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1.
Int J Mol Sci ; 24(16)2023 Aug 20.
Article in English | MEDLINE | ID: mdl-37629172

ABSTRACT

We sought to assess the impact of 4-Methylhistamine (4-MeH), a specific agonist targeting the Histamine H4 Receptor (H4R), on the progression of experimental autoimmune encephalomyelitis (EAE) and gain insight into the underlying mechanism. EAE is a chronic autoimmune, inflammatory, and neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, axonal damage, and neurodegeneration. Over the past decade, pharmacological research into the H4R has gained significance in immune and inflammatory disorders. For this study, Swiss Jim Lambert EAE mice were treated with 4-MeH (30 mg/kg/day) via intraperitoneal administration from days 14 to 42, and the control group was treated with a vehicle. Subsequently, we evaluated the clinical scores. In addition, flow cytometry was employed to estimate the impact of 4-Methylhistamine (4-MeH) on NF-κB p65, GM-CSF, MCP-1, IL-6, and TNF-α within CD19+ and CXCR5+ spleen B cells. Additionally, we investigated the effect of 4-MeH on the mRNA expression levels of Nf-κB p65, Gmcsf, Mcp1, Il6, and Tnfα in the brain of mice using RT-PCR. Notably, the clinical scores of EAE mice treated with 4-MeH showed a significant increase compared with those treated with the vehicle. The percentage of cells expressing CD19+NF-κB p65+, CXCR5+NF-κB p65+, CD19+GM-CSF+, CXCR5+GM-CSF+, CD19+MCP-1+, CXCR5+MCP-1+, CD19+IL-6+, CXCR5+IL-6+, CD19+TNF-α+, and CXCR5+TNF-α+ exhibited was more pronounced in 4-MeH-treated EAE mice when compared to vehicle-treated EAE mice. Moreover, the administration of 4-MeH led to increased expression of NfκB p65, Gmcsf, Mcp1, Il6, and Tnfα mRNA in the brains of EAE mice. This means that the H4R agonist promotes pro-inflammatory mediators aggravating EAE symptoms. Our results indicate the harmful role of H4R agonists in the pathogenesis of MS in an EAE mouse model.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Neurodegenerative Diseases , Animals , Mice , Granulocyte-Macrophage Colony-Stimulating Factor , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Interleukin-6 , Receptors, Histamine H4 , Tumor Necrosis Factor-alpha , NF-kappa B , Adaptor Proteins, Signal Transducing , Inflammation/drug therapy , Antigens, CD19 , Disease Progression
2.
Cureus ; 14(10): e30679, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36439564

ABSTRACT

OBJECTIVE: The aim of the present study was to estimate the prevalence of nonadherence to medication in multimorbid patients with polypharmacy and its relationship to social support in primary healthcare centers in Riyadh, Saudi Arabia. METHODS: We conducted a cross-sectional, convenience-sample, non-randomized study in three primary healthcare centers managed by National Guard Health Affairs. The participants included 417 adult patients - (a) with two or more chronic illnesses and (b) who were taking two or more medications. The primary outcome variable was the prevalence of medication nonadherence in multimorbid patients with polypharmacy as measured by the modified Morisky Medication Adherence Scale (MMAS-8). The second main variable was the impact of functional social support, as measured by the Duke-UNC Functional Social Support Questionnaire (FSSQ), on medication adherence. RESULTS: The level of medication adherence was low for 194 (46.5%) of the 417 patients, medium for 127 (30.5%), and high for 96 (23%). There were 256 (61.4%) male participants and 161 (38.6%) females, and their mean age was 59.15 (SD ± 11.186) years. Additionally, 171 (41%) participants used two or three medications, 127 (30.5%) used four or five medications, and 119 (28.5%) used more than five medications; 178 (42.7%) of the patients had two comorbidities, 136 (32.9%) had three comorbidities, 69 (16.5%) had four comorbidities, and 31 (7.5%) had five comorbidities. Some social support data from the Duke-UNC Functional Social Support Questionnaire (FSSQ) was missing for 58 (13.9%) of the participants. Among the rest of the sample, reported levels of social support levels were high for 246 (59%) patients, medium for 101 (24.2%), and low for 12 (2.9%) patients. None of the differences between social support and medication adherence were statistically significant. However, 61 (24.8%) patients reported both high social support and high medication adherence; 173 (48.2%) had low social support and low medication adherence (p = 0.470). CONCLUSION: We found that medication nonadherence in multimorbid patients with polypharmacy was high (46.5%). Although there were no statistically significant relationships between social support and medication adherence, certain patient characteristics were associated with low medication adherence - age over 60 years, male gender, and number of medications.

3.
Neurotoxicology ; 91: 340-348, 2022 07.
Article in English | MEDLINE | ID: mdl-35760230

ABSTRACT

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that are characterized by abnormal social interaction impairments in communication and repetitive and restricted activities or interests. Even though the exact etiology of ASD remains unknown. Lead (Pb) is a toxin known to harm many organs in the body, it is one of the most ubiquitous metal exposures which is associated with neurological deficits. Previous studies have shown that the exposure to Pb may play a role in ASD. BTBR T+ Itpr3tf/J (BTBR) mouse model is commonly used as a preclinical model for ASD. In this study, we investigated the effects of Pb exposure on sociability, self-grooming and marble burying behaviors tests in BTBR mice. We further examined the effects of Pb on IL-17A- RORγT-, STAT3-, NF-κB p65-, iNOS-, TLR-2- and TLR-4-producing CD45+ cells in spleen using flow cytometry. We also explored the effects of Pb on IL-17A, RORγT, STAT3, NF-κB p65, and TLR-2 mRNA expression in the brain tissue using RT-PCR analysis. Our results demonstrated that Pb exposure substantially increased repetitive behavior, marble burying and decrease social interactions in BTBR mice. In addition, in spleen cells, Pb exposure exaggerated CD45+IL-17A+, CD45+RORγT+, CD45+STAT3+, CD45+NF-κB p65+, CD45+iNOS+, CD45+TLR-2+ and CD45+TLR-4+ in BTBR mice. We also found that Pb significantly increased IL-17A, RORγT, STAT3, NF-κB p65, and TLR-2 mRNA in the brain tissue. Therefore, Pb exposure exacerbates behavioral and neuroimmune function in BTBR mice, suggesting a potentially strong role for Pb in ASD.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Animals , Autism Spectrum Disorder/chemically induced , Autistic Disorder/chemically induced , Autistic Disorder/metabolism , Calcium Carbonate , Disease Models, Animal , Interleukin-17/genetics , Interleukin-17/metabolism , Lead/toxicity , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , NF-kappa B/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , RNA, Messenger/metabolism , Toll-Like Receptor 2 , Toll-Like Receptor 4
4.
Immunol Lett ; 244: 19-27, 2022 04.
Article in English | MEDLINE | ID: mdl-35259423

ABSTRACT

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by impaired communication, impaired reciprocal social interaction, restricted sociability deficits, and the presence of stereotyped patterns of behaviors. Immune dysregulation has been suggested to play a possible etiological role in ASD. Recent studies have demonstrated that exposure to methylmercury chloride (MeHgCl) leads to abnormal gait, motor deficits, impaired hearing, and memory deficits; however, its effects on behavioral and immunological responses have not been adequately investigated in ASD. In this study, we investigated the effects of MeHgCl exposure on marble burying, self-grooming behaviors, sociability tests, and locomotor activities in BTBR T+ Itpr3tf/J (BTBR) mice. We also explored the possible molecular mechanism underlying the effects of MeHgCl administration on IFN-γ-, T-bet-, IL-9-, and IL-17A-producing CD4+, CXCR5+, CXCR6+, and CCR9+ cells isolated from spleens. Furthermore, the effects of MeHgCl exposure on the mRNA expression and levels of pro-inflammatory cytokines in the brain tissue and serum samples were also assessed. Our results demonstrated that MeHgCl exposure caused a significant increase in marble burying, self-grooming behaviors and a decrease in social interactions and adverse effects on locomotor activity in BTBR mice. MeHgCl exposure also significantly increased the production of CD4+IFN-γ+, CD4+T-bet+, CCR9+T-bet+, CXCR5+IL-9+, CD4+IL-9+, CXCR6+IL-17A+, and CD4+IL-17A+ cells in the spleen. Furthermore, MeHgCl exposure increased mRNA and protein levels of pro-inflammatory cytokines in the brain and serum respectively in BTBR mice. In conclusion, MeHgCl administration aggravated existing behavioral and immune abnormalities in BTBR mice.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Animals , Autism Spectrum Disorder/etiology , Autistic Disorder/chemically induced , Autistic Disorder/genetics , Calcium Carbonate/pharmacology , Cytokines/metabolism , Disease Models, Animal , Interleukin-17/metabolism , Interleukin-9 , Methylmercury Compounds , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , RNA, Messenger/metabolism , Signal Transduction
5.
Mol Immunol ; 144: 127-137, 2022 04.
Article in English | MEDLINE | ID: mdl-35219910

ABSTRACT

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. The disease manifestation is associated with the proliferation and activation of lymphocytes and astrocytes, leading to demyelination and neuronal damage. Most of the current therapies are not completely effective, and few target the underlying pathophysiology of MS. T helper 9 (Th9)- and Th22-dominant cells have been proven to play a pathogenic role in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The goal of the present study was to investigate the therapeutic efficacy of J-113863, a novel CCR1 chemokine receptor, on PLP139-151-induced EAE in SJL/J mice. Following induction of EAE, mice were treated with J-113863 (10 mg/kg) or saline intraperitoneally daily from day 14 until day 25, and the clinical score was evaluated. We further investigated the effect of J-113863 on IL-9, IRF4, IL-22, IFN-γ, STAT3, AhR, and IL-17A in CD3+, CD4+, CCR6+, and CCR8+ spleen cells using flow cytometry. We also analyzed the effect of J-113863 on IL-9, IRF4, IL-22, IFN-γ, STAT3, AhR, and IL-17A mRNA expression levels. Our results revealed that J-113863 treatment notably attenuated the severity of clinical scores in EAE mice. J-113863 treatment decreased the percentage expression of CD4+IL-9+, CCR8+IL-9+, CD4+IRF4+, CD3+IL-22+, CCR6+IL-22+, CD3+IFN-γ+, CCR6+IFN-γ+, CD3+STAT3+, CCR6+STAT3+, CD4+IL-17A+, and CCR6+IL-17A+, and increased the percentage of CD3+AhR+, and CCR6+AhR+ cells in the spleen. These results confirmed that J-113863 suppressed Th9/Th22 cells to reduce demyelination in EAE mice, suggesting its potential role as a novel drug candidate for MS treatment.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Animals , Biomarkers/metabolism , Brain/metabolism , Central Nervous System , Interleukin-17/metabolism , Interleukin-9/metabolism , Interleukin-9/therapeutic use , Mice , Mice, Inbred C57BL , Receptors, CCR1/metabolism
6.
J Neuroimmunol ; 349: 577430, 2020 12 15.
Article in English | MEDLINE | ID: mdl-33130460

ABSTRACT

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by communication deficits, impaired social interactions, and restricted stereotypical behaviors. Several immune cells are associated with immune dysfunction in ASD; however, IL-31 has not been explored in ASD. This study aims to investigate the role of inflammatory cytokines and transcription factors of the CXCR1 cells in children with ASD. In the current study, we investigated the cytokines and transcription factors produced by CXCR1+ cells (IL-31, IL-9, IL-21R, IL-21, NF-κB p65, RORγT, STAT1, and FoxP3) in peripheral blood mononuclear cells (PBMCs), from children with ASD and typically developing (TD) control children, using flow cytometric analysis. In addition, we measured mRNA and protein expression levels of IL-31 using quantitative real-time PCR and western blot analyses in PBMCs. In our study, children with ASD had increased CXCR1+IL-31+, CXCR1+IL-9+, CXCR1+IL-21R+, CXCR1+IL-21+, CXCR1+NF-κB+ p65, CXCR1+RORγT+, and CXCR1+STAT1+, and decreased CXCR1+FoxP3+ cells as compared with cells from the TD control samples. Similarly, children with ASD showed increased IL-31 mRNA and protein expression levels as compared to those of TD control samples. Our results suggest that upregulated production of inflammatory cytokines and transcription factors in CXCR1+ cells cause immunological imbalance in children with ASD. Therefore, attenuation of inflammatory cytokines/mediators and transcription factors could have a therapeutic potential in the treatment of ASD.


Subject(s)
Autism Spectrum Disorder/metabolism , Cytokines/biosynthesis , Interleukins/biosynthesis , Leukocytes, Mononuclear/metabolism , Receptors, Interleukin-8A/biosynthesis , Up-Regulation/physiology , Autism Spectrum Disorder/immunology , Child , Child, Preschool , Cross-Sectional Studies , Cytokines/immunology , Humans , Interleukins/immunology , Leukocytes, Mononuclear/immunology , Male , Receptors, Interleukin-8A/immunology
7.
Redox Rep ; 25(1): 51-58, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32396454

ABSTRACT

ABSTRACTObjectives: This study explores the protective role of losartan (LT) against oxidative and inflammatory damages in different physiological systems including heart, liver, and kidney tissue in hypercholesterolemic rats.Methods: After induction of hypercholesterolemia by high cholesterol diet for 6 weeks, LT was administered for 4 weeks. In serum, the levels of lipoproteins, aminotransferases, creatine kinases, urea, apoptosis, and inflammatory markers were measured. In cardiac, hepatic, and renal tissues, lipid peroxidation product and GSH as well as antioxidant enzymatic activities were assayed. Finally, histopathological assessment evaluated the structural damage in cardiac, hepatic, and renal tissues.Results: Serum markers of cardiac, hepatic, and renal toxicities including creatine kinases, aminotransferases, and urea were attenuated by LT in hypercholesterolemic animals. Moreover, LT markedly corrected the elevated levels of lipoproteins, apoptosis, and inflammatory biomarkers. Hypercholesterolemia-induced lipid peroxidation, low GSH levels, and diminished activities of antioxidant enzymes were prominently improved in LT treated animals. Histopathological alterations by hypercholesterolemia in heart, liver, and kidney tissues were ameliorated by LT.Conclusion: This study confirmed the pathological enrollment of renin-angiotensin system in hypercholesterolemia-associated metabolic alterations. LT had a significant cardiac, hepatic, and renal protective role against these impairments through down-regulation of oxidative damage, inflammation and necrosis.


Subject(s)
Antihypertensive Agents/pharmacology , Cholesterol, Dietary/toxicity , Hypercholesterolemia/complications , Inflammation/drug therapy , Losartan/pharmacology , Oxidative Stress , Renin-Angiotensin System/drug effects , Animals , Hypercholesterolemia/chemically induced , Hypercholesterolemia/pathology , Inflammation/etiology , Inflammation/pathology , Male , Rats , Rats, Wistar
9.
Toxicol Mech Methods ; 29(2): 119-127, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30273082

ABSTRACT

Although a plethora of studies have examined tobacco smoke-cancer disease association, the involvement of cellular genetic toxicity remains unclear. Therefore, the present study provides molecular evidence for a pathway involved in the DNA damage induced by long-term cigarette and waterpipe smoke in human subjects. The study population consisted of 45 subjects who were divided into three groups; healthy nonsmokers group, cigarette smokers group, and waterpipe smokers group. A questionnaire and consent form was distributed and signed by all participants. Total RNA was extracted from the blood using PAXgene Blood RNA Kit and mRNA expression levels of target genes were quantified by RT-PCR. Our results showed that 80% of the participants smoke 20-39 cigarettes/day, whereas 12% smoke more than 40 cigarettes/day. With regard to waterpipe smoke, the majority (46%) smoke more than 5 times/week. Both cigarette and waterpipe smokers showed increased the plasma levels 8-hydroxy-2'-deoxyguanosine (8-OHdG), of DNA damage marker. In addition, the mRNA expression levels of DNA repair genes (OGG1 and XRCC1) were significantly inhibited in both cigarette and waterpipe smokers groups by 30% and 60%, respectively. This was associated with a marked decrease (50%) in the expression of detoxifying genes (NQO1 and GSTA1) with an increase in CYP1A1 mRNA expression, a cancer-activating gene. Both cigarette and waterpipe smokers increased in the plasma concentrations of several toxic heavy metals such as Cd (130%), Pb (47%), and Ni (30%). In conclusion: the present findings clearly explore the genotoxic effect of cigarette and waterpipe smoking on human DNA.


Subject(s)
Cigarette Smoking/adverse effects , DNA Damage , Inhalation Exposure/adverse effects , Oxidative Stress , Smoke/adverse effects , Smokers , Water Pipe Smoking/adverse effects , 8-Hydroxy-2'-Deoxyguanosine , Adult , Biomarkers/blood , Case-Control Studies , Cigarette Smoking/blood , Cigarette Smoking/genetics , Cytochrome P-450 CYP1A1/blood , Cytochrome P-450 CYP1A1/genetics , DNA Glycosylases/blood , DNA Glycosylases/genetics , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/blood , Female , Gene Expression Regulation, Enzymologic , Glutathione Transferase/blood , Glutathione Transferase/genetics , Healthy Volunteers , Humans , Male , Middle Aged , NAD(P)H Dehydrogenase (Quinone)/blood , NAD(P)H Dehydrogenase (Quinone)/genetics , Risk Assessment , Time Factors , Transcriptome , Water Pipe Smoking/blood , Water Pipe Smoking/genetics , X-ray Repair Cross Complementing Protein 1/blood , X-ray Repair Cross Complementing Protein 1/genetics , Young Adult
10.
Cell Signal ; 52: 127-136, 2018 12.
Article in English | MEDLINE | ID: mdl-30213685

ABSTRACT

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose symptoms include communication deficits, a lack of social skills, and stereotyped repetitive behaviors. We used BTBR T+ Itpr3tf/J (BTBR) mice, a model that demonstrates most of the core behavioral features of ASD, such as decreased sociability and high levels of repetitive behaviors. Currently, there is no treatment available that is able to improve most of the ASD disorder symptoms; thus, finding novel therapies is immediately required. Stat3 inhibitors are potential targets in the treatment of several immune disorders. The aim of the present study was to investigate the effects of S3I-201, a selective Stat3 inhibitor, to determine its potential mechanism in BTBR mice. In this study, we first examined the effects of S3I-201 on repetitive behavior and marble burying. We also examined the treatment of S3I-201 on Th1 (IFN-γ and T-bet), Th17 (IL-17A, RORγt, Stat3, IL-21, and IL-22), and T regulatory (Treg, Foxp3 and Helios) production in spleen CD4+ T cells. We further assessed Th1, Th17, and Treg mRNA and protein expression levels in brain tissues. S3I-201 treatment in BTBR mice significantly prevents marble burying and repetitive behavior. Furthermore, S3I-201 administration causes a considerable decrease in IFN-γ, T-bet, IL-17A, RORγt, Stat3, IL-21, and IL-22 levels, and increases in Foxp3 and Helios production CD4+ T cells in BTBR mice. Additionally, S3I-201 treatment also significantly decreases Th1 and Th17 levels, and increases Treg mRNA and protein expression levels. Therefore, these results suggest that S3I-201 could be considered as a therapeutic option for ASD.


Subject(s)
Autism Spectrum Disorder , Benzenesulfonates/pharmacology , Brain , CD4-Positive T-Lymphocytes , STAT3 Transcription Factor/antagonists & inhibitors , Spleen , Aminosalicylic Acids/pharmacology , Animals , Autism Spectrum Disorder/drug therapy , Autism Spectrum Disorder/immunology , Brain/cytology , Brain/drug effects , Brain/immunology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Male , Mice , Mice, Inbred C57BL , Spleen/cytology , Spleen/drug effects , Spleen/immunology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/drug effects , Th17 Cells/immunology , Th17 Cells/metabolism , Transcription Factors/immunology , Transcription Factors/metabolism
11.
Toxicol Mech Methods ; 28(9): 678-684, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29975149

ABSTRACT

Dasatinib is a new selective tyrosine kinase inhibitor that targets certain kinases involved in cellular growth and development. This drug belongs to a novel anticancer therapy aiming to increase the survival in patients with imatinib-resistant mutations. However, the dasatinib toxicity was reported as a side effect leading to arrhythmias and/or heart failure. Here, we investigated the possibility of dasatinib-induced toxicity in rat cardiomyocyte H9c2 cells. Our objectives were to investigate the ability of dasatinib to induce expression of cytochrome P450 (CYP1A1, CYP1B1) and cardiac hypertrophy markers (BNP, ß-MHC) genes in H9c2 cells. To test this hypothesis, H9c2 cells were incubated with dasatinib at two concentrations (20 and 40 µM). Thereafter, CYP1A1, CYP1B1, BNP, and ß-MHC were determined at gene expression level. Our findings showed that dasatinib induces the CYP1A1, CYP1B1, BNP, and ß-MHC mRNA. The involvement of AhR/CYP1A1 pathway in dasatinib toxicity was tested by resveratrol (RES), an AhR antagonist. Interestingly, the increase in mRNA of different genes by dasatinib was not affected by RES, which confirms that these effects are not mediated through AhR. In addition, this was accompanied by a significant inhibition of constitutive expression of these genes by RES. The current work provides the first evidence for the ability of dasatinib to induce hypertrophic markers in H9c2 cells through AhR-independent pathway.


Subject(s)
Antineoplastic Agents/toxicity , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1B1/genetics , Dasatinib/toxicity , Myocytes, Cardiac/drug effects , Myosin Heavy Chains/genetics , Natriuretic Peptide, Brain/genetics , Animals , Biomarkers/analysis , Cardiomegaly/chemically induced , Cardiomegaly/genetics , Cardiotoxicity , Cell Culture Techniques , Cell Line , Cell Survival/drug effects , Gene Expression/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats
12.
Anticancer Res ; 37(9): 4899-4909, 2017 09.
Article in English | MEDLINE | ID: mdl-28870911

ABSTRACT

The tyrosine kinase inhibitor sunitinib was recently approved for use against gastrointestinal stromal tumors and advanced renal cell carcinoma. Yet, the protective effect of sunitinib against breast cancer has been poorly investigated. In this study, we investigated the antiproliferative and apoptogenic effects of sunitinib and the possible mechanism involved against the MCF7 human breast cancer cell line. Treatment of MCF7 cells with sunitinib caused concentration-dependent cell growth suppression due to apoptosis. Apoptotic death induced by sunitinib in MCF7 cells was mediated by activation of caspase-3 and p53 mRNA and protein expression and an increase in the percentage of apoptotic cells (40%) as determined by flow cytometry. Apoptosis was associated with a significant inhibition of nuclear factor-kappa B mRNA and protein expression. Mechanistically, blocking of de novo RNA synthesis by actinomycin D significantly inhibited sunitinib-induced expression of p53 mRNA, but not that of caspase-3, indicating involvement of a transcriptional mechanism. This apoptosis-mediated inhibition of MCF7 cell growth was attributed to inhibition of cell cycle-related genes (cyclin D1 and cyclin E2) and arrest of MCF7 cells in the G2/M phase in the cell cycle, allowing up-regulation of expression of DNA repair genes such as x-ray repair cross-complementing protein 1. In addition, sunitinib exhibited concentration-dependent induction of oxidative stress genes (heme oxygenase 1 and glutathione transferase A1) through the nuclear factor erythroid 2-related factor 2 pathway. These findings lead us to propose that sunitinib suppressed the proliferation of MCF7 cells via cell-cycle arrest and apoptotic- and oxidative stress-mediated pathways.


Subject(s)
Apoptosis/drug effects , Breast Neoplasms/drug therapy , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , DNA Repair/drug effects , Indoles/pharmacology , NF-kappa B/antagonists & inhibitors , Pyrroles/pharmacology , Antineoplastic Agents/pharmacology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Flow Cytometry , Gene Expression Regulation, Neoplastic/drug effects , Humans , NF-kappa B/metabolism , Sunitinib , Tumor Cells, Cultured
13.
Int Immunopharmacol ; 46: 1-8, 2017 May.
Article in English | MEDLINE | ID: mdl-28249219

ABSTRACT

Psoriatic patients have systemic inflammation as well as oxidative stress, which are associated with cardiovascular disorders such as atherosclerosis, hypertension myocardial infarction, and stroke. Psoriasis has also been shown to be associated with kidney disease in several studies. Both disorders also have strong component of oxidative stress which usually emanates from NADPH oxidases (NOXs) and inducible nitric oxide synthase (iNOS). However, whether psoriatic inflammation leads to renal oxidative stress and dysfunction remains unexplored. Therefore, this study investigated the effect of imiquimod (IMQ)-induced psoriatic inflammation on kidney function and inflammation in a murine model. Mice were topically applied IMQ followed by various analyses in kidney/blood related to inflammation and kidney function. Psoriatic inflammation in mice was associated with kidney dysfunction as reflected by increased serum creatinine and blood urea nitrogen. Kidney dysfunction was paralleled by upregulation of ROS generating enzymes such as NOX2, NOX4 and iNOS with concomitant oxidative stress. Treatment either with general antioxidant, N-acetyl cysteine or NOX/iNOS inhibitors led to improvement of IMQ-induced renal dysfunction and oxidative stress. On the contrary, buthionine sulfoximine, oxidant inducer further aggravated IMQ-induced renal impairment and oxidant-antioxidant imbalance. Our data suggest that psoriatic inflammation causes kidney dysfunction where NOXs and iNOS play important roles. Treatment with antioxidants may be considered as adjunct therapy in psoriatic patients with kidney disease.


Subject(s)
Inflammation/immunology , Kidney Diseases/immunology , Kidney/metabolism , Membrane Glycoproteins/metabolism , NADPH Oxidases/metabolism , Nitric Oxide Synthase Type II/metabolism , Psoriasis/immunology , Acetylcysteine/therapeutic use , Aminoquinolines , Animals , Antioxidants/therapeutic use , Buthionine Sulfoximine/administration & dosage , Disease Models, Animal , Humans , Imiquimod , Inflammation/chemically induced , Inflammation/drug therapy , Kidney/pathology , Kidney Diseases/chemically induced , Kidney Diseases/drug therapy , Male , Membrane Glycoproteins/genetics , Mice , Mice, Inbred BALB C , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/genetics , Nitric Oxide Synthase Type II/genetics , Oxidative Stress/drug effects , Psoriasis/chemically induced , Psoriasis/drug therapy
14.
Environ Toxicol Pharmacol ; 51: 100-107, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28233699

ABSTRACT

Cadmium (CD), an environmental and industrial pollutant, generates reactive oxygen species (ROS) and NOS responsible for oxidative and nitrosative stress that can lead to nephrotoxic injury, including proximal tubule and glomerulus dysfunction. Sinapic acid (SA) has been found to possess potent antioxidant and anti-inflammatory effects in vitro and in vivo. We aimed to examine the nephroprotective, anti-oxidant, anti-inflammatory, and anti-apoptotic effects of SA against CD-induced nephrotoxicity and its underlying mechanism. Kidney functional markers (serum urea, uric acid, creatinine, LDH, and calcium) and histopathological examinations of the kidney were used to evaluate CD-induced nephrotoxicity. Oxidative stress markers (lipid peroxidation and total protein), renal nitrosative stress (nitric oxide), antioxidant enzymes (catalase and NP-SH), inflammation markers (NF-κB [p65], TNF-α, IL-6, and myeloperoxidase [MPO]), and apoptotic markers (caspase 3, Bax, and Bcl-2) were also assessed. SA (10 and 20mg/kg) pretreatment restored kidney function, upregulated antioxidant levels, and prevented the elevation of lipid peroxidation and nitric oxide levels, significantly reducing oxidative and nitrosative stress. CD upregulated renal cytokine levels (TNF-α, IL-6), nuclear NF-κB (p65) expression, NF-κB-DNA-binding activity, and MPO activity, which were significantly downregulated upon SA pretreatment. Furthermore, SA treatment prevented the upregulation of caspase 3 and Bax protein expression and upregulated Bcl-2 protein expression. SA pretreatment also alleviated the magnitude of histological injuries and reduced neutrophil infiltration in renal tubules. We conclude that the nephroprotective potential of SA in CD-induced nephrotoxicity might be due to its antioxidant, anti-inflammatory, and anti-apoptotic potential via downregulation of oxidative/nitrosative stress, inflammation, and apoptosis in the kidney.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Apoptosis/drug effects , Cadmium/toxicity , Coumaric Acids/pharmacology , Environmental Pollutants/toxicity , Kidney/drug effects , NF-kappa B/genetics , Oxidative Stress/drug effects , Animals , Cytokines/immunology , Down-Regulation , Kidney/immunology , Kidney/metabolism , Kidney/pathology , Kidney Function Tests , Lipid Peroxidation/drug effects , Male , Rats, Wistar
15.
Mol Immunol ; 82: 57-65, 2017 02.
Article in English | MEDLINE | ID: mdl-28027499

ABSTRACT

Accumulating evidence suggests an association between immune dysfunction and autism disorders in a significant subset of children. In addition, an imbalance between pro- and anti-inflammatory pathways has been proposed to play an important role in the pathogenesis of several neurodevelopmental disorders including autism; however, the role of anti-inflammatory molecules IL-27 and CTLA-4 and pro-inflammatory cytokines IL-21 and IL-22 has not previously been explored in autistic children. In the current study, we investigated the expression of IL-21, IL-22, IL-27, and CD152 (CTLA-4) following an in-vitro immunological challenge of peripheral blood mononuclear cells (PBMCs) from children with autism (AU) or typically-developing children (TD) with phorbol-12-myristate 13-acetate (PMA) and ionomycin. In our study, cells from children with AU had increased IL-21 and IL-22 and decreased CTLA-4 expression on CD4+ T cells as compared with cells from the TD control. Similarly, AU cells showed decreased IL-27 production by CD14+ cells compared to that of TD control cells. These results were confirmed by real-time PCR and western blot analyses. Our study shows dysregulation of the immune balance in cells from autistic children as depicted by enhanced pro-inflammatory cytokines, 'IL-21/IL-22' and decreased anti-inflammatory molecules, 'IL-27/CTLA-4'. Thus, further study of this immune imbalance in autistic children is warranted in order to facilitate development of biomarkers and therapeutics.


Subject(s)
Autistic Disorder/immunology , Biomarkers/analysis , Cytokines/biosynthesis , Cytokines/immunology , Leukocytes, Mononuclear/immunology , Blotting, Western , CTLA-4 Antigen/biosynthesis , CTLA-4 Antigen/immunology , Child , Child, Preschool , Cross-Sectional Studies , Female , Flow Cytometry , Humans , Inflammation/immunology , Interleukins/biosynthesis , Interleukins/immunology , Male , Real-Time Polymerase Chain Reaction , Interleukin-22
16.
Environ Pollut ; 221: 64-74, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27916491

ABSTRACT

Heavy metals are the most commonly encountered toxic substances that increase susceptibility to various diseases after prolonged exposure. We have previously shown that healthy volunteers living near a mining area had significant contamination with heavy metals associated with significant changes in the expression of some detoxifying genes, xenobiotic metabolizing enzymes, and DNA repair genes. However, alterations of most of the molecular target genes associated with diseases are still unknown. Thus, the aims of this study were to (a) evaluate the gene expression profile and (b) identify the toxicities and potentially relevant human disease outcomes associated with long-term human exposure to environmental heavy metals in mining area using microarray analysis. For this purpose, 40 healthy male volunteers who were residents of a heavy metal-polluted area (Mahd Al-Dhahab city, Saudi Arabia) and 20 healthy male volunteers who were residents of a non-heavy metal-polluted area were included in the study. Total RNA was isolated from whole blood using PAXgene Blood RNA tubes and then reversed transcribed and hybridized to the gene array using the Affymetrix U219 GeneChip. Microarray analysis showed about 2129 genes were identified and differentially altered, among which a shared set of 425 genes was differentially expressed in the heavy metal-exposed groups. Ingenuity pathway analysis revealed that the most altered gene-regulated diseases in heavy metal-exposed groups included hematological and developmental disorders and mostly renal and urological diseases. Quantitative real-time polymerase chain reaction closely matched the microarray data for some genes tested. Importantly, changes in gene-related diseases were attributed to alterations in the genes encoded for protein synthesis. Renal and urological diseases were the diseases that were most frequently associated with the heavy metal-exposed group. Therefore, there is a need for further studies to validate these genes, which could be used as early biomarkers to prevent renal injury.


Subject(s)
Environmental Exposure/statistics & numerical data , Environmental Pollutants/toxicity , Environmental Pollution/statistics & numerical data , Metals, Heavy/toxicity , Biomarkers/metabolism , Environmental Pollutants/metabolism , Gene Expression Profiling , Humans , Inactivation, Metabolic/genetics , Kidney/metabolism , Male , Metals, Heavy/metabolism , Oligonucleotide Array Sequence Analysis , Protein Array Analysis , Real-Time Polymerase Chain Reaction , Saudi Arabia , Transcriptome
17.
Immunobiology ; 222(2): 206-217, 2017 02.
Article in English | MEDLINE | ID: mdl-27717524

ABSTRACT

We set out to investigate the influence of STA-21, a dynamic STAT-3 inhibitor, on the expansion and progression of rheumatoid arthritis (RA), and to determine its potential mechanisms of action in a mouse model of collagen antibody-induced arthritis (CAIA). To this end, arthritis was induced via intravenous (IV) injection of Balb/c mice with a cocktail of antibodies directed against type II collagen (1.5µg/mouse, IV), followed by lipopolysaccharide (LPS) at a dose of (25µg/mouse, i.p.) on day 3. Mice were then left untreated or were simultaneously treated with STA-21 (0.5mg/kg, i.p., once daily for 2 weeks) followed by evaluation for clinical and histological features of arthritic inflammation and flow cytometric analysis of cytokines and transcription factors in peripheral blood. STA-21 enhanced the clinical course of arthritis in CAIA mice and decreased CD8+RORγt+ and CD8+IL-21+ cells while inducing the production of CD8+Foxp3+ cells. Furthermore, STA-21 prevented the production of TNF-α and IL-6 in peripheral blood and increased IL-27 production by CD14+ cells. Moreover, STA-21 not only regulates Th1/Th2 serum cytokine levels but also the mRNA and protein expression of key factors including NF-κB p65, RORγt, T-bet, IL-4, GATA-3, JAK1, Stat3, and IL-21. Thus, administration of the Stat3 inhibitor STA-21 inhibits cellular signaling pathways and downstream activation of key transcription factors previously shown to play key roles in the pathogenesis of RA. Therefore, these data suggest that STA-21 could be considered as a potential treatment for patients with RA.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/etiology , Arthritis, Experimental/metabolism , Polycyclic Compounds/pharmacology , STAT3 Transcription Factor/antagonists & inhibitors , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Disease Progression , Female , Forkhead Transcription Factors/metabolism , Gene Expression Regulation/drug effects , Inflammation Mediators/metabolism , Mice , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
18.
BMC Complement Altern Med ; 15: 40, 2015 Mar 05.
Article in English | MEDLINE | ID: mdl-25879694

ABSTRACT

BACKGROUND: The rates of muscle aches, sprains, and inflammation are significantly increased during pregnancy. However, women are afraid to use systemic analgesics due to perceptions of fetal risks. Thus, topical products are important alternatives to consider for those women. Of interest, Professional Therapy MuscleCare (PTMC) has shown to be effective in alleviating the myofascial pain as reported in a randomized, placebo-controlled double-blinded comparative clinical study of five topical analgesics. However, to date, there is no complete review or long-term safety studies on the safety of these products during pregnancy and lactation. Thus, the aim of this article was to review toxicological, developmental, and reproductive effects associated with the use of PTMC products. METHODS: We performed a systematic review on safety of PTMC from all toxicological articles investigating the effects of PTMC's ingredients. This search was conducted through medical and toxicological databases including, Web of Science, EMBASE, Medline, and Micromedix. Both reported and theoretical adverse effects were extensively reviewed. RESULTS: Of the 1500 publications reviewed, 100 papers were retrieved and included in the review. Although some ingredients in PTMC products might cause adverse reproductive effects at high systemic doses, these doses are hundreds to thousands fold greater than those systemically available from topical use at the recommended maximum dose (i.e. 10 g/day). CONCLUSIONS: This study provides evidence that, when used as indicated, PTMC is apparently safe for pregnant women and their unborn babies as well as for breastfed infants.


Subject(s)
Analgesics/adverse effects , Breast Feeding , Lactation , Musculoskeletal Pain/drug therapy , Pregnancy Complications/drug therapy , Pregnancy Outcome , Administration, Topical , Analgesics/therapeutic use , Female , Humans , Pregnancy , Teratology , Toxicology
19.
Reprod Toxicol ; 53: 45-50, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25797654

ABSTRACT

Topiramate (TPM) is an increasingly used drug during childbearing ages for treatment of epilepsy, migraine, and appetite suppression as well as for off-label indications such as sleep and psychiatric disorders. Presently, while some reports suggested an increased risk of oral cleft (OC), these reports are balanced by studies that could not confirm such association. We conducted a meta-analysis of all studies reporting on women exposed to TPM during pregnancy. Of the 2327 publications reviewed, 6 articles met the inclusion criteria including 3420 patients and 1,204,981 controls. The odd ratio (OR) of OC after the first trimester exposure to TPM exposure was 6.26 (95% confidence interval: 3.13-12.51; P = 0.00001). This study provides strong evidence that TPM is associated with an increased risk of OC in infants exposed to TPM during embryogenesis and should lead to a careful review of TPM use in women of reproductive ages.


Subject(s)
Anti-Obesity Agents/adverse effects , Anticonvulsants/adverse effects , Cleft Palate/chemically induced , Fructose/analogs & derivatives , Prenatal Exposure Delayed Effects , Female , Fructose/adverse effects , Humans , Pregnancy , Pregnancy Trimester, First , Risk , Topiramate
20.
Reprod Toxicol ; 52: 78-82, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25724389

ABSTRACT

Vulvovaginal candidiasis (VVC) affects up to 75% of women at least once during their lifetime, mostly during the reproductive age, and recurrence rate is about 50%. Because half of all pregnancies are unplanned and pregnant women have an increased risk of VVC recurrence, the likelihood of inadvertently being exposed to fluconazole in pregnancy is increased. Thus, we aimed to examine the risk of congenital malformations in the offspring of women exposed to fluconazole in the first trimester of pregnancy. The rate for overall malformations was 1.10 (95% CI 0.98-1.25), for heart defect was 1.29 (95% CI 1.05-1.58), for craniofacial defects was 1.25 (95% CI 0.88-1.77), and for limb/musculoskeletal defects was 0.82 (95% CI 0.59-1.13). In conclusion, the use of fluconazole in the first trimester does not appear to increase the overall risk for congennital malformations. More studies are needed to address the potential increased rate of heart defects.


Subject(s)
Abnormalities, Drug-Induced/epidemiology , Antifungal Agents/adverse effects , Candidiasis, Vulvovaginal/drug therapy , Fluconazole/adverse effects , Abnormalities, Drug-Induced/etiology , Antifungal Agents/therapeutic use , Craniofacial Abnormalities/chemically induced , Craniofacial Abnormalities/epidemiology , Female , Heart Defects, Congenital/chemically induced , Heart Defects, Congenital/epidemiology , Humans , MEDLINE , Pregnancy , Pregnancy Trimester, First
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