Publications by authors named "Naif O Al-Harbi"

72 Publications

Role of ITK signaling in acute kidney injury in mice: Amelioration of acute kidney injury associated clinical parameters and attenuation of inflammatory transcription factor signaling in CD4+ T cells by ITK inhibition.

Int Immunopharmacol 2021 Oct 5;99:108028. Epub 2021 Aug 5.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Acute kidney injury (AKI) is a world-wide health problem and linked with increased risk of morbidity/mortality in hospitalized patients and its incidence has been on the rise in the last few decades. AKI is characterized by renal tubular injury which results from interactions between bacterial products and host immune responses which manifests as a rapid deterioration in renal function. Immune system dysfunction induced by sepsis plays a crucial role in AKI through activation of multiple immune cells of both innate and adaptive origin. These cells release pro-inflammatory cytokines such as IL-6, IL-17A, IFN-γ, and reactive oxygen metabolites. Adaptive immune cells, especially T cells also participate in the amplification of renal inflammation through release of pro-inflammatory cytokines such as IL-17A, IFN-γ, TNF-α, and IL-10. Non-receptor protein tyrosine kinases such as ITK play crucial role in T cell through modulation of key downstream molecules such as PLCγ, STAT3, NFkB, NFATc1, and p-38MAPK. However, it has not been explored in CD4+ T cells during AKI. Therefore, this study investigated the effect of ITK inhibitor on AKI linked clinical parameters (serum BUN, creatinine and renal histopathology), downstream signaling molecules in CD4+ T cells (PLCγ, STAT3, NFkB, and NFATc1), Th1/Th2/Treg cell markers (IL-17A, TNF-α, and IL-10), and neutrophil-mediated oxidative inflammation (MPO/carbonyl/nitrotyrosine formation) in mice. Our data exhibit elevated p-ITK levels in CD4+ T cells which is associated with renal dysfunction and elevated Th1/Th17/neutrophilic responses. Blockade of ITK signaling resulted in ameliorated of AKI associated biochemical; parameters through downregulation in transcription signaling in CD4+ T cells and Th1/Th17 immune responses. Therefore, this report suggests that ITK inhibition could be an effective strategy to halt renal dysfunction associated with AKI.
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http://dx.doi.org/10.1016/j.intimp.2021.108028DOI Listing
October 2021

Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing-Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL/J Mice.

Pharmaceutics 2021 Jun 22;13(7). Epub 2021 Jun 22.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that leads to demyelination and neuronal loss in the central nervous system. Immune cells of lymphoid and myeloid origin play a significant role in the initiation and amplification of neuronal inflammation in MS. STAT3 signaling plays a pivotal role in both myeloid and lymphoid immune cells, such as neutrophils and CD4+ T cells, through regulation of their inflammatory potential. Dysregulation in STAT3 signaling in myeloid and lymphoid cell compartments has been reported in MS. In this report, we attempted to investigate the effect of a small molecular inhibitor of STAT3, i.e., Stattic, in a relapsing-remitting (RR) model of experimental autoimmune encephalomyelitis (EAE). The effect of Stattic was investigated for clinical features, oxidative stress parameters, and Th17-related signaling in both the periphery and brain of SJL/J mice. Our data report that p-STAT3 expression is elevated in granulocytes, CD4+ T cells, and brain tissue in myelin proteolipid protein (PLP)-immunized SJL/J mice, which is associated with the presence of clinical symptoms and upregulation of inflammatory markers in these cells/tissues. Treatment with Stattic leads to the amelioration of disease symptoms and attenuation of inflammatory markers in neutrophils (iNOS/nitrotyrosine/IL-1β), CD4+ T cells (IL-17A/IL-23R), and brain tissue (IL-17A/iNOS/IL-1β/MPO activity/lipid peroxides) in mice with EAE. These data suggest that the blockade of STAT3 signaling in cells of lymphoid and myeloid origin may cause the attenuation of systemic and neuronal inflammation, which could be responsible for the amelioration of disease symptoms in an RR model of EAE. Therefore, pharmacological inhibition of STAT3 in RRMS could be a potential therapeutic strategy.
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http://dx.doi.org/10.3390/pharmaceutics13070925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308768PMC
June 2021

Exposure to the plasticizer, Di-(2-ethylhexyl) phthalate during juvenile period exacerbates autism-like behavior in adult BTBR T + tf/J mice due to DNA hypomethylation and enhanced inflammation in brain and systemic immune cells.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Jul 23;109:110249. Epub 2021 Jan 23.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Epigenetic modifications are known to play a crucial role in the behavioral modifications through regulation of gene expression. Environmental factors are known to regulate genetic transcription through DNA methylation which is one of the mechanisms of epigenetic modification. Di-2-ethylhexyl phthalate (DEHP) is one of the most abundant phthalate plasticizers in day-to-day products. Prenatal/postnatal DEHP administration has been reported to cause inflammation as well as behavioral dysregulation, however it is not known if exposure to DEHP during juvenile stage affects peripheral/neuronal inflammation and autism-like symptoms in BTBR mice at adulthood. This study investigated effect of DEHP exposure during juvenile period on DNA methylation (global DNA methylation/DNMT1 expression) and inflammation (IL-17A, IL-6, MCP-1, TNF-α) in CD4 + T cells/CD11c + DCs and cortex, and autism-like symptoms (three-chambered sociability test, self-grooming and marble burying test) in asocial BTBR and social C57 mice at adulthood. Our data reveal that BTBR mice exposed to DEHP during juvenile period have hypomethylated DNA/DNMT1 expression in CD11c + DCs and cortex as compared to vehicle-exposed BTBR mice. It was associated with upregulated inflammation in periphery [plasma IL-6/IL-17A, CD11c + DCs (IL-6/MCP-1/TNF-α), and CD4+ T cells (IL-17A)] and cortex (IL-6, MCP-1, TNF-α), and aggravation in autism-like symptoms in DEHP-treated BTBR mice. These data propose that exposure of DEHP during juvenile period may affect autism-like behavior and inflammation in BTBR mice at adulthood through epigenetic regulation. Therefore, underlying genetic predisposition may play a crucial role in worsening of autistic symptoms in ASD subjects in adulthood if they are exposed to environmental pollutants such as DEHP during juvenile period.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110249DOI Listing
July 2021

Aggravation of autism-like behavior in BTBR T+tf/J mice by environmental pollutant, di-(2-ethylhexyl) phthalate: Role of nuclear factor erythroid 2-related factor 2 and oxidative enzymes in innate immune cells and cerebellum.

Int Immunopharmacol 2021 Feb 29;91:107323. Epub 2020 Dec 29.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder which manifests itself in early childhood and is distinguished by recurring behavioral patterns, and dysfunction in social/communication skills. Ubiquitous environmental pollutant, di-2-ethylhexyl phthalate (DEHP) is one of the most frequently used plasticizers in various industrial products, e.g. vinyl flooring, plastic toys, and medical appliances. DEHP gets easily released into the environment and leads to human exposure through various routes. DEHP has been described to be linked with oxidative stress in various organs in animal/human studies. Increased concentration of DEHP has also been detected in ASD children which indicates an association between phthalates exposure and ASD. However, effect of DEHP on autism-like behavior has not been investigated previously. Therefore, this study probed the effect of DEHP on autism-like behavior (marble burying, self-grooming and sociability) and innate immune cells (dendritic cells/neutrophils)/cerebellar oxidant-antioxidant balance (NFkB, iNOS, NADPH oxidase, nitrotyrosine, lipid peroxides, Nrf2, SOD, GPx) in BTBR and C57 mice. Our data show that DEHP treatment causes worsening of autism-like behavior in BTBR mice which is associated with enhancement of oxidative stress in innate immune cells and cerebellum with concomitant lack of antioxidant protection. DEHP also causes oxidative stress in C57 mice in both innate immune cells and cerebellar compartment, however there is Nrf2-mediated induction of enzymatic antioxidants which protects them from upregulated oxidative stress. This proposes the notion that ubiquitous environmental pollutants such as DEHP may be involved in the pathogenesis/progression of ASD through dysregulation of antioxidant-antioxidant balance in innate immune cells and cerebellum.
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http://dx.doi.org/10.1016/j.intimp.2020.107323DOI Listing
February 2021

Role of carnitine in regulation of blood pressure (MAP/SBP) and gene expression of cardiac hypertrophy markers (α/β-MHC) during insulin-induced hypoglycaemia: Role of oxidative stress.

Clin Exp Pharmacol Physiol 2021 04 27;48(4):478-489. Epub 2020 Dec 27.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Cardiovascular disease is a leading cause of death in diabetic patients. Hyperglycaemia and iatrogenic hypoglycaemia exacerbate several pathogenic mechanisms underlying hypertension and heart diseases. Carnitine is a potent endogenous antioxidant and cellular fatty acid transporter for antioxidative stress and energy production in the cardiovascular system. The current study aimed to find the role of carnitine in the regulation of hypoglycaemia-induced hypertension and cardiac hypertrophy. Male rats received insulin glargine (InG) to induce hypoglycaemia followed by D-carnitine or acetyl-L-carnitine for carnitine depletion or carnitine supplementation, respectively. The obtained results showed that carnitine deficiency provoked hypoglycaemia-induced hypertension. Mean arterial pressure was elevated from 78.16 ± 11.4 to 100 ± 5.11 mm Hg in InG treated group, and from 78.2 ± 8.5 to 123.4 ± 28.2 mm Hg in InG + D-carnitine treated group. Acetyl-L-carnitine resisted the elevation in blood pressure in all hypoglycaemic animals and kept it within the normal values (68.33 ± 6.7 mm Hg). Acetyl-L-carnitine increased myocardial carnitine content leading to the attenuation of hypoglycaemia-induced oxidative stress, which was evaluated through measurement of the oxidative stress biomarkers such as inducible nitric oxide synthase, NAD(P)H quinone dehydrogenase-1, heme oxygenase-I, and glutathione S-transferase. Moreover, acetyl-L-carnitine prevented induction of gene expression of cardiac hypertrophy markers during hypoglycaemic conditions, which was assessed via the evaluation of mRNA expression of α-myosin heavy chain and β-myosin heavy chain. These findings demonstrate that carnitine might play an essential role in prevention of hypoglycaemia-induced hypertension and cardiac hypertrophy through providing energy and antioxidants to the cardiovascular system.
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http://dx.doi.org/10.1111/1440-1681.13455DOI Listing
April 2021

Bruton's tyrosine kinase inhibition attenuates oxidative stress in systemic immune cells and renal compartment during sepsis-induced acute kidney injury in mice.

Int Immunopharmacol 2021 Jan 7;90:107123. Epub 2020 Nov 7.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Sepsis is a life-threatening condition which affects multiple organs including the kidney. Sepsis-induced acute kidney injury (AKI) is a major health burden throughout the globe. Pathogenesis of sepsis-induced AKI is complex; however, it involves both innate and adaptive immune cells such as B cells, T cells, dendritic cells (DCs), macrophages, and neutrophils. Bruton's tyrosine kinase (BTK) is reportedly involved in inflammatory and oxidative signaling in different immune cells, however its contribution with respect to sepsis-induced AKI has not been delineated. This study attempted to investigate the role of BTK and its inhibition on oxidizing enzymes NADPH oxidase (NOX-2) and inducible nitric oxide synthase (iNOS) in DCs, neutrophils, and B cells during AKI. Our data reveal that BTK is activated in DCs, neutrophils, and B cells which causes an increase in AKI associated biochemical markers such as serum creatinine/blood urea nitrogen, renal myeloperoxidase activity, and histopathological disturbances in renal tubular structures. Activation of BTK causes upregulation of NOX-2/iNOS/nitrotyrosine in these immune cells and kidney. Treatment with BTK inhibitor, Ibrutinib causes attenuation in AKI associated dysfunction in biochemical parameters (serum creatinine/blood urea nitrogen, renal myeloperoxidase activity) and oxidative stress in immune cells and kidney (iNOS/NOX2/lipid peroxides/nitrotyrosine/protein carbonyls). In summary, the current investigation reveals a compelling role of BTK signaling in sepsis-induced AKI which is evident from amelioration of AKI associated renal dysfunction after its inhibition.
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http://dx.doi.org/10.1016/j.intimp.2020.107123DOI Listing
January 2021

Inhibition of interleukin-2-inducible T-cell kinase causes reduction in imiquimod-induced psoriasiform inflammation through reduction of Th17 cells and enhancement of Treg cells in mice.

Biochimie 2020 Dec 29;179:146-156. Epub 2020 Sep 29.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Psoriasis is a debilitating chronic skin disease with a worldwide prevalence. Its main features include well-marked silvery scales on the skin of hands and feet and back which arise due to hyperproliferation of keratinocytes and infiltration of immune cells in the skin. Multiple interactions exist between adaptive immune cells such as T cells and innate immune cells such as neutrophils and macrophages which are key players in the pathogenesis of psoriasis. Interleukin-2-inducible T-cell kinase (ITK) plays a key role in Th17 cell development through control of several transcription factors. ITK has been shown to control NFATc1, NFkB and STAT3 in CD4 T cells. Effect of ITK inhibitor in imiquimod (IMQ)-induced psoriasiform inflammation remains to be explored. In the current examination, role of ITK signaling and its inhibition blockade were evaluated on NFATc1, NFkB and STAT3, IL-17A, TNF-α, IFN-γ, Foxp3, IL-10 in CD4 T cells in IMQ model. Our data display that ITK signaling is involved in IMQ-induced psoriatic inflammation as paralleled by enhancement of p-ITK, NFATc1, p-NFkB and p-STAT3 in CD4 T cells. It was associated with enhancement of Th17/Th1 cells and neutrophilic inflammation in the skin. Preventive treatment with ITK inhibitor led to a reduction in Th17/Th1 cells and enhancement of Treg cells. Overall, this study suggests that ITK signaling is an important modulator of transcription factor signaling in CD4 T cells which is associated with Th17/Th1 cells and psoriasiform inflammation in mice. ITK signaling blockade could be a therapeutic target for the treatment of psoriatic inflammation.
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http://dx.doi.org/10.1016/j.biochi.2020.09.023DOI Listing
December 2020

Ubiquitous plasticizer, Di-(2-ethylhexyl) phthalate enhances existing inflammatory profile in monocytes of children with autism.

Toxicology 2020 12 28;446:152597. Epub 2020 Sep 28.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Genetic as well as environmental factors are believed to play a significant role in the pathogenesis and progression of autism spectrum disorder (ASD). Phthalates are ubiquitous environmental contaminants as they are used plasticizers in several household/industrial products such as vinyl flooring, plastic toys, and cosmetic products. One of the plasticizers that is quite prevalent in these products is di-2-ethylhexyl phthalate (DEHP) which can cause human exposure via dermal/inhalation/ingestion routes. DEHP and its metabolites are associated with behavioral dysregulations and reported to be increased in systemic circulation of ASD children. DEHP is reported to cause upregulation of several inflammatory cytokines in different cells/tissues, however its role in inflammatory signaling of ASD monocytes has not been investigated earlier. Therefore, this study evaluated the effects of DEHP (at 5 μM final concentration for 24 h) on inflammatory profile (NFkB, STAT3, IL-6, TNF-α, IL-1β) in monocytes of ASD subjects and typically developing control (TDC) children. Our data show that DEHP upregulates NFkB/STAT3 expression which is associated with increased inflammatory profile in monocytes of ASD and TDC subjects, however its effect is much greater in magnitude in the former group. This was confirmed by utilization of NFkB inhibitor, PDTC and STAT3 inhibitor, Stattic which caused reduction in inflammatory cytokines from DEHP-treated monocytes in ASD group. In short, DEHP causes further elevation in inflammatory signaling in ASD monocytes which could be due to existing inflammation in this group. These data suggest that use of plasticizers such as DEHP should be minimized in order to avoid their potential effects on immune dysfunction associated with ASD.
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http://dx.doi.org/10.1016/j.tox.2020.152597DOI Listing
December 2020

Elevated expression of toll-like receptor 4 is associated with NADPH oxidase-induced oxidative stress in B cells of children with autism.

Int Immunopharmacol 2020 Jul 6;84:106555. Epub 2020 May 6.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Autism spectrum disorder (ASD) is a childhood disorder with neurodevelopmental dysfunction which manifests as impairment in social behavior and communication skills. B cells play an important role in immune dysfunction where toll-like receptor 4 (TLR4) may contribute through oxidative inflammatory process. TLR4 related signaling and oxidative stress have been reported in the periphery of ASD subjects, however it has not been evaluated in peripheral B cells of ASD subjects and compared with typically developing control (TDC) children. This study evaluated TLR4 expression and related signaling [Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), NF-kB, NADPH oxidase (NOX2), nitrotyrosine, superoxide dismutase (SOD)] in ASD and TDC subjects. Current investigation in B cells shows that ASD subjects have increased TLR4 expression and oxidative stress as exhibited by upregulated NOX2 and nitrotyrosine expression as compared to TDC subjects. B cell relevant pathways, BTK/SYK/NF-kB were also upregulated in B cells of ASD group. Treatment with TLR4 agonist, LPS led to upregulation of NOX2 and nitrotyrosine in B cells of ASD whereas it had no significant effect on TDC subjects. Treatment with NF-kB inhibitor caused inhibition of LPS-induced upregulation of NOX2 and nitrotyrosine in B cells of ASD. Therefore, current investigation proposes the notion that TLR4 expression is elevated in B cells which is associated with increased NF-kB signaling and oxidant stress in ASD subjects. In short, peripheral B cells could contribute to systemic oxidative inflammation and contribute to the immune dysfunction in ASD.
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http://dx.doi.org/10.1016/j.intimp.2020.106555DOI Listing
July 2020

Role of rivaroxaban in sunitinib-induced renal injuries via inhibition of oxidative stress-induced apoptosis and inflammation through the tissue nacrosis factor-α induced nuclear factor-κappa B signaling pathway in rats.

J Thromb Thrombolysis 2020 Aug;50(2):361-370

Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, 72341, Saudi Arabia.

Rivaroxaban (RIVA) inhibits factor Xa and exhibits antithrombotic and anti-inflammatory activities by inhibiting several cellular signaling molecules. Sunitinib (SUN) is FDA approved first-line drug for metastatic renal cancers and advanced cancerous states of gastrointestinal tract. Present hypothesis was aimed to examine the nephroprotective potential of RIVA in SUN-induced nephrotoxicity, mediated through the inhibition of oxidative stress-induced apoptosis and inflammation, via the TNF-α/NFk-B signaling pathways. Wistar rats 200-250 g were selected and divided randomely in 5 groups (n = 6): Group 1 kept as normal control; Group 2 as disease control and exposed to SUN 50 mg/kg thrice-weekly upto 21 days; Groups 3 and 4, were treatment groups and administered SUN 50 mg/kg thrice-weekly as of group 2 and treated with RIVA 5 and 10 mg/kg/daily for 21 days, respectively; and Group 5 fed with RIVA alone (10 mg/kg/daily for 21 days). Serum was separated from blood to estimate serum biochemical parameters and kidney tissues were collected to estimate antioxidant enzyme, mRNA and protein expression. SUN exposure significantly elevated levels of creatinine, urea, uric acid, blood urea nitrogen, albumin, and bilirubin, and decreased serum magnesium and iron levels. Malondialdehyde and catalase levels were significantly increased and glutathione and glutathione reductase levels were significantly decreased. Intracellular levels of caspase-3 and TNF-α were significantly increased; RIVA treatment restored the altered levels. In SUN-exposed animals, western blotting revealed significantly elevated NFk-B, IL-17, and MCP-1 expression, and IKBα levels were significantly downregulated; RIVA restored these levels to normal values.RIVA treatment significantly restored the apoptotic and inflammatory parameters in SUN-damaged renal tissues.
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http://dx.doi.org/10.1007/s11239-020-02123-6DOI Listing
August 2020

Liraglutide attenuates gefitinib-induced cardiotoxicity and promotes cardioprotection through the regulation of MAPK/NF-κB signaling pathways.

Saudi Pharm J 2020 Apr 19;28(4):509-518. Epub 2020 Mar 19.

Department of Pharmacy Services, Prince Mohammed Bin Abdulaziz Hospital, Riyadh 14214, Saudi Arabia.

Gefitinib is an effective treatment for patients with locally advanced non-small cell lung cancer. However, it is associated with cardiotoxicity that can limit its clinical use. Liraglutide, a glucagon-like peptide 1 receptor agonist, showed potent cardioprotective effects with the mechanism is yet to be elucidated. Therefore, this study aimed to determine the efficiency of liraglutide in protecting the heart from damage induced by gefitinib. Adult male Wistar rats were randomly divided into control group, liraglutide group (200 µg/kg by i.p. injection), gefitinib group (30 mg/kg orally) and liraglutide plus gefitinib group. After 28 days, blood and tissue samples were collected for histopathological, biochemical, gene and protein analysis. We demonstrated that gefitinib treatment (30 mg/kg) resulted in cardiac damage as evidenced by histopathological studies. Furthermore, serum Creatine kinase-MB (CK-MB), N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac Troponin-I (cTnI) were markedly elevated in gefitinib group. Pretreatment with liraglutide (200 µg/kg), however, restored the elevation in serum markers and diminished gefitinib-induced cardiac damage. Moreover, liraglutide improved the gene and protein levels of anti-oxidant (superoxide dismutase) and decreased the oxidative stress marker (NF-κB). Mechanistically, liraglutide offered protection through upregulation of the survival kinases (ERK1/2 and Akt) and downregulation of stress-activated kinases (JNK and P38). In this study, we provide evidence that liraglutide protects the heart from gefitinib-induced cardiac damage through its anti-oxidant property and through the activation of survival kinases.
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http://dx.doi.org/10.1016/j.jsps.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132601PMC
April 2020

Therapeutic treatment with Ibrutinib attenuates imiquimod-induced psoriasis-like inflammation in mice through downregulation of oxidative and inflammatory mediators in neutrophils and dendritic cells.

Eur J Pharmacol 2020 Jun 28;877:173088. Epub 2020 Mar 28.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Psoriasis is clinically characterized by well-demarcated silvery plaques which may appear on the extremities, scalp, and sacral area. The multidimensional interactions among innate immune cells [neutrophils and dendritic cells (DCs)], adaptive immune cells and skin resident cells result in characteristic features of psoriatic inflammation such as acanthosis, hyperkeratosis, and parakeratosis. Tec family kinases are involved in the pathogenesis of several inflammatory diseases. One of them is Bruton's tyrosine kinase (BTK) which is reported to carry out inflammatory and oxidative signaling in neutrophils and DCs. Effect of BTK inhibitor with regard to psoriatic inflammation has not been explored previously especially in a therapeutic setting. In the current investigation, effect of BTK inhibitor, Ibrutinib on oxidative/inflammatory signaling in dermal/splenic neutrophils [phosphorylated BTK (p-BTK), inducible nitric oxide synthase (iNOS), nitrotyrosine], CD11c + DCs (p-BTK, iNOS, nitrotyrosine, MCP-1, TNF-α) and enzymatic antioxidants [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR)] in imiquimod (IMQ)-induced psoriatic inflammation was evaluated using therapeutic mode. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in oxidative stress in neutrophils, and CD11c + DCs in skin/periphery. Therapeutic treatment with Ibrutinib caused attenuation of IMQ-induced oxidative stress in CD11c + DCs and neutrophils. Further there were dysregulations in antioxidants enzymes (SOD/GPx/GR) in the skin of IMQ-treated mice, which were corrected by Ibrutinib. In short, our study reveals that BTK signaling in neutrophils and CD11c + DCs upregulates oxidative stress which is concomitant with psoriatic inflammation in mice. Ibrutinib attenuates psoriasis inflammation through downregulation of oxidative stress in these innate immune cells.
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http://dx.doi.org/10.1016/j.ejphar.2020.173088DOI Listing
June 2020

Adverse drug reaction prevalence and mechanisms of action of first-line anti-tubercular drugs.

Saudi Pharm J 2020 Mar 31;28(3):316-324. Epub 2020 Jan 31.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box: 2457, Riyadh 11451, Saudi Arabia.

Purpose: Understanding the appearance of anti-tubercular drug-related adverse drug reactions (ADRs) in patients receiving tuberculosis (TB) treatment is important, and may be related to morbidity and mortality if not recognized early. Here, we aimed to characterize the mechanisms underlying adverse drug reactions due to combination anti-tuberculosis therapy of the Revised National Tuberculosis Control Program (RNTCP).

Methods: This was a prospective observational study conducted in 9 DOTS centers of New Delhi, India. All enrolled TB patients receiving first-line tuberculosis treatment as per RNTCP guidelines were monitored for ADRs. All ADRs that appeared during the treatment were recorded and analyzed.

Results: The study included 1011 TB patients on anti-TB treatment under DOTS. According to Naranjo's probability scale, of a total 351 (34.72%) reported adverse events, 102 (10.09%) were definite, 59 (5.83%) probable, 123 (12.17%) possible, and 67 (6.63%) doubtful. On the Hartwig severity scale, of the 351 adverse drug events, 225 (22.26%) were mild, 105 (10.38%) were moderate, and 21 (2.08%) were severe. Out of 102 reported adverse drug reactions, 81 (79.41%) were moderate and 21 (20.59%), while 65.28% did not experience any ADRs.

Conclusions: Directly Observed Treatment (DOT) is effective and safe compared to daily treatment regimens. Patients receiving DOTS therapy needed close monitoring for adverse events. Therefore, a pharmacovigilance program should be added at the National level to accesses the adverse event incidence.
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http://dx.doi.org/10.1016/j.jsps.2020.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078525PMC
March 2020

Upregulation of enzymatic antioxidants in CD4 T cells of autistic children.

Biochimie 2020 Apr - May;171-172:205-212. Epub 2020 Mar 12.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder which begins in early childhood and presents itself with characteristic symptoms such as repetitive behavioral patterns and problems in speech/social interactions. Adaptive immune system is thought to be involved in the etiology of ASD. T cells orchestrate amplification of inflammation through release of inflammatory mediators; however, antioxidant defenses have not been evaluated in CD4 T cells of ASD subjects. In this study we evaluated intracellular enzymatic antioxidant potential through measurement of major antioxidant enzymes (SOD, GPx, and GR) in ASD subjects and typically developing control (TDC) children and further assessed its role in modulation of inflammation. Our data reveal that there is an increase in antioxidant potential (SOD, GPx, GR) in CD4 T cells of ASD subjects as compared to TDC children at both protein and activity level. Further, this antioxidant increase was associated with upregulated IL-17A levels in CD4 T cells. This was corroborated by oxidant treatment in vitro. Pretreatment with oxidant, HO led to attenuation of IL-17A levels along with increased oxidative stress in stimulated CD4 T cells from ASD subjects. These data reveal that antioxidant play an essential role in modulation of inflammatory potential in CD4 T cells of ASD subjects.
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http://dx.doi.org/10.1016/j.biochi.2020.03.009DOI Listing
December 2020

Blockade of interleukin-2-inducible T-cell kinase signaling attenuates acute lung injury in mice through adjustment of pulmonary Th17/Treg immune responses and reduction of oxidative stress.

Int Immunopharmacol 2020 Jun 9;83:106369. Epub 2020 Mar 9.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Acute lung injury (ALI) is linked with considerable morbidity and mortality. ALI can be caused by various agents, one of them being sepsis. ALI is characterized by injury to vascular endothelium and alveolar epithelium that results in edema, pulmonary immune cells infiltration and hypoxemia. Neutrophils and T cells particularly play a huge role in amplification of pulmonary inflammation through release of multiple inflammatory mediators. Recent reports suggest a strong involvement of Th17 cells and oxidative stress in initiation/amplification of pulmonary inflammation during ALI. Interleukin-2-inducible T-cell kinase (ITK) plays a key role in Th17 cell development through control of several transcription factors. Therefore, our study explored the role of ITK on airway inflammation (total/neutrophilic cell counts, myeloperoxidase activity, E-cadherin expression, histopathological analyses) and effect of its inhibition on various inflammatory/anti-inflammatory pathways during ALI [phosphorylated-ITK (p-ITK), NFATc1, IL-17A, STAT3, Foxp3, IL-10, iNOS, nitrotyrosine, lipid peroxides). ALI was associated with increased total/neutrophilic cell counts and myeloperoxidase activity, and decreased E-cadherin expression in airway epithelial cells (AECs) which was concurrent with upregulation of p-ITK, NFATc1, IL-17A, STAT3 in CD4+ T cells and iNOS/nitrotyrosine in AECs. Treatment with ITK inhibitor reversed ALI-induced changes in airway inflammation and Th17 cells/oxidative stress. Treatment with ITK inhibitor further expanded Treg cells in mice with ALI. In short, our study proposes that ITK signaling plays a significant role in sepsis-induced ALI through upregulation of Th17 cells and oxidative stress. Further, findings provide evidence that ITK blockade could be a potential treatment strategy to attenuate airway inflammation associated with ALI.
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http://dx.doi.org/10.1016/j.intimp.2020.106369DOI Listing
June 2020

Bruton's tyrosine kinase inhibitor suppresses imiquimod-induced psoriasis-like inflammation in mice through regulation of IL-23/IL-17A in innate immune cells.

Int Immunopharmacol 2020 Mar 24;80:106215. Epub 2020 Jan 24.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Psoriasis is an unchecked chronic inflammation characterized by thick, erythematous, and scaly plaques on the skin. The role of innate immune cells in the pathogenesis of psoriasis is well documented. Bruton's tyrosine kinase (BTK) has been reported to execute important signaling functions in innate immune cells such as dendritic cells (DCs) and gamma delta T cells. However, whether inhibition of BTK would lead to modulation of innate immune function in the context of psoriatic inflammation remains largely unexplored. In the present study, we investigated the effect of selective BTK inhibitor, PCI-32765 on inflammatory signaling in CD11c + DCs and gamma delta T cells in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in inflammatory cytokines (IL-23, TNF-α) in CD11c + DCs in the skin. Preventive treatment with BTK inhibitor led to significant reversal in IMQ-induced inflammatory changes in CD11c + DCs of skin. Further, there was a significant decrease in dermal IL-17A levels and IL-17A + γδ + T cells after treatment with BTK inhibitor. Furthermore, short treatment of back skin with IMQ led to upregulated expression of p-BTK along with inflammatory cytokines in CD11c + DCs (IL-23, TNF-α) and IL-17A in γδ + T cells which were reversed by BTK inhibitor. Overall, our study proposes that BTK signaling serves a crucial signaling function in innate immune cells in the context of psoriatic inflammation in mice. Therefore, BTK might be a promising therapeutic target to treat psoriatic inflammation.
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http://dx.doi.org/10.1016/j.intimp.2020.106215DOI Listing
March 2020

Differential regulation of Nrf2 is linked to elevated inflammation and nitrative stress in monocytes of children with autism.

Psychoneuroendocrinology 2020 03 23;113:104554. Epub 2019 Dec 23.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Autism spectrum disorder (ASD) is a very complex neurodevelopmental disorder characterized by deficits in social and communication skills. Innate immune cells like monocytes are believed to play a cardinal role in neuroimmune inflammation and nitrative stress. On the other hand, Nrf2, a basic leucine zipper transcription factor plays a significant role in protecting the immune cells against inflammation and oxidants. However, its role in monocytes of ASD children and typically developing control (TDC) children has not been elucidated in relation with inflammation and nitrative stress. Therefore, this study was undertaken to evaluate Nrf2 expression/activity along with parameters of inflammation (NFkB, IL-6, IL-1β) and nitrative stress (iNOS, nitrotyrosine) in monocytes of ASD/TDC children. Further, sulforaphane (SFN) was utilized as an Nrf2 activator to assess its effect on above said inflammatory and nitrative stress parameters. Our study shows that monocytes of ASD subjects have decreased Nrf2 expression/activity along with increased inflammation and nitrative stress. Further, monocytes from ASD have deficiency in induction of Nrf2 activity upon stimulation with LPS. However, activation of Nrf2 in vitro by SFN reverses LPS-induced effects on inflammation in monocytes by reduction in NFkB signaling. Further, treatment with SFN also reverses LPS-induced effects on nitrative stress (iNOS, nitrotyrosine) in monocytes of ASD subjects. This study propounds the idea that SFN protects against nitrative stress and inflammation by downregulating oxidative stress and inflammation through blockade of NFkB signaling in autistic children. This may be the reason behind reported ameliorative effects of SFN in ASD subjects.
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http://dx.doi.org/10.1016/j.psyneuen.2019.104554DOI Listing
March 2020

Dysregulation in IL-6 receptors is associated with upregulated IL-17A related signaling in CD4+ T cells of children with autism.

Prog Neuropsychopharmacol Biol Psychiatry 2020 03 23;97:109783. Epub 2019 Oct 23.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Autism spectrum disorder (ASD) is a heterogeneous syndrome characterized by dysregulations in speech and social interactions as well as repetitive and stereotypical behavioral patterns in which immune system plays a significant role. IL-6, an essential cytokine for polarization of Th0 cells into Th17 cells has been demonstrated to be crucial in the etiology of ASD in past studies both in humans and mice. Th17 cells are also believed to be central players in the pathogenesis of ASD through release of IL-17A. However, there is still insufficient data regarding identification of Th17 cells with respect to IL-6 signaling in ASD subjects. Therefore, this study explored IL-6 receptors (IL-6R/sIL-6R) and Th17 (p-STAT3/IL-17A/IL-23R) related markers comprehensively in the blood of typically-developing control (TDC, n = 35) and ASD children (n = 45). Our data show that there is enhanced sIL-6R levels in plasma and CD4+ T cells of ASD subjects as compared to TDC group. Increased sIL-6R signaling is associated with upregulated Th17 development in ASD subjects. Further, severe ASD subjects have higher inflammation in terms of IL-6/IL-17A related signaling as compared to moderate ASD patients. Furthermore, treatment of CD4 + T cells in vitro with IL-6 leads to much greater upregulation of p-STAT3, and IL-17A in ASD subjects than similarly treated CD4+ T cells in TDC group. Antagonism of IL-6 signaling by SC144 in vitro led to blockade of IL-6 mediated effects on CD4+ T cells. These data display unequivocally that IL-6 signaling components are dysregulated which play a crucial in enhancement of Th17 development in ASD subjects.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109783DOI Listing
March 2020

Inhibition of Bruton's tyrosine kinase and IL-2 inducible T-cell kinase suppresses both neutrophilic and eosinophilic airway inflammation in a cockroach allergen extract-induced mixed granulocytic mouse model of asthma using preventative and therapeutic strategy.

Pharmacol Res 2019 10 7;148:104441. Epub 2019 Sep 7.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Asthma is a complex airways disease with a wide spectrum which ranges from eosinophilic (Th2 driven) to mixed granulocytic (Th2/Th17 driven) phenotypes. Mixed granulocytic asthma is a cause of concern as corticosteroids often fail to control this phenotype. Different kinases such as Brutons's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) play a pivotal role in shaping allergic airway inflammation. Ibrutinib is primarily a BTK inhibitor, however it is reported to be an ITK inhibitor as well. In this study, we sought to determine the effect of Ibrutinib on Th1, Th17 and Th2 immune responses in a cockroach allergen extract (CE)-induced mixed granulocytic (eosinophilic and neutrophilic) mouse model in preventative mode. Ibrutinib attenuated neutrophilic inflammation at a much lower doses (25-75 μg/mouse) in CE-induced mixed granulocytic asthma whereas Th2/Th17 immune responses remained unaffected at these doses. However, at a much higher dose, i.e. 250 μg/mouse, Ibrutinib remarkably suppressed both Th17/Th2 and lymphocytic/neutrophilic/eosinophilic airway inflammation. At molecular level, Ibrutinib suppressed phosphorylation of BTK in neutrophils at lower doses and ITK in CD4 + T cells at higher doses in CE-treated mice. Further, effects of Ibrutinib were compared with dexamethasone on CE-induced mixed granulocytic asthma in therapeutic mode. Ibrutinib was able to control granulocytic inflammation along with Th2/Th17 immune response in therapeutic mode whereas dexamethasone limited only Th2/eosinophilic inflammation. Thus, Ibrutinib has the potential to suppress both Th17/Th2 and neutrophilic/eosinophilic inflammation during mixed granulocytic asthma and therefore may be pursued as alternative therapeutic option in difficult-to-treat asthma which is resistant to corticosteroids.
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http://dx.doi.org/10.1016/j.phrs.2019.104441DOI Listing
October 2019

Protective role of Roflumilast against cadmium-induced cardiotoxicity through inhibition of oxidative stress and NF-κB signaling in rats.

Saudi Pharm J 2019 Jul 2;27(5):673-681. Epub 2019 Apr 2.

Department of Basic Sciences, Preparatory Year Deanship, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.

Cadmium (Cd), a potent cardiotoxic environmental heavy metal, induces oxidative stress and membrane disturbances in cardiac myocytes. Phosphodiesterase (PDEs) retards the positive inotropic effects of β-adrenoceptor activation by decreasing levels of cAMP via degradation. Hence, PDE inhibitors sensitize the heart to catecholamine and are therefore, used as positive inotropic agents. The present study was designed to probe the potential attenuating effects of the selective PDE4 inhibitor (Roflumilast, ROF), on cardiac biomarkers, lipid profile, lipid peroxidation products, antioxidant status and histology of cardiac tissues against Cd-induced cardiotoxicity in rats. Rats were randomly distributed into four different groups: group 1, served as the normal control group. Group 2, served as the toxic control group and were administered Cd (3 mg/kg, i.p.) for next 7 days. Groups 3 and 4, served as treatment groups that received Cd with concomitant oral administration of ROF doses (0.5 and 1.5 mg/kg), respectively for 7 days. Serum samples of toxic control group rats resulted in significant ( < 0.001) increase in lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total cholesterol (TC), triglycerides (TG) and low density lipoproteins (LDL) levels with concomitant decrease in high density lipoproteins (HDL) levels in serum which were found reversed with both of ROF treatment groups. Cd also causes significant increased ( < 0.001) in myocardial malondialdehyde (MDA) contents while cardiac glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) enzyme activities were found decreased whereas both doses of ROF, significantly reversed these oxidative stress markers and antioxidant enzymes. Cardiotoxicity induced by Cd also resulted in enhanced expression of non-phosphorylated and phosphorylated form of NF-κB p65 and decreased expression of glutathione-S-transferase (GST) and NQO1 which were found reversed with ROF treatments, comparable to normal control group. Histopathological changes were also improved by ROF administration as compared to Cd treated rats alone. In conclusion, Roflumilast exhibited attenuating effect against Cd-induced cardiac toxicity.
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http://dx.doi.org/10.1016/j.jsps.2019.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598217PMC
July 2019

Sulforaphane treatment reverses corticosteroid resistance in a mixed granulocytic mouse model of asthma by upregulation of antioxidants and attenuation of Th17 immune responses in the airways.

Eur J Pharmacol 2019 Jul 14;855:276-284. Epub 2019 May 14.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Sulforaphane has received considerable attention in recent years due to its antioxidant and anti-inflammatory properties. Its preventive effect in the inhibition of airway inflammation is known; however, whether it affects mixed granulocyte asthma (corticosteroid resistance phenotype) is largely undiscovered. Therefore, we assessed the effect of pharmacological activation of Nrf2, a redox-sensitive transcription factor, using sulforaphane in a mouse model of mixed granulocyte airway inflammation. Mice were sensitized and challenged with cockroach allergen extract (CE), and airway inflammatory parameters and markers of steroid resistance [Nrf2 activity, oxidant-antioxidant balance in airway epithelial cells (AECs)/lung, and IL-17A-related pathway in Th17 cells and dendritic cells (DCs)] were investigated. Our results show that sulforaphane administration reduced neutrophilic airway inflammation, myeloperoxidase (MPO) activity, and Th17 immune responses in a mixed granulocyte mouse model of asthma through Nrf2 activation. On the other hand, corticosteroid treatment decreased Th2/eosinophilic immune responses but had little on Th17/neutrophilic immune responses. However, combined treatment with both almost completely blocked both neutrophilic/eosinophilic and Th17/Th2 immune responses in the lung. Sulforaphane treatment led to induction of antioxidant enzymes (SOD, GPx) in AECs and pulmonary non-enzymatic antioxidants. Further, it led to reduction in inflammatory cytokines (IL-6/IL-23/IL-17A) in Th17 cells/CD11c + DCs during mixed granulocytic inflammation. Collectively, our study presents the evidence that activation of Nrf2 by sulforaphane reduces neutrophilic airway inflammation by upregulation of antioxidants and downregulation of inflammatory cytokines in airways. This is possibly the basis for reversal of corticosteroid resistance in this model. This shows the therapeutic potential of sulforaphane in mixed granulocyte asthma.
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http://dx.doi.org/10.1016/j.ejphar.2019.05.026DOI Listing
July 2019

Protease activated receptor-2 mediated upregulation of IL-17 receptor signaling on airway epithelial cells is responsible for neutrophilic infiltration during acute exposure of house dust mite allergens in mice.

Chem Biol Interact 2019 May 7;304:52-60. Epub 2019 Mar 7.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Asthma, a chronic inflammatory disease affecting the airways is primarily caused due to immune system dysfunction. Different inhaled allergens such as house dust mites (HDM), fungi, cockroach allergens are the main contributors to allergic asthma. Protease activated receptor-2 (PAR-2) signaling plays an important role in allergic asthma through modulation of immune mediators in airway epithelial cells (AECs). Interleukin-17A (IL-17A) signals via subunits of IL-17 receptor (IL-17R), i.e. interleukin-17 receptor A (IL-17RA) and interleukin-17 receptor C (IL-17RC), and plays a necessary role in neutrophilic infiltration in response to infectious/allergenic stimuli, however it is not known if PAR-2 activation affects IL-17A/IL-17R signaling during acute exposure to house dust mite (HDM) allergens. Therefore, our study exposed mice to HDM allergens for five days and evaluated its effect on IL-17A/IL-17R signaling, chemokine/cytokines and neutrophilic inflammation in mice. Our study shows that HDM allergens upregulate IL-17A levels in the lung and IL-17RA/IL-17RC expression in AECs. PAR-2 activation by trypsin also upregulates neutrophilic influx and IL-17A/IL-17R signaling in the lung. Upregulated IL-17A/IL-17R signaling was associated with increased BAL neutrophils, pulmonary MPO activity and proinflammatory chemokines and cytokines (IL-23, IL-6, and MCP-1 in AECs/lung) in HDM exposed mice. Further, HDM-induced IL-17A, IL-17R and chemokines/cytokines were attenuated by PAR-2 antagonist, ENMD-1068. Furthermore, HDM-primed mice treated with IL-17A had greater neutrophilic inflammation and higher levels of inflammatory cytokines/chemokines than PBS-exposed mice treated with IL-17A. This proposes that acute exposure to HDM allergens activate AECs at a very early stage where PAR-2/IL-17R signaling serves a crucial role in neutrophilic inflammation.
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http://dx.doi.org/10.1016/j.cbi.2019.03.001DOI Listing
May 2019

Nrf2 activator, sulforaphane ameliorates autism-like symptoms through suppression of Th17 related signaling and rectification of oxidant-antioxidant imbalance in periphery and brain of BTBR T+tf/J mice.

Behav Brain Res 2019 05 19;364:213-224. Epub 2019 Feb 19.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Autism is a neurodevelopmental disease which is characterized by its core behavioral symptoms such as impairment in social interaction and stereotyped repetitive behavior. Th17 immune responses and oxidative stress are reported to be elevated in both human autistic subjects and BTBR T + Itpr3tf/J (BTBR) mice. On the other hand, activation of nuclear factor erythroid 2 related factor (Nrf2), a master transcription factor is essential for the management of anti-inflammatory and antioxidant genes. Sulforaphane activates Nrf2 and thus is considered a potential approach to treat several neurological disorders including autism. In the current work, we used sulforaphane in asocial BTBR mice and its social counterpart C57/BL6 (C57) mice to assess its therapeutic potential and molecular mechanisms (Th17 immune responses, and oxidant-antioxidant balance) through which it acts. Our results demonstrate that BTBR treated with sulforaphane had reduced self-grooming/marble burying behavior, and increased social interaction in three chambered sociability test as compared to untreated BTBR mice. Further, sulforaphane-treated BTBR mice had reduced Th17 immune responses (STAT3, RORC, IL-17 A and IL-23R expression in CD4 + T cells), oxidative stress parameters in neutrophils/cerebellum (NFkB, iNOS, and lipid peroxides). Furthermore, sulforaphane-treated BTBR and C57 mice had upregulated enzymatic antioxidant defenses in neutrophils/cerebellum (SOD, GPx and GR expression and activity). We reason that activation of Nrf2 by sulforaphane corrected Th17 immune dysfunction and oxidant-antioxidant imbalance in periphery and brain in BTBR mice. These mechanisms lead to improvement in autism-like symptoms in BTBR mice.
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http://dx.doi.org/10.1016/j.bbr.2019.02.031DOI Listing
May 2019

Inhibition of spleen tyrosine kinase signaling protects against acute lung injury through blockade of NADPH oxidase and IL-17A in neutrophils and γδ T cells respectively in mice.

Int Immunopharmacol 2019 Mar 2;68:39-47. Epub 2019 Jan 2.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Acute lung injury (ALI) is one of the most serious complications in critically ill patients which often leads to morbidity and mortality. ALI characterized by severe inflammation of lungs occurs due to uncontrolled inflammatory immune response. However, the immunological mechanism(s) are far from being understood. The spleen tyrosine kinase (SYK), a key component of immune receptor signaling, plays a critical role in the modulation of inflammatory signaling in different immune cells. However, its role in ALI remains to be explored. Therefore, in this study, we investigated the effect of R406, a SYK inhibitor in lipopolysaccharide (LPS)-induced ALI mouse model. LPS led to increased SYK expression in neutrophils and gamma delta (γδ) T cells. This was associated with increased neutrophilic airway inflammation, vascular permeability, myeloperoxidase activity in the lung with upregulated expression of NADPH oxidase (NOX2)/MCP-1/TNF-α in neutrophils and IL-17A in γδ T cells/lung. Pulmonary inflammation was associated with higher mortality in mice with ALI. Inhibition of SYK signaling using R406 in the lung led to blockade of neutrophilic airway inflammation, vascular permeability, pro-inflammatory cytokine release and oxidative stress in innate immune cells, i.e. γδ T cells and neutrophils and the lung. R406 administered LPS group had better survival rate than LPS group. This suggests that SYK upregulation in γδ T cells and neutrophils plays an important role in inflammatory process during ALI. In conclusion, R406 exhibited a great potential to block the LPS-induced airway inflammation and mortality which could be developed as a potential future therapy in ALI.
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http://dx.doi.org/10.1016/j.intimp.2018.12.062DOI Listing
March 2019

Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway.

Inflammopharmacology 2019 Aug 1;27(4):817-827. Epub 2019 Jan 1.

Department of Pathology, College of Medicine, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia.

Background: Carfilzomib (CFZ), a proteasome inhibitor approved by the FDA to treat multiple myeloma, may cause nephrotoxicity.

Hypothesis: Rutin is a bioflavonoid with antioxidant properties. We aimed to examine whether rutin protects the kidney from CFZ-induced nephrotoxicity.

Study Design: This study aimed to demonstrate the effect of rutin on CFZ-induced renal injury via the inhibition of oxidative stress and inflammation.

Methods: Wistar albino rats were divided into six groups (n = 6): Group 1 (normal control; NC) was administered normal saline for 3 weeks; Group 2 (CFZ/toxic group) received CFZ [4 mg/kg, intraperitoneal (i.p.) injection] twice weekly for 3 weeks; Group 3 (standard treatment group) was administered CFZ (4 mg/kg, i.p.) and olmesartan (2 mg/kg, p.o.) for 3 weeks; Group 4 was administered CFZ (4 mg/kg, i.p.) and rutin (10 mg/kg, p.o.) for 3 weeks; Group 5 was administered CFZ (4 mg/kg, i.p.) and rutin (20 mg/kg, p.o.) for 3 weeks; and Group 6 was administered CFZ (4 mg/kg, i.p.) and rutin (40 mg/kg, p.o.) for 3 weeks. We carried out haematological and biochemical analyses, determined oxidative stress, caspase-3 activity, and protein levels, and performed a histopathological evaluation to confirm CFZ-induced nephrotoxicity and its prevention by rutin administration.

Results: Exposure to only CFZ significantly (p < 0.05) increased white blood cell (WBC) count, Hb%, and HTC% concentration; however, these features were significantly decreased (p < 0.05) when olmesartan and rutin were administered. CFZ administration significantly decreased (p < 0.0001) the level of antioxidant enzymes; whereas, administration of olmesartan and rutin significantly reversed (p < 0.05) their levels toward the normal range. The levels of caspase-3 enzyme significantly increased (p < 0.001) in the CFZ group and were reduced toward the normal values by olmesartan and rutin administration. Furthermore, the results of NOS-2, NF-κB, IkBa, and IL-17 protein estimation and the histopathological evaluation strengthened our findings that rutin exhibits a protective effect against CFZ-induced nephrotoxicity.

Conclusion: These findings clearly demonstrate that rutin ameliorates CFZ-induced oxidative stress and inflammation in nephrotoxicity via the NOS-mediated NF-κB signaling pathway.
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http://dx.doi.org/10.1007/s10787-018-0550-5DOI Listing
August 2019

Amelioration of sepsis-induced acute kidney injury through inhibition of inflammatory cytokines and oxidative stress in dendritic cells and neutrophils respectively in mice: Role of spleen tyrosine kinase signaling.

Biochimie 2019 Mar 29;158:102-110. Epub 2018 Dec 29.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Sepsis often leads to complications such as acute kidney injury (AKI) which is reported to range from 30 to 50% in critically ill patients. Dendritic (DCs) and neutrophils play a decisive role in the advancement of AKI through release of inflammatory cytokines and reactive oxygen species (ROS) respectively. Both of these processes are assumed to be controlled by spleen tyrosine kinase (Syk) signaling in DCs and neutrophils. However, the role of Syk signaling in these immune cells in sepsis-induced AKI has not been investigated. Therefore, the purpose of this study was to evaluate the effect of a Syk inhibitor, R406 on sepsis-induced AKI in a mouse model. Renal function (creatinine/blood urea nitrogen), inflammatory cytokines (IL-6/MCP-1) in CD11c + DCs and oxidant parameters in neutrophils [inducible nitric oxide synthase (iNOS), NADPH oxidase (NOX2), nitrotyrosine] were assessed. Our results showed elevated expression of Syk in neutrophils and CD11c + DC which was linked with increased IL-6/MCP-1 in CD11c + DCs, and iNOS, NOX2 and nitrotyrosine in neutrophils during sepsis-induced AKI. Inhibitor of Syk signaling, R406 led to improvement of sepsis-induced AKI as depicted by an attenuation of creatinine/blood urea nitrogen in serum, renal myeloperoxidase activity, and repair of tubular structures in kidney. Further, R406 led to a decrease in IL-6/MCP-1 in CD11c + DCs, and iNOS, NOX2 and nitrotyrosine in neutrophils during sepsis-induced AKI. In conclusion, our study proposes that Syk signaling in DCs and neutrophils plays a critical role during sepsis-induced AKI. Therefore, Syk inhibition in innate immune cells might serve as an effective strategy to limit inflammatory cascade during AKI.
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http://dx.doi.org/10.1016/j.biochi.2018.12.014DOI Listing
March 2019

Inhibition of spleen tyrosine kinase attenuates psoriasis-like inflammation in mice through blockade of dendritic cell-Th17 inflammation axis.

Biomed Pharmacother 2019 Mar 25;111:347-358. Epub 2018 Dec 25.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Psoriasis is a debilitating autoimmune disease of the skin characterized by acanthosis and hyperkeratosis resulting from excessive growth of keratinocytes in the epidermis and inflammatory infiltrates in the dermis. Innate immune cells such as dendritic cells (DCs), perform a critical role in the pathophysiology of psoriasis by presenting inflammatory/costimulatory signals for differentiation of Th17 cells. Recent studies point to the involvement of spleen tyrosine kinase (SYK) in inflammatory signaling cascade of DCs. However, it is yet to be determined whether SYK inhibition in DCs would lead to diminishment of psoriatic inflammation. Therefore, our study evaluated the effects of SYK inhibitor, R406 on imiquimod (IMQ)-induced psoriasis-like inflammation, expression of costimulatory/inflammatory molecules in DCs and their relationship with Th17/Treg cells. Our data show that R406 causes attenuation of IMQ-induced dermal inflammation as shown by reduction in ear/back skin thickness, acanthosis and myeloperoxidase activity. This was concurrent with reduction in inflammatory cytokines and co-stimulatory molecules in CD11c + DCs such as IL-6, IL-23, MHCII, and CD40. This favoured the suppression of Th17 cells and upregulation of Treg cells in R406-treated mice with psoriasis-like inflammation. Direct activation of TLR7 by IMQ in splenocytic cultures led to increased SYK expression in CD11c + DCs and release of IL-23/IL-6. IMQ-induced IL-6/IL-23 levels were significantly diminished by SYK inhibitor, R406 in splenocytic cultures. In essence, our study shows that SYK inhibition supresses psoriasis-like inflammation by modifying DC function in mice. Further, it implies that SYK inhibition could be a prospective therapeutic approach for the treatment of psoriasis-like inflammation.
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http://dx.doi.org/10.1016/j.biopha.2018.12.060DOI Listing
March 2019

Oxidative and inflammatory mediators are upregulated in neutrophils of autistic children: Role of IL-17A receptor signaling.

Prog Neuropsychopharmacol Biol Psychiatry 2019 03 6;90:204-211. Epub 2018 Dec 6.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Autism spectrum disorder (ASD) is characterized by repetitive behaviors, impaired social communication and stereotyped interests, and often associated with dysregulations in innate/adaptive immune cells. IL-17A has been linked with abnormal behavioral patterns observed in autistic children and animal models of autism. However, it is yet to be investigated if IL-17A and its receptors are implicated in regulation of oxidative and inflammatory mediators in neutrophils of ASD patients. Therefore, we pursued to identify the effect of IL-17 receptor (IL-17R), and its inflammatory potential in neutrophils from ASD (n = 45) and typically developing control (TDC; n = 40) subjects. IL-17A, its receptor (IL-17R), associated signaling pathways [nuclear transcription factor nuclear factor-kappa B (NF-κB), IL-6 and oxidative stress parameters such as NADPH oxidase (NOX2), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and nitrotyrosine] were determined in the neutrophils from TDC and ASD subjects. Our data show that IL-17A expression, and IL-17R are increased in neutrophils of ASD patients. Further, inflammatory signaling pathways such as such as phospho-NFκB, and ROS generating enzymes, i.e. NOX2/iNOS are increased in neutrophils of ASD patients as compared TDC subjects. Furthermore, activation of IL-17A/IL-17R signaling in neutrophils of ASD subjects leads to upregulation of phospho-NFκB, IL-6 and NOX2/ROS, thus suggesting a compelling role of IL-17A in modulation of inflammation. Our study displays for the first time that IL-17A/IL-17R signaling in neutrophils could play a pivotal role in autism through upregulation of oxidative and inflammatory mediators.
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http://dx.doi.org/10.1016/j.pnpbp.2018.12.002DOI Listing
March 2019

Apremilast ameliorates carfilzomib-induced pulmonary inflammation and vascular injuries.

Int Immunopharmacol 2019 Jan 28;66:260-266. Epub 2018 Nov 28.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Acute lung injury (ALI) due to chemotherapy occurs frequently. It presents a challenge for clinicians managing therapies for different types of cancers. Carfilzomib (Kyprolis™) is a new proteasome inhibitor that shows promise for the treatment of relapsing multiple myeloma. However, several cases of severe ALI have raised concern about the use of carfilzomib against relapsed multiple myelomas. To improve the efficacy of carfilzomib, a new anti-inflammatory drug for psoriasis treatment, apremilast (Otezla™) was investigated for its protective effects against carfilzomib-induced ALI in rats. RT-PCR analyses revealed that carfilzomib administration in rats markedly increased the levels of tumor necrosis factor-alpha and nuclear factor-kappa B and myeloperoxidase activity with a concomitant increase in lipid peroxidation. The anti-inflammatory cytokine, interleukin-10, was downregulated following carfilzomib administration. Reduction in glutathione levels indicated diminished cellular antioxidant defenses in response to carfilzomib-induced ALI. ALI was confirmed by histopathological observations in lung tissue slices. Apremilast administration reduced lung inflammation in terms of reduction in myeloperoxidase activity and levels of tumor necrosis factor-alpha and alveolar infiltrating cells. Apremilast reversed all observed toxic effects of carfilzomib and prevented ALI in rats.
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http://dx.doi.org/10.1016/j.intimp.2018.11.023DOI Listing
January 2019
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