 cardiomyocytes, without altering the expression of catalase, heme-oxygenase 1, superoxide dismutase 2, or ferritin. Anti-inflammatory activity in LPS-stimulated RAW 264.7 macrophages showed that VF (IC50 400 µg/mL) reduced NO release to control levels, while BP achieved a ~60% reduction. Cytotoxicity was assessed on cancer cell lines: CaCo-2 (IC50 [µg/mL]: VF 154.1 ± 6.22; BP 305.2 ± 15.94), MCF-7 (IC50 [µg/mL]: VF 624.6 ± 10.27; BP 917.9 ± 9.87), and A549 (IC50 [µg/mL]: VF 720.8 ± 13.66; BP 920.2 ± 16.79), with no cytotoxicity on normal fibroblasts HFF-1 (IC50 > 1000 µg/mL for both extracts). Finally, both extracts slightly inhibited only CYP1A2 (IC50 [µg/mL]: VF 497.45 ± 9.64; BP 719.72 ± 11.37) and CYP2D6 (IC50 [µg/mL]: VF 637.15 ± 14.78, BP 588.70 ± 11.01). These results support the potential reuse of O. majorana stems as a sustainable source of bioactive compounds for nutraceutical and health-related applications. Full article
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23 pages, 2748 KiB  
Article
Relationships Between H2S and OT/OTR Systems in Preeclampsia
by Tamara Merz, Sarah Ecker, Nicole Denoix, Oscar McCook, Stefanie Kranz, Ulrich Wachter, Edit Rottler, Thomas Papadopoulos, Christoph Fusch, Cosima Brucker, Jakob Triebel, Thomas Bertsch, Peter Radermacher and Christiane Waller
Antioxidants 2025, 14(7), 880; https://doi.org/10.3390/antiox14070880 - 18 Jul 2025
Viewed by 267
Abstract
Pre-eclampsia (PE) is a hypertensive pregnancy complication. Oxidative stress is hypothesized to contribute to the pathophysiology of PE. Both the hydrogen sulfide (H2S) and oxytocin (OT) systems might play a role in the pathophysiology of PE, like their antioxidant and hypotensive [...] Read more.
Pre-eclampsia (PE) is a hypertensive pregnancy complication. Oxidative stress is hypothesized to contribute to the pathophysiology of PE. Both the hydrogen sulfide (H2S) and oxytocin (OT) systems might play a role in the pathophysiology of PE, like their antioxidant and hypotensive effects. Thus, the role of the interaction of the OT and H2S systems in the context of PE was further elucidated in the present clinical case–control study “NU-HOPE” (Nürnberg-Ulm: The role of H2S and Oxytocin Receptor in Pre-Eclampsia; ethical approval by the Landesärztekammer Bayern, file number 19033, 29 August 2019), comparing uncomplicated pregnancies, early onset PE (ePE, onset < 34 weeks gestational age) and late onset PE (lPE, onset > 34 weeks gestational age). Routine clinical data, serum H2S and homocysteine levels, and tissue protein expression, as well as nitrotyrosine formation, were determined. The main findings were (i) unchanged plasma sulfide levels, (ii) significantly elevated homocysteine levels in ePE, but not lPE, (iii) significantly elevated expression of H2S enzymes and OT receptor in the placenta in lPE, and (iv) significantly elevated nitrotyrosine formation in the lPE myometrium. Taken together, these findings suggest a role for the interaction of the endogenous H2S- and OT/OTR systems in the pathophysiology of pre-eclampsia, possibly linked to impaired antioxidant protection. Full article
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15 pages, 1389 KiB  
Article
Suppression of LPS-Induced Inflammation by Phragmites communis Young Leaf Extract via Multi-Target Inhibition of IκB, AP-1, and STAT1/3 Pathways in RAW 264.7 Cells
by Kyung-Yun Kang and Kyung-Wuk Park
Plants 2025, 14(14), 2178; https://doi.org/10.3390/plants14142178 - 14 Jul 2025
Viewed by 309
Abstract
Young leaves of reed (Phragmites communis) have been reported to exhibit antioxidant effects; however, their anti-inflammatory properties have not yet been investigated. In this study, we evaluated the effects of young reed leaf extract (PCE) on LPS-induced inflammation in RAW 264.7 [...] Read more.
Young leaves of reed (Phragmites communis) have been reported to exhibit antioxidant effects; however, their anti-inflammatory properties have not yet been investigated. In this study, we evaluated the effects of young reed leaf extract (PCE) on LPS-induced inflammation in RAW 264.7 cells and elucidated the underlying molecular mechanisms. Our results demonstrate that PCE significantly inhibited the production of nitric oxide (NO) by approximately 45% at 100 μg/mL (p < 0.01) and pro-inflammatory cytokines such as IL-6, TNF-α, and GM-CSF by 40–60% (p < 0.01) in LPS-stimulated RAW 264.7 macrophages, without cytotoxicity up to 100 μg/mL. PCE also downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and upregulated heme oxygenase-1 (HO-1) expression by approximately 2-fold at 100 μg/mL (p < 0.05). Mechanistically, these effects were associated with the inhibition of IκBα phosphorylation/degradation, IKKα/β phosphorylation, and AP-1 activation via the suppression of JNK and ERK signaling pathways, as well as the inhibition of STAT1/3 phosphorylation. Collectively, our findings suggest that PCE exerts anti-inflammatory effects by modulating the IκB, AP-1, and STAT1/3 signaling pathways, thereby suppressing inflammatory mediator production and enhancing antioxidant defense mechanisms in LPS-treated macrophages. Full article
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20 pages, 1227 KiB  
Review
Oxidative Stress Defense Module in Lung Cancers: Molecular Pathways and Therapeutic Approaches
by Eunsun Lee and Jeong Hee Hong
Antioxidants 2025, 14(7), 857; https://doi.org/10.3390/antiox14070857 - 13 Jul 2025
Viewed by 531
Abstract
The regulation of oxidative stress is an effective strategy for treating cancers. Therapeutic strategies for modulating an undesirable redox balance against cancers have included the enhancement of oxidative components, reducing the action of antioxidant systems, and the combined application of radiation and redox-modulating [...] Read more.
The regulation of oxidative stress is an effective strategy for treating cancers. Therapeutic strategies for modulating an undesirable redox balance against cancers have included the enhancement of oxidative components, reducing the action of antioxidant systems, and the combined application of radiation and redox-modulating drugs. A precise understanding of redox regulation is required to treat different kinds of cancer. This review focuses on the redox regulation and oxidative stress defense systems of lung cancers. Thus, we highlighted several enzymatic antioxidant components, such as superoxide dismutase, catalase, heme oxygenase-1, peroxiredoxin, glutaredoxin, thioredoxin, thioredoxin reductase, glutathione peroxidase, and antioxidant components, including glutathione, nuclear factor erythroid 2–related factor 2, 8-oxo-7,8-dihydro-2′-deoxyguanosine, and mitochondrial citrate carrier SLC25A1, based on PubMed and Scopus-indexed literature. Understanding the oxidative stress defense system in lung cancer would be beneficial for developing and expanding therapeutic strategies, such as drug development, drug design, and advanced delivery platforms. Full article
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22 pages, 2242 KiB  
Article
Quercetin Can Alleviate ETECK88-Induced Oxidative Stress in Weaned Piglets by Inhibiting Quorum-Sensing Signal Molecule Autoinducer-2 Production in the Cecum
by Hailiang Wang, Min Yao, Dan Wang, Mingyang Geng, Shanshan Nan, Xiangjian Peng, Yuyang Xue, Wenju Zhang and Cunxi Nie
Antioxidants 2025, 14(7), 852; https://doi.org/10.3390/antiox14070852 - 11 Jul 2025
Viewed by 422
Abstract
This study evaluated the inhibitory activity of quercetin at sub-inhibitory concentrations on quorum-sensing (QS) molecules in vitro and the effects of dietary supplementation with quercetin (for 24 consecutive days) on enterotoxigenic Escherichia coli (ETEC)-induced inflammatory and oxidative stress responses in weaned piglets. The [...] Read more.
This study evaluated the inhibitory activity of quercetin at sub-inhibitory concentrations on quorum-sensing (QS) molecules in vitro and the effects of dietary supplementation with quercetin (for 24 consecutive days) on enterotoxigenic Escherichia coli (ETEC)-induced inflammatory and oxidative stress responses in weaned piglets. The piglets were fed one of three diets: the basal diet (Con), ETEC challenge (K88) after the basal diet, or ETEC challenge (quercetin + K88) after the basal diet supplemented with 0.2% quercetin. In vitro experiments revealed that 5 mg/mL quercetin exhibited the strongest QS inhibitory activity and reduced pigment production by Chromobacterium violaceum ATCC12472 by 67.70%. In vivo experiments revealed that quercetin + K88 significantly increased immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG) levels in the serum, ileum mucosa, and colon mucosa; increased glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) levels in the serum, liver, and colon mucosa; and decreased cluster of differentiation 3 (CD3) and cluster of differentiation 8 (CD8)activity in the serum compared with K88 alone. Quercetin + K88 significantly alleviated pathological damage to the liver and spleen and upregulated antioxidant genes (nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1(HO-1), CAT, SOD, and glutathione s-transferase (GST)). Inducible nitric oxide synthase (iNOS) and kelch-like ech-associated protein 1 (Keap1), which cause oxidative damage to the liver and spleen, were significantly downregulated. The acetic acid content in the cecum was significantly increased, and the E. coli count and QS signal molecule autoinducer-2 (AI-2) yield were significantly reduced. In conclusion, 0.2% dietary quercetin can alleviate ETEC-induced inflammation and oxidative stress in weaned piglets. Full article
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18 pages, 5392 KiB  
Article
Kaempferol Alleviates Carbon Tetrachloride-Induced Liver Fibrosis in Mice by Regulating Intestinal Short-Chain Fatty Acids
by Siqi Zhang, Fei Tang, Zhe Zhou, Linhui Li, Yang Tang, Kaiwen Fu, Yang Tan and Ling Li
Int. J. Mol. Sci. 2025, 26(14), 6666; https://doi.org/10.3390/ijms26146666 - 11 Jul 2025
Viewed by 296
Abstract
Liver fibrosis remains a critical health concern with limited therapeutic options. Kaempferol (Kae) is a natural flavonoid widely present in natural plants, yet its role in modulating gut–liver axis interactions during fibrosis is unexplored. This study investigates the hepatoprotective effects of Kae on [...] Read more.
Liver fibrosis remains a critical health concern with limited therapeutic options. Kaempferol (Kae) is a natural flavonoid widely present in natural plants, yet its role in modulating gut–liver axis interactions during fibrosis is unexplored. This study investigates the hepatoprotective effects of Kae on alleviating carbon tetrachloride (CCl4)-induced liver fibrosis, and its underlying mechanisms, focusing on oxidative stress, gut microbiota, and short-chain fatty acids (SCFAs), are revealed. A mouse model of hepatic fibrosis was built by the subcutaneous injection of CCl4. Meanwhile, Kae was administered by gavage at doses of 25, 50, and 100 mg/kg body weight. Serum biomarkers, liver histopathology, oxidative damage markers, and nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase 1 (HO-1) signaling were analyzed. AML12 hepatocytes were pretreated with Kae or SCFAs (acetate, propionate, butyrate) before H2O2-induced oxidative injury. The changes in gut microbiota and the levels of SCFAs were assessed via 16S rRNA sequencing and GC-MS, respectively. Kae effectively alleviated the destruction of the liver morphology and tissue structure, reduced the infiltration of inflammatory cells, collagen deposition in the liver, and the expression of fibrotic factors, and downregulated the oxidative stress level in the liver of mice with liver fibrosis by activating the Nrf2/Keap1/HO-1 pathway (p < 0.05 or 0.01). In vitro, Kae significantly mitigated H2O2-induced cytotoxicity and oxidative damage (p < 0.05 or 0.01). Furthermore, Kae restored gut microbiota diversity, increased beneficial genera (e.g., Lactobacillus), and elevated both intestinal and hepatic SCFA levels (p < 0.01). The discrepant SCFA pretreatment similarly protected AML12 cells by activating Nrf2 signaling (p < 0.05 or 0.01). Our research suggests that Kae could inhibit CCl4-induced liver fibrosis by restoring the levels of intestinal metabolite SCFAs to reduce oxidative damage. Full article
(This article belongs to the Section Molecular Pharmacology)
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18 pages, 3608 KiB  
Article
Biochemical Insights into the Effects of a Small Molecule Drug Candidate on Imatinib-Induced Cardiac Inflammation
by Renáta Szabó, Denise Börzsei, András Nagy, Viktória Kiss, Zoltán Virág, Gyöngyi Kis, Nikoletta Almási, Szilvia Török, Médea Veszelka, Mária Bagyánszki, Nikolett Bódi, Bence Pál Barta, Patrícia Neuperger, Gabor J. Szebeni and Csaba Varga
Int. J. Mol. Sci. 2025, 26(14), 6661; https://doi.org/10.3390/ijms26146661 - 11 Jul 2025
Viewed by 403
Abstract
BGP-15, a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor exerts cardioprotective effects; however, the underlying mechanisms remain unclear. Therefore, our study aimed to investigate the effects of BGP-15 on the imatinib (Imtb)-induced cardiac inflammation at the biochemical level. Male rats were divided to control, Imtb-treated (60 [...] Read more.
BGP-15, a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor exerts cardioprotective effects; however, the underlying mechanisms remain unclear. Therefore, our study aimed to investigate the effects of BGP-15 on the imatinib (Imtb)-induced cardiac inflammation at the biochemical level. Male rats were divided to control, Imtb-treated (60 mg/kg/day for 14 days), and Imtb + BGP-15-treated animals. In this group Imtb was co-administered with BGP-15 at the dose of 10 mg/kg/day. At the end of the experiment, nuclear factor-kappa B/p65 (NF-κB/p65), nuclear transcription factor erythroid-2 related factor (Nrf2), heme oxygenase-1 (HO-1), high mobility group box 1 (HMGB1), and myeloperoxidase (MPO) were measured by Western blot. Chemokine and interleukins (ILs) were determined by Legendplex. Additionally, cardiac specific changes were visualized by immunohistochemistry. We demonstrated that Imtb increased NF-κB/p65, IL-6, IL-1β, IL-18, MCP-1, HMGB1, as well as the expression and activity of MPO. Conversely, the expressions of antioxidant Nrf2 and HO-1 were decreased. Administration of BGP-15 effectively mitigated these inflammatory alterations by significantly reducing pro-inflammatory cytokines and MPO activity, while simultaneously restoring and enhancing the levels of Nrf2 and HO-1, thereby promoting antioxidant defenses. The immunohistochemical staining further supported these biochemical changes. Our study provides new and comprehensive biochemical insight for managing Imtb-induced inflammatory responses via BGP-15-induced PARP1 inhibition. Full article
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21 pages, 7342 KiB  
Article
Synergistic Antioxidant Effects of C3G-Enriched Oryza sativa L. cv. RD83 Extract and α-Tocopherol Against H2O2-Induced Oxidative Stress in SH-SY5Y Cells
by Nootchanat Mairuae and Nut Palachai
Int. J. Mol. Sci. 2025, 26(13), 6490; https://doi.org/10.3390/ijms26136490 - 5 Jul 2025
Viewed by 325
Abstract
Oxidative stress, which contributes to neuronal cell dysfunction, is a critical factor in the pathogenesis of neurodegenerative diseases. Anthocyanins and α-tocopherol have shown potential in mitigating oxidative damage, and their combination may provide synergistic effects. This study investigated the combined effects of a [...] Read more.
Oxidative stress, which contributes to neuronal cell dysfunction, is a critical factor in the pathogenesis of neurodegenerative diseases. Anthocyanins and α-tocopherol have shown potential in mitigating oxidative damage, and their combination may provide synergistic effects. This study investigated the combined effects of a cyanidin-3-glucoside (C3G)-enriched extract derived from Oryza sativa L. cv. RD83 and α-tocopherol (C3GE) on hydrogen peroxide (H2O2)-induced oxidative stress in SH-SY5Y cells. Cells were treated with C3GE during exposure to 200 µM H2O2. Cell viability, intracellular reactive oxygen species (ROS), and oxidative stress biomarkers, including the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as malondialdehyde (MDA) levels, were evaluated. Protein expression levels of histone deacetylase 1 (HDAC1), nuclear factor erythroid 2 related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and SOD1 were also assessed. The combined treatment markedly improved cell viability, suppressed ROS accumulation, enhanced antioxidant enzyme activities, and significantly reduced MDA levels, suggesting effective protection against oxidative damage. Mechanistically, C3GE downregulated HDAC1 expression while upregulating Nrf2, HO-1, and SOD1, indicating that its antioxidant and neuroprotective effects are mediated, at least in part, through epigenetic modulation of redox-related signaling pathways. These results demonstrate a synergistic interaction between C3G and α-tocopherol that enhances cellular antioxidant defenses and supports redox homeostasis. In conclusion, the C3GE combination offers a promising therapeutic approach for preventing or attenuating oxidative stress-induced neuronal injury, with potential relevance for the treatment of neurodegenerative disorders. Full article
(This article belongs to the Special Issue Oxidative Stress and Disease: Basic and Biochemical Approaches)
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14 pages, 2340 KiB  
Article
Oral Administration of 5-Aminolevulinic Acid Does Not Ameliorate Autoimmune Diabetes in NOD Mice
by Shinpei Nishikido, Satoru Akazawa, Tetsuro Niri, Shin-Ichi Inoue, Katsuya Matsuda, Taiki Aoshi, Masahiro Nakashima, Ai Haraguchi, Ichiro Horie, Masakazu Kobayashi, Minoru Okita, Atsushi Kawakami and Norio Abiru
Diabetology 2025, 6(7), 62; https://doi.org/10.3390/diabetology6070062 - 1 Jul 2025
Viewed by 268
Abstract
Background/Objectives: 5-Aminolevulinic acid (5-ALA) is a biosynthetic precursor of heme that induces heme oxygenase-1 (HO-1). Therapeutic induction of HO-1 has shown effectiveness in various autoimmune disease models, including type 1 diabetes (T1D). However, the efficacy of 5-ALA as an HO-1 inducer in [...] Read more.
Background/Objectives: 5-Aminolevulinic acid (5-ALA) is a biosynthetic precursor of heme that induces heme oxygenase-1 (HO-1). Therapeutic induction of HO-1 has shown effectiveness in various autoimmune disease models, including type 1 diabetes (T1D). However, the efficacy of 5-ALA as an HO-1 inducer in T1D models remains unexplored. This study aimed to investigate the therapeutic efficacy of oral 5-ALA administration in preventing autoimmune diabetes development in nonobese diabetic (NOD) mice. Methods: We evaluated diabetes incidence, levels of insulin autoantibody, and severity of insulitis in 5-ALA-treated and control NOD mice. HO-1 expression of dendritic cells in the pancreatic islets and spleen of 5-ALA-treated NOD mice was measured. The IFN-γ/IL-17 of islet-infiltrating T cells and IL-10/IL-12 productions of dendritic cells in the spleen of 5-ALA-treated NOD mice were assessed. We stimulated islet antigen-specific CD4+ T cells with islet antigen-pulsed dendritic cells in the presence of 5-ALA and examined the proliferation of the T cells. Finally, we adoptively transferred islet antigen-specific CD4+ T cells into 5-ALA-treated, immunodeficient NOD-Rag1 knockout mice, and diabetes incidence in recipients was determined. Results: Oral 5-ALA treatment did not significantly impact diabetes incidence, levels of insulin autoantibody, and insulitis. No significant difference was observed in HO-1 expression in dendritic cells and cytokine production of T cells and dendritic cells. Similarly, there was no significant difference in the proliferation of islet antigen-specific CD4+ T cells in vitro and diabetes induction in transfer experiments. Conclusions: Oral administration of 5-ALA has a limited effect on suppressing the development of autoimmune diabetes in NOD mice. Full article
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17 pages, 5378 KiB  
Article
Toxicogenomics of Arsenic, Lead and Mercury: The Toxic Triad
by Joel Henrique Ellwanger, Marina Ziliotto and José Artur Bogo Chies
Pollutants 2025, 5(3), 18; https://doi.org/10.3390/pollutants5030018 - 30 Jun 2025
Cited by 1 | Viewed by 674
Abstract
The metalloid arsenic (As) and the metals lead (Pb) and mercury (Hg), which together we call the “Toxic Triad”, are among the pollutants of greatest global concern, harming the health of millions of people and contributing to biodiversity loss. The widespread distribution of [...] Read more.
The metalloid arsenic (As) and the metals lead (Pb) and mercury (Hg), which together we call the “Toxic Triad”, are among the pollutants of greatest global concern, harming the health of millions of people and contributing to biodiversity loss. The widespread distribution of As, Pb and Hg facilitates the exposure of humans and other species to these elements simultaneously, potentially amplifying their individual toxic effects. While As, Pb and Hg are well established as toxic elements, the mechanisms by which they interact with genetic material and impact the health of various species remain incompletely understood. This is particularly true regarding the combined effects of these three elements. In this context, the objective of this work was to perform a toxicogenomic analysis of As, Pb and Hg to highlight multiple aspects of element-gene interactions, in addition to revisiting information on the genotoxicity and carcinogenicity of the Toxic Triad. By using The Comparative Toxicogenomics Database, it was possible to identify that As interacts with 7666 genes across various species, while Pb influences 3525 genes, and Hg affects 692 genes. Removing duplicate gene names, the three elements interact with 9763 genes across multiple species. Considering the top-20 As/Pb/Hg-interacting genes, catalase (CAT), NFE2 like bZIP transcription factor 2 (NFE2L2), caspase 3 (CASP3), heme oxygenase (HMOX1), tumor necrosis factor (TNF), NAD(P)H quinone dehydrogenase 1 (NQO1) and interleukin 6 (IL6) were the most frequently observed. In total, 172 genes have the potential to interact with the three elements. Gene ontology analysis based on those genes evidenced that the Toxic Triad affects several cellular compartments and molecular functions, highlighting its effect on stimulation of toxic stress mechanisms. These 172 genes are also associated with various diseases, especially those of the urogenital tract, as well as being related to biological pathways involved in infectious diseases caused by viruses, bacteria and parasites. Arsenic was the element with the best-substantiated genotoxic and carcinogenic activity. This article details, through a toxicogenomic approach, the genetic bases that underlie the toxic effects of As, Pb and Hg. Full article
(This article belongs to the Special Issue Genotoxic Pollutants)
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16 pages, 1545 KiB  
Article
Lidocaine Affects Collagen Breakdown Without Compromising Cell Viability in Cultured Human Tenocytes: An In Vitro Study
by Filippo Randelli, Manuel G. Mazzoleni, Alessandra Menon, Alberto Fioruzzi, Dolaji Henin, Michele Sommariva and Nicoletta Gagliano
Cells 2025, 14(13), 988; https://doi.org/10.3390/cells14130988 - 27 Jun 2025
Viewed by 368
Abstract
Local anesthetics (LAs) are frequently administered via peritendinous ultrasound-guided injections for diagnostic and therapeutic purposes. Since in vitro studies have demonstrated LAs’ tenotoxic effects, raising concerns about their safety in infiltrative treatments, and since lidocaine (LD) emerged as one of the most cytotoxic [...] Read more.
Local anesthetics (LAs) are frequently administered via peritendinous ultrasound-guided injections for diagnostic and therapeutic purposes. Since in vitro studies have demonstrated LAs’ tenotoxic effects, raising concerns about their safety in infiltrative treatments, and since lidocaine (LD) emerged as one of the most cytotoxic LAs, we analyzed apoptosis, oxidative stress, and collagen turnover pathways in human tenocytes treated with LD, as well as the possible protection from LD-induced injury elicited by antioxidant ascorbic acid (AA). Tenocytes from gluteal tendons were treated with 0.2 and 1 mg/mL LD, or left untreated (CT), and treated with 50 μg/mL or 250 μg/mL AA. Nuclear morphology, cytochrome c expression, and caspase 3 activation were analyzed to study the effect of LD on apoptosis. Heme Oxygenase 1 (HO-1) mRNA and genes and proteins involved in collagen turnover were investigated using molecular approaches. Our results show that 0.2 and 1 mg/mL LD did not induce apoptosis and did not modify collagen synthesis and maturation. Conversely, increased collagen degradation was observed, and AA was not protective against oxidative stress induction in the presence of LD. Our findings suggest that LD does not affect the cell viability of tenocytes and that peritendinous LD injections are safe in this regard. LD-associated collagen degradation and the AA buffer effect are still debatable. Overall, our study contributes to clarifying the effect of LD on tenocytes’ viability and ECM homeostasis and provides new additional information useful for the safe clinical application of this drug and for further analysis. Full article
(This article belongs to the Special Issue Role of Extracellular Matrix in Cancer and Disease)
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18 pages, 4677 KiB  
Article
Swertiamarin Rescues 3-NPA-Induced Defective Follicular Development via Modulating the NRF2/HO-1 Signaling Pathway in Granulosa Cells
by Luoyu Mo, Gan Yang, Dongju Liu, Huai Zhang, Xiaodong Dong, Fuyong Li, Ziqian Huang, Dini Zhang, Yan Xiong, Xianrong Xiong, Honghong He, Jian Li and Shi Yin
Antioxidants 2025, 14(7), 794; https://doi.org/10.3390/antiox14070794 - 27 Jun 2025
Viewed by 378
Abstract
The normal development of ovarian follicles, characterized by oocyte growth and granulosa cell proliferation, is essential for maintaining female fertility. Elevated oxidative stress, resulting from various in vivo and in vitro factors, significantly impairs follicular development, ovulation, and overall female fertility. Swertiamarin, [...] Read more.
The normal development of ovarian follicles, characterized by oocyte growth and granulosa cell proliferation, is essential for maintaining female fertility. Elevated oxidative stress, resulting from various in vivo and in vitro factors, significantly impairs follicular development, ovulation, and overall female fertility. Swertiamarin, a naturally occurring iridoid terpenoid compound, exhibits multiple beneficial properties, including anti-hyperlipidemic, anti-diabetic, and antioxidant effects. This study investigates the impact of Swertiamarin on follicular development impairment induced by oxidative stress, using the commonly applied oxidant 3-nitrophthalic acid (3-NPA) in a murine model. Our findings indicate that Swertiamarin administration mitigates the adverse effects of 3-NPA on follicular development and ovulation. Further analyses reveal that Swertiamarin treatment partially enhances granulosa cell proliferation and inhibits apoptosis under oxidative stress in vivo and in vitro. Moreover, Swertiamarin reduces oxidative stress in ovaries and granulosa cells exposed to 3-NPA. The expression levels of key members of the NRF2/HO-1 signaling pathway, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (Ho-1), and superoxide dismutase 1 (Sod1), were upregulated following Swertiamarin supplementation in 3-NPA-treated ovaries and granulosa cells. In conclusion, the present study demonstrates that Swertiamarin can partially restore defective follicular development induced by oxidative stress via modulating the NRF2/HO-1 pathway in granulosa cells. These findings provide novel insights into the potential application of Swertiamarin in enhancing female reproductive health and offer a promising strategy for addressing reproductive damage caused by oxidative stress. Full article
(This article belongs to the Special Issue Redox Regulation in Animal Reproduction)
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17 pages, 1052 KiB  
Review
Dietary Heme Iron: A Review of Efficacy, Safety and Tolerability
by Douglas Kalman, Susan Hewlings, Alexis Madelyn-Adjei and Blake Ebersole
Nutrients 2025, 17(13), 2132; https://doi.org/10.3390/nu17132132 - 27 Jun 2025
Viewed by 1624
Abstract
Iron is a fundamental micronutrient essential for oxygen transport, enzymatic activity, and metabolic homeostasis. Yet it remains the most deficient nutrient in the world, with more than 2 billion people estimated with iron deficiency anemia. In the diet, animal foods provide iron primarily [...] Read more.
Iron is a fundamental micronutrient essential for oxygen transport, enzymatic activity, and metabolic homeostasis. Yet it remains the most deficient nutrient in the world, with more than 2 billion people estimated with iron deficiency anemia. In the diet, animal foods provide iron primarily as heme iron. Dietary heme iron is absorbed through the active transport pathways catalyzed by heme oxygenase in the intestinal enterocyte. This form of heme differs in its bioavailability, absorption mechanisms, and tolerability compared to non-heme forms of iron, including iron salts and chelates. Adding more heme iron to a diet, including through iron supplements, may help to reduce the prevalence of iron deficiency. Future research should focus on research of heme iron supplementation strategies to enhance absorption efficiency, gut microbiome health, and safety, ensuring optimal iron status across diverse populations. Full article
(This article belongs to the Section Micronutrients and Human Health)
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