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14 pages, 5715 KiB

Open AccessArticle

Neuroprotective Effect of Resveratrol against Manganese-Induced Oxidative Stress and Matrix Metalloproteinase-9 in an “In Vivo” Model of Neurotoxicity

by Tiziana Latronico, Rocco Rossano, Daniela Valeria Miniero, Elisabetta Casalino and Grazia Maria Liuzzi

Int. J. Mol. Sci. 2024, 25(4), 2142; https://doi.org/10.3390/ijms25042142 - 10 Feb 2024

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Abstract

Chronic exposure to manganese (Mn) leads to its accumulation in the central nervous system (CNS) and neurotoxicity with not well-known mechanisms. We investigated the involvement of matrix metalloproteinase (MMP)-2 and -9 in Mn neurotoxicity in an in vivo model of rats treated through [...] Read more.

Chronic exposure to manganese (Mn) leads to its accumulation in the central nervous system (CNS) and neurotoxicity with not well-known mechanisms. We investigated the involvement of matrix metalloproteinase (MMP)-2 and -9 in Mn neurotoxicity in an in vivo model of rats treated through an intraperitoneal injection, for 4 weeks, with 50 mg/kg of MnCl₂ in the presence or in the absence of 30 mg/kg of resveratrol (RSV). A loss of weight was observed in Mn-treated rats compared with untreated and RSV-treated rats. A progressive recovery of body weight was detected in rats co-treated with Mn and RSV. The analysis of brain homogenates indicated that RSV counteracted the Mn-induced increase in MMP-9 levels and reactive oxygen species production as well as the Mn-induced decrease in superoxide dismutase activity and glutathione content. In conclusion, Mn exposure, resulting in MMP-9 induction with mechanisms related to oxidative stress, represents a risk factor for the development of CNS diseases. Full article

(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity)

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15 pages, 3752 KiB

Open AccessArticle

Sb-Phenyl-N-methyl-5,6,7,12-tetrahydrodibenz[c,f][1,5]azastibocine Induces Perlecan Core Protein Synthesis in Cultured Vascular Endothelial Cells

by Takato Hara, Tomoko Konishi, Shuji Yasuike, Yasuyuki Fujiwara, Chika Yamamoto and Toshiyuki Kaji

Int. J. Mol. Sci. 2023, 24(4), 3656; https://doi.org/10.3390/ijms24043656 - 11 Feb 2023

Cited by 2 | Viewed by 2053

Abstract

Vascular endothelial cells synthesize and secrete perlecan, a large heparan sulfate proteoglycan that increases the anticoagulant activity of vascular endothelium by inducing antithrombin III and intensifying fibroblast growth factor (FGF)-2 activity to promote migration and proliferation in the repair process of damaged endothelium [...] Read more.

Vascular endothelial cells synthesize and secrete perlecan, a large heparan sulfate proteoglycan that increases the anticoagulant activity of vascular endothelium by inducing antithrombin III and intensifying fibroblast growth factor (FGF)-2 activity to promote migration and proliferation in the repair process of damaged endothelium during the progression of atherosclerosis. However, the exact regulatory mechanisms of endothelial perlecan expression remain unclear. Since organic–inorganic hybrid molecules are being developed rapidly as tools to analyze biological systems, we searched for a molecular probe to analyze these mechanisms using a library of organoantimony compounds and found that the Sb-phenyl-N-methyl-5,6,7,12-tetrahydrodibenz[c,f][1,5]azastibocine (PMTAS) molecule promotes the expression of perlecan core protein gene without exhibiting cytotoxicity in vascular endothelial cells. In the present study, we characterized proteoglycans synthesized by cultured bovine aortic endothelial cells using biochemical techniques. The results indicated that PMTAS selectively induced perlecan core protein synthesis, without affecting the formation of its heparan sulfate chain, in vascular endothelial cells. The results also implied that this process is independent of the endothelial cell density, whereas in vascular smooth muscle cells, it occurred only at high cell density. Thus, PMTAS would be a useful tool for further studies on the mechanisms underlying perlecan core protein synthesis in vascular cells, which is critical in the progression of vascular lesions, such as those during atherosclerosis. Full article

(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity)

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14 pages, 848 KiB

Open AccessArticle

Cadmium-Induced Proteinuria: Mechanistic Insights from Dose–Effect Analyses

by Soisungwan Satarug, David A. Vesey and Glenda C. Gobe

Int. J. Mol. Sci. 2023, 24(3), 1893; https://doi.org/10.3390/ijms24031893 - 18 Jan 2023

Cited by 8 | Viewed by 2526

Abstract

Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of [...] Read more.

Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of Cd (E_Cd), total protein (E_Prot), albumin (E_alb), β₂-microglobulin (E_β2M), and α1-microglobulin (E_α1M), which were recorded for residents of a Cd contamination area and a low-exposure control area of Thailand. Excretion of Cd and all proteins were normalized to creatinine clearance (C_cr) as E_Cd/C_cr and E_Prot/C_cr to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR ≤ 60 mL/min/1.73 m², while proteinuria was indicted by E_Pro/C_cr ≥ 20 mg/L of filtrate. E_Prot/C_cr varied directly with E_Cd/C_cr (β = 0.263, p < 0.001) and age (β = 0.252, p < 0.001). In contrast, eGFR values were inversely associated with E_Cd/C_cr (β = −0.266, p < 0.001) and age (β = −0.558, p < 0.001). At E_Cd/C_cr > 8.28 ng/L of filtrate, the prevalence odds ratios for proteinuria and low eGFR were increased 4.6- and 5.1-fold, respectively (p < 0.001 for both parameters). Thus, the eGFR and tubular protein retrieval were both simultaneously diminished by Cd exposure. Of interest, E_Cd/C_cr was more closely correlated with E_Prot/C_cr (r = 0.507), E_β2M (r = 0.430), and E_α1M/C_cr (r = 0.364) than with E_Alb/C_cr (r = 0.152). These data suggest that Cd may differentially reduce the ability of tubular epithelial cells to reclaim proteins, resulting in preferential reabsorption of albumin. Full article

(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity)

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11 pages, 3333 KiB

Open AccessArticle

Alterations in UPR Signaling by Methylmercury Trigger Neuronal Cell Death in the Mouse Brain

by Ryosuke Nomura, Nobumasa Takasugi, Hideki Hiraoka, Yuta Iijima, Takao Iwawaki, Yoshito Kumagai, Masatake Fujimura and Takashi Uehara

Int. J. Mol. Sci. 2022, 23(23), 15412; https://doi.org/10.3390/ijms232315412 - 6 Dec 2022

Cited by 6 | Viewed by 2011

Abstract

Methylmercury (MeHg), an environmental toxicant, induces neuronal cell death and injures specific areas of the brain. MeHg is known to induce oxidative and endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) pathway has a dual nature in that it regulates and protects [...] Read more.

Methylmercury (MeHg), an environmental toxicant, induces neuronal cell death and injures specific areas of the brain. MeHg is known to induce oxidative and endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) pathway has a dual nature in that it regulates and protects cells from an overload of improperly folded proteins in the ER, whereas excessively stressed cells are eliminated by apoptosis. Oxidative stress/ER stress induced by methylmercury exposure may tilt the UPR toward apoptosis, but there is little in vivo evidence of a direct link to actual neuronal cell death. Here, by using the ER stress-activated indicator (ERAI) system, we investigated the time course signaling alterations of UPR in vivo in the most affected areas, the somatosensory cortex and striatum. In the ERAI-Venus transgenic mice exposed to MeHg (30 or 50 ppm in drinking water), the ERAI signal, which indicates the activation of the cytoprotective pathway of the UPR, was only transiently enhanced, whereas the apoptotic pathway of the UPR was persistently enhanced. Furthermore, detailed analysis following the time course showed that MeHg-induced apoptosis is strongly associated with alterations in UPR signaling. Our results suggest that UPR modulation could be a therapeutic target for treating neuropathy. Full article

(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity)

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17 pages, 53620 KiB

Open AccessArticle

Chronic Arsenic Exposure Upregulates the Expression of Basal Transcriptional Factors and Increases Invasiveness of the Non-Muscle Invasive Papillary Bladder Cancer Line RT4

by Aaron A. Mehus, Nicholas Bergum, Peter Knutson, Swojani Shrestha, Matthew Kalonick, Xudong Zhou, Scott H. Garrett, Donald A. Sens, Mary Ann Sens and Seema Somji

Int. J. Mol. Sci. 2022, 23(20), 12313; https://doi.org/10.3390/ijms232012313 - 14 Oct 2022

Cited by 5 | Viewed by 1962

Abstract

The bladder is a target organ for inorganic arsenic, a carcinogen and common environmental contaminant found in soil and water. Urothelial carcinoma (UC) is the most common type of bladder cancer (BC) that develops into papillary or non-papillary tumors. Papillary tumors are mostly [...] Read more.

The bladder is a target organ for inorganic arsenic, a carcinogen and common environmental contaminant found in soil and water. Urothelial carcinoma (UC) is the most common type of bladder cancer (BC) that develops into papillary or non-papillary tumors. Papillary tumors are mostly non-muscle invasive (NMIUC), easier treated, and have a better prognosis. Urothelial carcinoma can be molecularly sub-typed as luminal or basal, with papillary tumors generally falling into the luminal category and basal tumors exclusively forming muscle invasive urothelial carcinomas (MIUC). It is unclear why some UCs develop more aggressive basal phenotypes. We hypothesized that chronic arsenic exposure of a papillary luminal bladder cancer would lead to the development of basal characteristics and increase in invasiveness. We treated the human papillary bladder cancer cell line RT4 with 1 µM arsenite (As³⁺) for twenty passages. Throughout the study, key luminal and basal gene/protein markers in the exposed cells were evaluated and at passage twenty, the cells were injected into athymic mice to evaluate tumor histology and measure protein markers using immunohistochemistry. Our data indicates that chronic As³⁺- treatment altered cellular morphology and decreased several luminal markers in cell culture. The histology of the tumors generated from the As³⁺-exposed cells was similar to the parent (non-treated) however, they appeared to be more invasive in the liver and displayed elevated levels of some basal markers. Our study demonstrates that chronic As³⁺ exposure is able to convert a non-invasive papillary bladder cancer to an invasive form that acquires some basal characteristics. Full article

(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity)

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14 pages, 1915 KiB

Open AccessArticle

Cadmium Toxicity Is Regulated by Peroxisome Proliferator-Activated Receptor δ in Human Proximal Tubular Cells

by Chikage Mori, Jin-Yong Lee, Maki Tokumoto and Masahiko Satoh

Int. J. Mol. Sci. 2022, 23(15), 8652; https://doi.org/10.3390/ijms23158652 - 3 Aug 2022

Cited by 5 | Viewed by 2140

Abstract

Cadmium (Cd) is a toxic heavy metal that is widely present in the environment. Renal proximal tubule disorder is the main symptom of Cd chronic poisoning. Our previous study demonstrated that Cd inhibits the total activities of peroxisome proliferator-activated receptor (PPAR) transcription factors [...] Read more.

Cadmium (Cd) is a toxic heavy metal that is widely present in the environment. Renal proximal tubule disorder is the main symptom of Cd chronic poisoning. Our previous study demonstrated that Cd inhibits the total activities of peroxisome proliferator-activated receptor (PPAR) transcription factors in human and rat proximal tubular cells. In this study, we investigated the involvement of PPAR in Cd renal toxicity using the HK-2 human proximal tubular cell line. Among PPAR isoform genes, only PPARD knockdown significantly showed resistance to Cd toxicity in HK-2 cells. The transcriptional activity of PPARδ was decreased not only by PPARD knockdown but also by Cd treatment. DNA microarray analysis showed that PPARD knockdown changed the expression of apoptosis-related genes in HK-2 cells. PPARD knockdown decreased apoptosis signals and caspase-3 activity induced by Cd treatment. PPARD knockdown did not affect the intracellular Cd level after Cd treatment. These results suggest that PPARδ plays a critical role in the modification of susceptibility to Cd renal toxicity and that the apoptosis pathway may be involved in PPARδ-related Cd toxicity. Full article

(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity)

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16 pages, 2674 KiB

Open AccessArticle

Selenium Antagonizes Cadmium-Induced Inflammation and Oxidative Stress via Suppressing the Interplay between NLRP3 Inflammasome and HMGB1/NF-κB Pathway in Duck Hepatocytes

by Zhanyou Cao, Fan Yang, Yiqun Lin, Jiyi Shan, Huabin Cao, Caiying Zhang, Yu Zhuang, Chenghong Xing and Guoliang Hu

Int. J. Mol. Sci. 2022, 23(11), 6252; https://doi.org/10.3390/ijms23116252 - 2 Jun 2022

Cited by 10 | Viewed by 2369

Abstract

Cadmium (Cd) is a toxic heavy metal that can accumulate in the liver of animals, damaging liver function. Inflammation and oxidative stress are considered primary causes of Cd-induced liver damage. Selenium (Se) is an antioxidant and can resist the detrimental impacts of Cd [...] Read more.

Cadmium (Cd) is a toxic heavy metal that can accumulate in the liver of animals, damaging liver function. Inflammation and oxidative stress are considered primary causes of Cd-induced liver damage. Selenium (Se) is an antioxidant and can resist the detrimental impacts of Cd on the liver. To elucidate the antagonism of Se on Cd against hepatocyte injury and its mechanism, duck embryo hepatocytes were treated with Cd (4 μM) and/or Se (0.4 μM) for 24 h. Then, the hepatocyte viability, oxidative stress and inflammatory status were assessed. The findings manifested that the accumulation of reactive oxygen species (ROS) and the levels of pro-inflammatory factors were elevated in the Cd group. Simultaneously, immunofluorescence staining revealed that the interaction between NOD-like receptor pyran domain containing 3 (NLRP3) and apoptosis-associated speck-like protein (ASC) was enhanced, the movement of high-mobility group box 1 (HMGB1) from nucleus to cytoplasm was increased and the inflammatory response was further amplified. Nevertheless, the addition of Se relieved the above-mentioned effects, thereby alleviating cellular oxidative stress and inflammation. Collectively, the results suggested that Se could mitigate Cd-stimulated oxidative stress and inflammation in hepatocytes, which might be correlated with the NLRP3 inflammasome and HMGB1/nuclear factor-κB (NF-κB) signaling pathway. Full article

(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity)

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12 pages, 1200 KiB

Open AccessReview

Cellular Conditions Responsible for Methylmercury-Mediated Neurotoxicity

by Masatake Fujimura and Fusako Usuki

Int. J. Mol. Sci. 2022, 23(13), 7218; https://doi.org/10.3390/ijms23137218 - 29 Jun 2022

Cited by 20 | Viewed by 2540

Abstract

Methylmercury (MeHg) is a widely known environmental pollutant that causes severe neurotoxicity. MeHg-induced neurotoxicity depends on various cellular conditions, including differences in the characteristics of tissues and cells, exposure age (fetal, childhood, or adulthood), and exposure levels. Research has highlighted the importance of [...] Read more.

Methylmercury (MeHg) is a widely known environmental pollutant that causes severe neurotoxicity. MeHg-induced neurotoxicity depends on various cellular conditions, including differences in the characteristics of tissues and cells, exposure age (fetal, childhood, or adulthood), and exposure levels. Research has highlighted the importance of oxidative stress in the pathogenesis of MeHg-induced toxicity and the site- and cell-specific nature of MeHg-induced neurotoxicity. The cerebellar granule cells and deeper layer cerebrocortical neurons are vulnerable to MeHg. In contrast, the hippocampal neurons are resistant to MeHg, even at high mercury accumulation levels. This review summarizes the mechanisms underlying MeHg-mediated intracellular events that lead to site-specific neurotoxicity. Specifically, we discuss the mechanisms associated with the redox ability, neural outgrowth and synapse formation, cellular signaling pathways, epigenetics, and the inflammatory conditions of microglia. Full article

(This article belongs to the Special Issue Mechanisms of Heavy Metal Toxicity)

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