Endocrine, Metabolic & Immune Disorders-Drug Targets - Volume 20, Issue 7, 2020

Background: Nickel (Ni) is mostly applied in a number of industrial areas such as printing inks, welding, alloys, electronics and electrical professions. Occupational or environmental exposure to nickel may lead to cancer, allergy reaction, nephrotoxicity, hepatotoxicity, neurotoxicity, as well as cell damage, apoptosis and oxidative stress. Methods: In here, we focused on published studies about cell death, carcinogenicity, allergy reactions and neurotoxicity, and promising agents for the prevention and treatment of the toxicity by Ni. Results: Our review showed that in the last few years, more researches have focused on reactive oxygen species formation, oxidative stress, DNA damages, apoptosis, interaction with involving receptors in allergy and mitochondrial damages in neuron induced by Ni. Conclusion: The collected data in this paper provide useful information about the main toxicities induced by Ni, also, their fundamental mechanisms, and how to discover new ameliorative agents for prevention and treatment by reviewing agents with protective and therapeutic consequences on Ni induced toxicity.

Background: Nickel ions (Ni²⁺) are a heavy metal with wide industrial uses. Environmental and occupational exposures to Ni are potential risk factors for brain dysfunction and behavioral and neurological symptoms in humans. Methods: We reviewed the current evidence about neurochemical and behavioral alterations associated with Ni exposure in laboratory animals and humans. Results: Ni²⁺ exposure can alter (both inhibition and stimulation) dopamine release and inhibit glutamate NMDA receptors. Few reports claim an effect of Ni²⁺ at the level of GBA and serotonin neurotransmission. At behavioral levels, exposure to Ni²⁺ in rodents alters motor activity, learning and memory as well as anxiety and depressive-like symptoms. However, no analysis of the dose-dependent relationship has been carried out regarding these effects and the levels of the Ni²⁺ in the brain, in blood or urine. Conclusion: Further research is needed to correlate the concentration of Ni²⁺ in biological fluids with specific symptoms/deficits. Future studies addressing the impact of Ni²⁺ under environmental or occupational exposure should consider the administration protocols to find Ni²⁺ levels similar in the general population or occupationally exposed workers.

Nickel is the most common cause of contact allergy in the general population and the most frequently detected allergen in patients patch tested for suspected allergic contact dermatitis (ACD). ACD from nickel is a typical type IV hypersensitivity. Nickel allergy is mostly caused by nonoccupational exposure, such as jewelry and clothing decorations, metal tools, medical devices (mainly orthopedic and orthodontic implants, cardiovascular prosthesis), eyeglasses, utensils, keys, pigment for paint, cosmetics, and food (mainly legumes, chocolate, salmon, peanuts). Occupational exposure can involve several workers (mechanics, metalworkers, platers, hairdressers, jewelers, workers in the constructions and electronic industries), classically involving hands and forearms. The classic clinical pattern of ACD caused by nickel is characterized by eczematous dermatitis involving the sites of direct contact with the metal. Non-eczematous-patterns are reported, including lichenoid dermatitis, granuloma annulare, vitiligo-like lesions, dyshidrosiform dermatitis, and vasculitis. In the case of systemic exposure to nickel, sensitized patients could develop systemic contact dermatitis. Patch testing represents the gold standard for the diagnosis of ACD from nickel. Treatment includes avoidance of contact with products containing nickel and the patient’s education about the possible use of alternative products. A recent EU nickel directive, regulating the content and release of nickel from products, has caused a decrease of nickel contact allergy in some European countries. Nickel allergy is a relevant issue of public health with significant personal, social, and economic impact. This review summarizes epidemiology, pathomechanism, clinical patterns, treatment, and prevention programs.

Background: Hypersensitization to nickel is one of the most common contact allergies in the modern world and it is considered to be a major cause of contact dermatitis, especially for hand eczema. Objective: The aim of this paper is to describe many faces of the nickel allergy and to find out different diagnostic, potential strategies for treatment and prevention in hypersensitized patients. A personal clinical experience with practical clinical cases of contact dermatitis to nickel has also been presented. Methods: Electronic databases on this topic was carried out using PubMed-Medline. Results: The literature review identified many articles reporting for nickel contact allergy and pointing the metal as number one allergen in the frequency of positive skin patch test reactions in a large population worldwide. Herein, a summary of the current understanding and evidence on nickel allergy with practical approach and proposed recommendations to the dermatologist, general practitioner, and the allergist were prepared. Conclusion: The prevalence of nickel allergy represents an important socio-economical and health issue. Metal is one of the most common sensitizing agents worldwide. The morbidity due to this metal represents the allergic contact dermatitis and it is constantly growing in many countries. There are also cases of systemic allergic contact dermatitis, where they could be easily misdiagnosed as adverse drug reactions, which lead to delay of the correct diagnosis and inappropriate treatment.

Background: Hypersensitivity to nickel is a very common cause of allergic contact dermatitis since this metal is largely present in industrial and consumer products as well as in some commonly consumed foods, air, soil, and water. In nickel-sensitized individuals, a cell-mediated delayed hypersensitivity response results in contact to dermatitis due to mucous membranes coming in long-term contact with nickel-containing objects. This process involves the generation of reactive oxidative species and lipid peroxidation-induced oxidative damage. Immunologically, the involvement of T helper (h)-1 and Th-2 cells, as well as the reduced function of T regulatory cells, are of importance. The toxicity, mutagenicity, and carcinogenicity of nickel are attributed to the generation of reactive oxygen species and induction of oxidative damage via lipid peroxidation, which results in DNA damage. Objective: The aim of this research is to identify nutritionally actionable interventions that can intercept nickel-induced cell damage due to their antioxidant capacities. Conclusion: Nutritional interventions may be used to modulate immune dysregulation, thereby intercepting nickel-induced cellular damage. Among these nutritional interventions are a low-nickel diet and an antioxidant-rich diet that is sufficient in iron needed to minimize nickel absorption. These dietary approaches not only reduce the likelihood of nickel toxicity by minimizing nickel exposure but also help prevent oxidative damage by supplying the body with antioxidants that neutralize free radicals.

Background: The increased use of heavy metal nickel in modern industries results in increased environmental impact. Occupational and environmental exposure to nickel is closely linked to an increased risk of human lung cancer and nasal cancer. Objective: Unlike other heavy metal carcinogens, nickel has weak mutagenic activity. Carcinogenesis caused by nickel is intensively studied, but the precise mechanism of action is not yet known. Results: Epigenetic changes, activation of hypoxia signaling pathways, and generation of reactive oxygen species (ROS) are considered to be the major molecular mechanisms involved in nickelinduced carcinogenesis. Conclusion: This review provides insights into current research on nickel-induced carcinogenesis and suggests possible effective therapeutic strategies for nickel-induced carcinogenesis.

Background: Nickel activates the signaling pathways through the oxygen sensing mechanism and the signaling cascades that control hypoxia-inducible transcriptional gene expressions through oxidative stress. This review emphasizes on the recent updates of nickel toxicities on oxidant and antioxidant balance, molecular interaction of nickel and its signal transduction through low oxygen microenvironment in the in-vivo physiological system. Discussion: Nickel alters intracellular chemical microenvironment by increasing ionized calcium concentration, lipid peroxidation, cyclooxygenase, constitutive nitric oxide synthase, leukotriene B4, prostaglandin E2, interleukins, tumor necrosis factor-α, caspases, complement activation, heat shock protein 70 kDa and hypoxia-inducible factor-1α. The oxidative stress induced by nickel is responsible for the progression of metastasis. It has been observed that nickel exposure induces the generation of reactive oxygen species which leads to the increased expression of p53, NF-kβ, AP-1, and MAPK. Ascorbic acid (vitamin C) prevents lipid peroxidation, oxidation of low-density lipoproteins and advanced oxidation protein products. The mechanism involves that vitamin C is capable of reducing ferric iron to ferrous iron in the duodenum, thus the availability of divalent ferrous ion increases which competes with nickel (a divalent cation itself) and reduces its intestinal absorption and nickel toxicities. Conclusion: Reports suggested the capability of ascorbic acid as a regulatory factor to influence gene expression, apoptosis and other cellular functions of the living system exposed to heavy metals, including nickel.

Introduction & Objectives: Cutaneous and systemic reactions to various metal implants and medical devices have been well documented. The aim of this review was to focus on the probable common mechanisms of allergy and autoimmunity that may lead to similar clinical outcomes following the growing evidence in the literature of metal and nickel-related systemic, autoimmune or autoinflammatory disorders. Methods: Detailed search of the available electronic databases (PubMed-Medline) was conducted for review of the literature on that topic till the present moment. Results: Multiple reports on the immunological effects of metals including immunomodulation, allergy, or autoimmunity were identified. It was found that metals may act through immunosuppression, immunotoxicity, or as immune adjuvants thus provoking allergy and autoimmunity in susceptible individuals. Both external or internal exposure to metals was observed. Nickel has been identified as the most common sensitizer, and also the most studied one. The coexistence of both allergic and autoimmune symptoms, induced by nickel, has been published, suggesting the autoimmune potential of nickel compounds. Conclusion: Clinical experience and scientific literature together demonstrate that metals may play an important role in the development of autoimmune diseases. While metal implant allergies and complications are on the rise, they remain a diagnostic and therapeutic challenge. Elucidation of their possible mechanisms will contribute to the more successful and safer treatment of affected individuals.

Background: Heavy metals [arsenic, aluminium, cadmium, chromium, cobalt, lead, nickel (Ni), palladium and titanium] are environmental contaminants able to impact with host human cells, thus, leading to severe damage. Objective: In this review, the detrimental effects of several heavy metals on human organs will be discussed and special emphasis will be placed on Ni. In particular, Ni is able to interact with Toll-like receptor-4 on immune and non-immune cells, thus, triggering the cascade of pro-inflammatory cytokines. Then, inflammatory and allergic reactions mediated by Ni will be illustrated within different organs, even including the central nervous system, airways and the gastrointestinal system. Discussion: Different therapeutic strategies have been adopted to mitigate Ni-induced inflammatoryallergic reactions. In this context, the ability of polyphenols to counteract the inflammatory pathway induced by Ni on peripheral blood leukocytes from Ni-sensitized patients will be outlined. In particular, polyphenols are able to decrease serum levels of interleukin (IL)-17, while increasing levels of IL- 10. These data suggest that the equilibrium between T regulatory cells and T helper 17 cells is recovered with IL-10 acting as an anti-inflammatory cytokine. In the same context, polyphenols reduced elevated serum levels of nitric oxide, thus, expressing their anti-oxidant potential. Finally, the carcinogenic potential of heavy metals, even including Ni, will be highlighted. Conclusion: Heavy metals, particularly Ni, are spread in the environment. Nutritional approaches seem to represent a novel option in the treatment of Ni-induced damage and, among them, polyphenols should be taken into consideration for their anti-oxidant and anti-inflammatory activities.

Objective: This study aimed to evaluate the effect of the aqueous extract of Anvillea radiate (A. radiata) aerial parts (AEAR) on arterial blood pressure in normotensive and hypertensive rats. Methods: The effect of the acute and sub-chronic administration of AEAR on the following blood pressure parameters: systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP), and heart rate (HR) was evaluated in normotensive and L-NAME induced hypertensive rats. In the second experiment, the vasorelaxant effect of AEAR was assessed in isolated aortic rings from rats with functional endothelium pre-contracted with epinephrine (EP) or KCl, and six antagonists/ inhibitors were used to explore the mechanisms of action involved in the vasorelaxant effect. In order to determine the phytochemical contents of Anvillea radiata, HPLC-ESI-MS analysis was conducted. Results: Daily oral administration of AEAR (100 mg/kg) provoked a significant decrease in SBP, MBP, and DBP without affecting HR in hypertensive rats. In addition, AEAR (0.08-0.64 mg/ml) revealed a vasorelaxant effect in thoracic aortic rings pre-contracted by EP (10 μM) or KCl (80 mM). This effect was reduced in the presence of Nifedipine, L-Name or Methylene blue. The polyphenolic compounds of AEAR were determined. Conclusion: This study revealed that AEAR possesses a potent antihypertensive activity and its vasorelaxant activity seems to be mediated through Ca2+ channels, direct nitric oxide (NO), and NO/cGMP pathways. Chlorogenic acid and caffeic acid identified in A. radiata could be at least partially responsible for the antihypertensive activity of this extract.

Background: Yokukansan is a traditional Japanese herbal medicine that has an antiallodynic effect in patients with chronic pain. However, the mechanisms by which yokukansan inhibits neuropathic pain are unclear. Objective: This study aimed to investigate the molecular effects of yokukansan on neuroinflammation in U373 MG glioblastoma astrocytoma cells, which express a functional high-affinity neurokinin 1 receptor (substance P receptor), and produce interleukin (IL)-6 and IL-8 in response to stimulation by substance P (SP). Methods: We assessed the effect of yokukansan on the expression of ERK1/2, P38 MAPK, nuclear factor (NF)-ΚB, and cyclooxygenase-2 (COX-2) in U373 cells by western blot assay. Levels of IL-6 and IL-8 in conditioned medium obtained after stimulation of cells with SP for 24 h were measured by enzyme-linked immunosorbent assay. All experiments were conducted in triplicate. Results were analyzed by one-way ANOVA, and significance was accepted at p < 0.05. Results: Yokukansan suppressed SP-induced production of IL-6 and IL-8 by U373 MG cells, and downregulated SP-induced COX-2 expression. Yokukansan also inhibited phosphorylation of ERK1/2 and p38 MAPK, as well as nuclear translocation of NF-ΚB, induced by SP stimulation of U373 MG cells. Conclusion: Yokukansan exhibits anti-inflammatory activity by suppressing SP-induced production of IL-6 and IL-8 and downregulating COX-2 expression in U373 MG cells, possibly via inhibition of the activation of signaling molecules, such as ERK1/2, p38 MAPK, and NF-ΚB.

Background: The sTNFRII-adiponectin fusion protein previously showed strong TNFα antagonistic activity. However, the fusion protein exists as mixture of different multimers. The aim of the present study was to characterize its active components. Methods: In this study, the fusion protein was isolated and purified by Ni-NTA affinity and gel exclusion chromatography, and further identified by Coomassie staining and western blotting. The TNFα antagonistic and glucose uptake-promoting activities were determined in vitro. The glucose detection kit and 2- NBDG (2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose) were used to measure their effects on glucose metabolism (including glucose consumption and glucose uptake in HepG2 and H9C2 cells). The effect of the fusion protein on glucose uptake was also examined in free fatty acid (FFA)- induced insulin resistance cell model. Results: The sTNFRII-adiponectin fusion protein was found to exist in three forms: 250 kDa (hexamer), 130 kDa (trimer), and 60 kDa (monomer), with the final purity of 90.2%, 60.1%, and 81.6%, respectively. The fusion protein could effectively antagonize the killing effect of TNFα in L929 cells, and the multimer was found to be superior to the monomer. In addition, the fusion protein could increase glucose consumption without impacting the number of cells (HepG2, H9C2 cells) in a dosedependent manner. Mechanistically, glucose uptake was found to be enhanced by the translocation of GLUT4. However, it could not improve glucose uptake in the cell model of insulin resistance. Conclusion: In summary, the active components of the fusion protein are hexamers and trimers. The hexamer and trimer of sTNFRII-adiponectin fusion protein had both TNFα-antagonizing and glucose uptake-promoting activities, although neither of them could improve glucose uptake in the cell model of insulin resistance.

Objective: Proton pump inhibitor (PPI) drugs reduce gastric acid secretion and lead to an increase in serum gastrin levels. Many preclinical and some clinical researches have established some positive effects of gastrin or PPI therapy on glucose regulation. The aim of this study was to prospectively investigate the short term effects of esomeprazole on glycaemic control in patients with type 2 diabetes mellitus. In addition, the presence of an association between this effect and gastrin levels was evaluated. Methods: Thirty-two subjects with type 2 diabetes mellitus were enrolled and grouped as intervention (n=16) and control (n=16). The participants in the intervention group were prescribed 40 mg of esomeprazole treatment for three months. At the beginning of the study and at the 3rd month, HbA1c level (%) and gastrin levels (pmol/L) of participants were assessed. Then, the groups were compared in terms of their baseline and 3rd month values. Results: In the intervention group, the mean gastrin level increased significantly from 34.3±14.4 pmol/L to 87.4±43.6 pmol/L (p<0.001). The mean HbA1c level was similar to the pre-treatment level (6.3±0.7% vs. 6.4±0.9%, p=0.441). There were no statistically significant differences in all parameters of the control group. The majority of individuals were on metformin monotherapy (65.6 %). The subgroup analysis of metformin monotherapy revealed that, in intervention group, there was a significant increase in gastrin levels (39.9±12.6 vs. 95.5±52.5, p=0.026), but the HbA1c levels did not change (6.0±0.4 % vs. 5.9±0.6 %, p=0.288); and in control group, gastrin levels did not change (37.5 ± 26.7 vs. 36.1 ±23.3, p=0.367), but there was an increase in HbA1c levels (6.1 ± 0.50 vs. 6.4 ± 0.60, p=0.01). Conclusion: Our study demonstrates that esomeprazole has no extra benefit for the controlled diabetic patient in three months. However, in only the metformin-treated subgroup, esomeprazole may prevent the rise in HbA1c level.

Background: Clerodendrum paniculatum has ethnomedicinal importance in treatment of disorders like wound, typhoid, jaundice, malaria and anemia. Objective: To evaluate the antioxidant and hepatoprotective activity of Clerodendrum paniculatum leaves against carbon tetrachloride (CCl4) induced rat model and identification of its bioactive constituents by Gas Chromatography Mass Spectroscopy (GC MS). Methods: Successive solvent extraction was carried out. Total phenolic, flavonoid content and antioxidant activity by 2,2- diphenyl-1-picryl hydrazyl (DPPH), nitric oxide and 2-Azino-bis [3-ethyl benzothiazoline- 6-sufonic acid] (ABTS method) were done. Ethyl acetate extract was selected for hepatoprotective study in carbon tetrachloride intoxicated model followed by the measurement of liver function marker enzymes such as SGOT (Serum Glutamate Oxaloacetate Transaminase), SGPT (Serum Glutamate Pyruvate Transaminase), and ALP (Alkaline Phosphatase). Biochemical parameters like bilirubin and protein were measured. Histopathologic liver sections were carried out. Bioactive constituents were evaluated by GC MS. Results: By DPPH and ABTS method, ethyl acetate extract showed IC50 as 70.14±0.92 μg/ml,2958.24±2.460 μg/ml, respectively. The alcoholic extract showed maximum IC50 (197.22 ±7.16 μg/ml) by Nitric oxide radical scavenging method. Hepatoprotective study reveals that intoxicated animal groups have elevated levels of enzymes and bilirubin and suppress the production of protein. The extract pre-treatment showed a significant decrease in enzymes and increased production of total protein in a dose-dependent manner. Histopathologic studies also support the hepatoprotective activity. GC MS analysis revealed the presence of seven major bioactive constituents with ethyl palmitate as the major one. Conclusion: The results support the proof for the hepatoprotective potential of the CPLE extract with potent antioxidant activity and enhanced liver enzyme level. The observed activity could be due to the presence of bioactive compounds as identified by GC MS analysis.

Background: Cytokines as important mediators have a critical role in appropriate immune responses, the irregular production of which can lead to Multiple Sclerosis (MS). Proinflammatory cytokine interleukin-1 (IL-1) triggers inflammatory responses. Function and production of the cytokine are influenced by IL-1 coding gene polymorphism and those antagonists gene polymorphism. Objective: The aim of the present study was to evaluate the possible correlation between MS and IL-1 related alleles in Azeri population of Iran. Methods: Variable number tandem repeats (VNTR) genotypes of 150 MS patients and 220 healthy non-relative controls were determined. Results: In the healthy controls, genotype TT at IL-1A (-889) location was significantly higher than the MS patients (p=0.0001). However, a significant difference was not found between the two groups in genotypic/allelic frequency at IL- 1B+ 3953 location. Evaluation of the IL-1RA gene revealed that genotype 1/2, and genotype 1/3 were significantly higher in the healthy controls and MS patients, respectively. Our findings indicated that the consumption of fast-food in MS patients was significantly higher than controls (p= <0.05). Also, a considerable number of MS patients had inappropriate dieting behaviors such as not eating breakfast (p= 0.0001), and irregular eating habits (p= 0.0001). Conclusion: Polymorphisms of the IL-1B genes and common alleles of IL-1RA were not considered as risk factors for MS disease. However, genotype TT at IL-1A (-889) location and the rare allele of IL-1RA3 can be a potential risk factor for the disease. Furthermore, inappropriate dieting behaviors and consumption of fast-food can increase the risk of MS.

Background and Aims: In the current work, we studied the effects of exercise and stevia rebaudiana (R) extracts on diabetic cardiomyopathy (DCM) in type 2 diabetic rats and their possible underlying mechanisms. Methods: Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group, b) DM group, type 2 diabetic rats received 2 ml oral saline daily for 4 weeks, c) DM+ Exercise, type 2 diabetic rats were treated with exercise for 4 weeks and d) DM+ stevia R extracts: type 2 diabetic rats received methanolic stevia R extracts. By the end of the experiment, serum blood glucose, HOMA-IR, insulin and cardiac enzymes (LDH, CK-MB), cardiac histopathology, oxidative stress markers (MDA, GSH and CAT), myocardial fibrosis by Masson trichrome, the expression of p53, caspase-3, α-SMA and tyrosine hydroxylase (TH) by immunostaining in myocardial tissues were measured. Results: T2DM caused a significant increase in blood glucose, HOMA-IR index, serum CK-MB and LDH, myocardial damage and fibrosis, myocardial MDA, myocardial α-SMA, p53, caspase-3, Nrf2 and TH density with a significant decrease in serum insulin and myocardial GSH and CAT (p< 0.05). On the other hand, treatment with either exercise or stevia R extracts significantly improved all studied parameters (p< 0.05). Moreover, the effects of stevia R was more significant than exercise (p< 0.05). Conclusion: Both exercise and methanolic stevia R extracts showed cardioprotective effects against DCM and Stevia R offered more cardioprotective than exercise. This cardioprotective effect of these lines of treatment might be due to attenuation of oxidative stress, apoptosis, sympathetic nerve density and fibrosis and upregulation of the antioxidant transcription factor, Nrf2.