PMID: 

J Trace Elem Med Biol. 2019 Mar ;52:37-47. Epub 2018 Nov 14. PMID: 30732897

Abstract Title: 

The relationship between mercury exposure and epigenetic alterations regarding human health, risk assessment and diagnostic strategies.

Abstract: 

BACKGROUND: Exposure to the environmental toxicants poses a serious threat to human health. The extent of exposure and the development of diseases are interrelated with each other. Chronic exposure to mercury (Hg) increases the risk of developing serious human disorders from embryo to adulthood.OBJECTIVES: The purpose of this review is to highlight the most common human disorders induced by Hg exposure on the basis of epigenetic mechanisms. A growing body of evidence shows that Hg exposure leads to alterations in the epigenetic markers.METHODS: We performed an organized search of the available literature using PubMed, Google Scholar, Medline, Reaxys, EMBASE and Scopus databases. All the relevant citations, including research and review articles in English were evaluated. The search terms included mercury, Hg, epigenetics, epigenetic alterations, DNA methylation, histone modifications, microRNAs (miRNAs), and risk assessment.RESULTS: Data on human toxicity due to Hg exposure shows broad variations in terms of chemical nature, doses, and the rate of exposure. Hg consumption either via foods or environmental sources may create deleterious health effects on various physiological systems at least partially through an epigenetic mechanism.CONCLUSION: Hg exposure could trigger epigenetic alterations, hence leading to various human disorders including reduced newborn cerebellum size, adverse behavioral outcomes, atherosclerosis and myocardial infarction. Similarly, in adults, occupational Hg exposure has been associated with an increased risk of autoimmunity. It has been revealed that miRNAs in the woman's cervix are a novel responder to maternal Hg exposure during pregnancy. Hg-induced epigenetic alterations analysis of kidney tissues showed a significant interruption in renal function. DNA methylation and histone post-translation modifications are predominant types of Hg epigenetic alterations.

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PMID: 

Biochim Biophys Acta Gen Subj. 2019 Dec ;1863(12):129299. Epub 2019 Feb 10. PMID: 30742953

Abstract Title: 

Mercury-induced inflammation and autoimmunity.

Abstract: 

BACKGROUND: Human exposure to mercury leads to a variety of pathologies involving numerous organ systems including the immune system. A paucity of epidemiological studies and suitable diagnostic criteria, however, has hampered collection of sufficient data to support a causative role for mercury in autoimmune diseases. Nevertheless, there is evidence that mercury exposure in humans is linked to markers of inflammation and autoimmunity. This is supported by experimental animal model studies, which convincingly demonstrate the biological plausibility of mercury as a factor in the pathogenesis of autoimmune disease.SCOPE OF THE REVIEW: In this review, we focus on ability of mercury to elicit inflammatory and autoimmune responses in both humans and experimental animal models.MAJOR CONCLUSIONS: Although subtle differences exist, the inflammatory and autoimmune responses elicited by mercury exposure in humans and experimental animal models show many similarities. Proinflammatory cytokine expression, lymphoproliferation, autoantibody production, and nephropathy are common outcomes. Animal studies have revealed significant strain dependent differences in inflammation and autoimmunity suggesting genetic regulation. This has been confirmed by the requirement for individual genes as well as genome wide association studies. Importantly, many of the genes required for mercury-induced inflammation and autoimmunity are also required for idiopathic systemic autoimmunity. A notable difference is that mercury-induced autoimmunity does not require type I IFN. This observation suggests that mercury-induced autoimmunity may arise by both common and specific pathways, thereby raising the possibility of devising criteria for environmentally associated autoimmunity.GENERAL SIGNIFICANCE: Mercury exposure likely contributes to the pathogenesis of autoimmunity.

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PMID: 

Toxicol Appl Pharmacol. 2019 May 1 ;370:1-13. Epub 2019 Mar 9. PMID: 30862457

Abstract Title: 

Developmental exposure to mercury chloride impairs social behavior in male offspring dependent on genetic background and maternal autoimmune environment.

Abstract: 

To date, the connection between inorganic mercury (Hg) and social behavior remains incompletely understood. The aim of this study was to investigate the influence of maternal autoimmunity by inorganic Hg (Hg) exposure on social behavior of offspring. Wild-type (WT) and immunoglobulin deficient (Ig) B10.S dams fertilized by male WT B10.S or SJL mice were treated with 50 μM Hg chloride (HgCl). Non-pregnant female WT B10.S mice were used to investigate factors regulating HgCl-induced autoimmunity to brain. HgClselectively impaired social behavior in male offspring, but not female offspring from WT B10.S dams× male SJL, in that only male offspring displayed reduced time distribution with the stranger mouse, decreased sniffing to the stranger mouse and increased self-grooming. HgCldid not disrupt social behavior of male or female offspring from WT B10.S dams× male WT B10.S or IgB10.S dams× male SJL. The offspring from WT and IgB10.S dams× male SJL had equivalent autoimmunity to brain antigens during HgClexposure, indicating that maternal, but not offspring-derived anti-brain antibodies (Ab) impaired social behavior of the offspring. Non-pregnant WT B10.S mice treated with HgClhad increased anti-brain Ab dependent on increase in CD4 T cell activation and IFNγ signaling to macrophages. IFNγ interaction with macrophages drove B cells and plasma cells to produce IgG. Therefore, HgClselectively impaired social behavior in males with certain genetic background via maternally derived anti-brain Ab production, thus providing a novel insight into our current understanding of Hg toxicity.

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PMID: 

Clin Immunol. 2020 Feb 4:108352. Epub 2020 Feb 4. PMID: 32032765

Abstract Title: 

Mercury-induced autoimmunity: Drifting from micro to macro concerns on autoimmune disorders.

Abstract: 

Mercury (Hg) is widely recognized as a neurotoxic metal, besides it can also act as a proinflammatory agent and immunostimulant, depending on individual exposure and susceptibility. Mercury exposure may arise from internal body pathways, such as via dental amalgams, preservatives in drugs and vaccines, and seafood consumption, or even from external pathways, i.e., occupation, environmental pollution, and handling of metallic items and cosmetics containing Hg. In susceptible individuals, chronic low Hg exposure may trigger local and systemic inflammation, even exacerbating the already existing autoimmune response in patients with autoimmunity. Mercury exposure can trigger dysfunction of the autoimmune responses and aggravate immunotoxic effects associated with elevated serum autoantibodies titers. The purpose of the present report is to provide a critical overview of the many issues associated with Hg exposure and autoimmunity. In addition, the paper also focuses on individual susceptibility and other health effects of Hg.

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PMID: 

Int J Mol Sci. 2019 Jun 22 ;20(12). Epub 2019 Jun 22. PMID: 31234550

Abstract Title: 

The Potential of Flavonoids for the Treatment of Neurodegenerative Diseases.

Abstract: 

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no treatments that slow or prevent disease development and progression. Regardless of the underlying cause of the disorder, age is the strongest risk factor for developing these maladies, suggesting that changes that occur in the aging brain put it at increased risk for neurodegenerative disease development. Moreover, since there are a number of different changes that occur in the aging brain, it is unlikely that targeting a single change is going to be effective for disease treatment. Thus, compounds that have multiple biological activities that can impact the various age-associated changes in the brain that contribute to neurodegenerative disease development and progression are needed. The plant-derived flavonoids have a wide range of activities that could make them particularly effective for blocking the age-associated toxicity pathways associated with neurodegenerative diseases. In this review, the evidence for beneficial effects of multiple flavonoids in models of AD, PD, HD, and ALS is presented and common mechanisms of action are identified. Overall, the preclinical data strongly support further investigation of specific flavonoids for the treatment of neurodegenerative diseases.

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PMID: 

J Cell Mol Med. 2020 Jan 19. Epub 2020 Jan 19. PMID: 31955523

Abstract Title: 

Catechin relieves hypoxia/reoxygenation-induced myocardial cell apoptosis via down-regulating lncRNA MIAT.

Abstract: 

BACKGROUND: Catechin protects heart from myocardial ischaemia/reperfusion (MI/R) injury. However, whether catechin inhibits H/R-induced myocardial cell apoptosis is largely unknown.OBJECTIVE: This study aims to investigate the underlying mechanism of catechin in inhibiting the apoptosis of H/R-induced myocardial cells.METHODS: LncRNA MIAT expression was detected by qRT-PCR. Cell viability of H9C2 cells was detected using CCK-8 assay. The apoptosis of H9C2 cells was detected by flow cytometry. The interaction between CREB and MIAT promoter regions was confirmed by dual-luciferase reporter gene assay and ChIP assay.RESULTS: In MI/R rats, catechin improved heart function and down-regulated lncRNA MIAT expression in myocardial tissue. In H/R-induced H9C2 cells, catechin protected against cell apoptosis, and lncRNA MIAT overexpression attenuated this protective effect of catechin. We confirmed that transcription factor CREB could bind to MIAT promoter region, and catechin suppressed lncRNA MIAT expression through up-regulating CREB. Catechin improved mitochondrial function and relieved apoptosis through promoting Akt/Gsk-3β activation. In addition, MIAT inhibited Akt/Gsk-3β activation and promoted cell apoptosis in H/R-induced H9C2 cells. Finally, we found catechin promoted Akt/Gsk-3β activation through inhibiting MIAT expression in H/R-induced H9C2 cells.CONCLUSION: Catechin relieved H/R-induced myocardial cell apoptosis through regulating CREB/lncRNA MIAT/Akt/Gsk-3β pathway.

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PMID: 

Biomed Res Int. 2016 ;2016:8502123. Epub 2016 Jun 22. PMID: 27419139

Abstract Title: 

Synergistic Effects of Sulfated Polysaccharides from Mexican Seaweeds against Measles Virus.

Abstract: 

Sulfated polysaccharides (SPs) extracted from five seaweed samples collected or cultivated in Mexico (Macrocystis pyrifera, Eisenia arborea, Pelvetia compressa, Ulva intestinalis, and Solieria filiformis) were tested in this study in order to evaluate their effect on measles virus in vitro. All polysaccharides showed antiviral activity (as measured by the reduction of syncytia formation) and low cytotoxicity (MTT assay) at inhibitory concentrations. SPs from Eisenia arborea and Solieria filiformis showed the highest antiviral activities (confirmed by qPCR) and were selected to determine their combined effect. Their synergistic effect was observed at low concentrations (0.0274 μg/mL and 0.011 μg/mL of E. arborea and S. filiformis SPs, resp.), which exhibited by far a higher inhibitory effect (96% syncytia reduction) in comparison to the individual SP effects (50% inhibition with 0.275 μg/mL and 0.985 μg/mL of E. arborea and S. filiformis, resp.). Time of addition experiments and viral penetration assays suggest that best activities of these SPs occur at different stages of infection. The synergistic effect would allow reducing the treatment dose and toxicity and minimizing or delaying the induction of antiviral resistance; sulfated polysaccharides of the tested seaweed species thus appear as promising candidates for the development of natural antiviral agents.

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PMID: 

PLoS Negl Trop Dis. 2020 Jan ;14(1):e0007843. Epub 2020 Jan 13. PMID: 31929528

Abstract Title: 

Antileishmanial activity of Urtica dioica extract against zoonotic cutaneous leishmaniasis.

Abstract: 

BACKGROUND: Neglected parasitic diseases (NTDs) like cutaneous leishmaniasis (CL) have caused high mortality and morbidity rate in developing countries. This disease is considered as one of the six major tropical diseases, and has a great importance in HIV infected individuals as an opportunistic infection in those areas that both infections are endemic. This study evaluated the therapeutic effects of the Urtica dioica L (U. dioica) aqueous extract as an anti-leishmanial herbal drug in-vitro and in-vivo, and in addition to that, evaluated two vital immune system cytokines including gamma interferon (IFN-γ) and interleukin-4 (IL-4) plus nitric oxide (NO) and arginase activity against Leishmania major (L. major) infected mice.METHODOLOGY/PRINCIPAL FINDINGS: In-vitro anti-leishmanial activity of U. dioica aqueous extract was determined using MTT method and also Parasite Rescue Transformation Assay. Also, the footpad lesion size and parasite load in BALB/c mice infected with L. major were quantified for in-vivo assessment. Furthermore, for evaluating the immune responses, the levels of IFN-γ, IL-4, NO and arginase were measured in the BALB/c mice. These results indicated that U. dioica extract significantly reduced the L. major promastigotes viability. According to the in-vitro cytotoxicity assay of the extract on Leishmania parasites (CC50) and infected macrophages (EC50), the extract had no toxicity to the macrophages, however it efficiently killed the L. major amastigotes. In addition, the lesion size, parasite load, IL-4, and ARG were decreased in the treated infected mice, however IFN-γ and NO were significantly increased.CONCLUSIONS/SIGNIFICANCE: This study established satisfactory results in Leishmania parasite clearing both in-vivo and in-vitro. Therefore, U. dioica extract can be considered as an effective and harmless herbal compound for killing the parasite without toxicity to the host macrophages. Furthermore, it also can treat the CL by switching the mouse immune response towards a cell-mediated response (Th1); hence, it may be identified as a perfect therapeutic herbal drug for CL treatment.

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PMID: 

Biomed Mater Eng. 2014 ;24(1):1019-25. PMID: 24211992

Abstract Title: 

Licochalcone A inhibiting proliferation of bladder cancer T24 cells by inducing reactive oxygen species production.

Abstract: 

The aim of this study was to determine the relationship between proliferation inhibition and the production of reactive oxygen species (ROS) induced by Licochalcone A (LCA). Cell viability was evaluated using sulforhodamine B (SRB) assay. Intracellular ROS level was assessed using the 2, 7-dichlorofluorescein diacetate (H2DCFDA) probe and dihydroethidium (DHE) probe assay. The results indicate that LCA inhibits human bladder cancer T24 proliferation in a concentration-dependent manner, with an IC50 value of approximately 55μM. The LCA-induced ROS production is inhibited by the co-treatment of LCA and free radical scavenger N-acetyl-cysteine (NAC), on the contrary, the proliferation rate and ROS production increase when treated by the combination of LCA and L-buthionine-(S,R)-sulfoximine (BSO). The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) decreases in a concentration-dependent manner. The results suggest that LCA inhibits proliferation by increasing intracellular ROS levels resulted in an oxidative stress status in T24 cells.

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PMID: 

Apoptosis. 2014 Apr ;19(4):682-97. PMID: 24337903

Abstract Title: 

Licochalcone A induces apoptosis through endoplasmic reticulum stress via a phospholipase Cγ1-, Ca(2+)-, and reactive oxygen species-dependent pathway in HepG2 human hepatocellular carcinoma cells.

Abstract: 

Licochalcone A (LicA), an estrogenic flavonoid, induces apoptosis in multiple types of cancer cells. In this study, the molecular mechanisms underlying the anti-cancer effects of LicA were investigated in HepG2 human hepatocellular carcinoma cells. LicA induced apoptotic cell death, activation of caspase-4, -9, and -3, and expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by CHOP knockdown or treatment with the ER stress inhibitors, salubrinal and 4-phenylbutyric acid, reduced LicA-induced cell death. LicA also induced reactive oxygen species (ROS) accumulation and the anti-oxidant N-acetylcysteine reduced LicA-induced cell death and CHOP expression. In addition, LicA increased the levels of cytosolic Ca(2+), which was blocked by 2-aminoethoxydiphenyl borate (an antagonist of inositol 1,4,5-trisphosphate receptor) and BAPTA-AM (an intracellular Ca(2+) chelator). 2-Aminoethoxydiphenyl borate and BAPTA-AM inhibited LicA-induced cell death. Interestingly, LicA induced phosphorylation of phospholipase Cγ1 (PLCγ1) and inhibition of PLCγ1 reduced cell death and ER stress. Moreover, the multi-targeted receptor tyrosine kinase inhibitors, sorafenib and sunitinib, reduced LicA-induced cell death, ER stress, and cytosolic Ca(2+) and ROS accumulation. Finally, LicA induced phosphorylation of vascularendothelial growth factor receptor 2 (VEGFR2) and c-Met receptor and inhibition of both receptors by co-transfection with VEGFR2 and c-Met siRNAs reversed LicA-induced cell death, Ca(2+) increase, and CHOP expression. Taken together, these findings suggest that induction of ER stress via a PLCγ1-,Ca(2+)-, and ROS-dependent pathway may be an important mechanism by which LicA induces apoptosis in HepG2 hepatocellular carcinoma cells.

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