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Psoriasis is classified as an autoimmune disorder characterized by abnormal immune response leading to the development of chronic dermal inflammation. Most individuals have a genetic vulnerability that may be further influenced by epigenetic changes occurring due to multiple variables such as pollutant exposure. Epigenetic modifications such as DNA methylation possess a dynamic nature, enabling cellular differentiation and adaptation by controlling gene expression. Di(2-ethylhexyl) phthalate (DEHP) and psoriatic inflammation are known to cause modification of DNA methylation via DNA methyltransferase (DNMT). However, it is not known whether DEHP, a ubiquitous plasticizer affects psoriatic inflammation via DNMT modulation. Therefore, this study investigated the effect of DNMT inhibitor, 5-aza-2'-deoxycytidine (AZA) on DEHP-induced changes in the expression of DNMT1, global DNA methylation, and anti-/inflammatory parameters (p-STAT3, IL-17A, IL-6, iNOS, IL-10, Foxp3, Nrf2, HO-1) in the skin and the peripheral adaptive/ myeloid immune cells (CD4+ T cells/CD11b+ cells) in imiquimod (IMQ) model of psoriasiform inflammation. Further, psoriasis-associated clinical/histopathological features (ear thickness, ear weight, ear PASI score, MPO activity, and H&E staining of the ear and the back skin) were also analyzed in IMQ model. Our data show that IMQ-treated mice with DEHP exposure had increased DNMT1 expression and DNA methylation which was associated with elevated inflammatory (p-STAT3, IL-17A, IL-6, iNOS) and downregulated anti-inflammatory mediators (IL-10, Foxp3, Nrf2, HO-1) in the peripheral immune cells (CD4+ T cells/CD11b+ cells) and the skin as compared to IMQ-treated mice. Treatment with DNMT1 inhibitor caused reduction in inflammatory and elevation in anti-inflammatory parameters with significant improvement in clinical/histopathological symptoms in both IMQ-treated and DEHP-exposed IMQ-treated mice. In conclusion, our study shows strong evidence indicating that DNMT1 plays an important role in DEHP-induced exacerbation of psoriasiform inflammation in mice through hypermethylation of DNA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Psoriasis is a devastating autoimmune illness resulting from excessive keratinocyte growth and leukocyte infiltration into the dermis/epidermis. In the pathogenesis of psoriasis, different immune cells such as myeloid cells and CD4 + T cells play a key role. Th17/Th1 immune responses and oxidant-antioxidant responses are critical in regulation of psoriatic inflammation. Di-2-ethylhexyl phthalate (DEHP) is one of the well-known plasticizers and has widespread use worldwide. DEHP exposure through ingestion may produce harmful effects on the skin through systemic inflammation and oxidative stress, which may modify psoriatic inflammation. However, the effect of oral DEHP exposure on inflammatory cytokines and Nrf2/iNOS signaling in myeloid cells and CD4 + T cells in the context of psoriatic inflammation has not been investigated earlier. Therefore, this study explored the effect of DEHP on systemic inflammation in myeloid cells (IL-6, IL-17A, IL-23), Th17 (p-STAT3, IL-17A, IL-23R, TNF-α), Th1 (IFN-γ), Treg (Foxp3, IL-10), and Nrf2/iNOS signaling in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our study showed increased Th17 signaling in imiquimod model which was further aggravated by DEHP exposure. Further, Nrf2 and iNOS signaling were also elevated in IMQ model where DEHP exposure further increased iNOS expression but did not modify the Nrf2 expression. Most importantly, IL-17A levels were also elevated in myeloid cells along with IL-6 which were further elevated by DEHP exposure. Overall, this study shows that IL-17A signaling is upregulated, whereas there is deficiency of Nrf2/HO-1 signaling by DEHP exposure in mice with psoriasiform inflammation. These observations suggest that DEHP aggravates IL-17A-mediated signaling both in CD4 + T cells as well as myeloid cells which is linked to exacerbation of IMQ-induced psoriatic inflammation in mice. Strategies that counteract the effect of DEHP exposure in the context of psoriatic inflammation through downregulation of IL-17A may be fruitful., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Asthma is a complex and heterogenous disease affected by a multitude of factors. Several phenotypes of asthma exist which are influenced by various molecular mechanisms that include presence of antioxidant and oxidant enzymes in different immune cells such as dendritic cells (DCs), alveolar macrophages (AMs), neutrophils, and T cells. Close interaction between epithelial cells and dendritic cells initiates complex pathogenesis of asthma followed by involvement of other innate and adaptive immune cells. In chronic phase of the disease, these immune cells support each other in amplification of airway inflammation where oxidant-antioxidant balance is known to be an important contributing factor. Genetic variability in antioxidant response may influence the development of airway inflammation, however it has not been studied in mice yet. The two most studied mice strains, i.e. BALB/c and C57BL/6 are reported to have dissimilar airway responses to the same allergens due to their genetic makeup. In this investigation, we explored whether these strains had any differences in pulmonary oxidant-antioxidant system (Nrf2, SOD2, iNOS, HO-1, nitrotyrosine) in different immune cells (DCs, AMs, neutrophils, T cells), airway inflammation (presence of eosinophils and/or neutrophils) and mucus production in response to repeated cockroach allergen extract (CE) mouse model of asthma. Our data show that C57BL/6 mice had better induction of antioxidant system than BALB/c mice. Consequently, iNOS/nitrotyrosine levels were much exaggerated in BALB/c than C57BL/6 mice. As a result, BALB/c mice developed mixed granulocytic airway inflammation, whereas C57BL/6 developed mostly eosinophilic airway inflammation. Our data suggest that an exaggerated oxidant generation along with a weak antioxidant induction in response to a natural allergen on a susceptible genetic background may determine development of severe asthma phenotype such as mixed granulocyte inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is one of the most prevalent chronic inflammatory autoimmune diseases. It causes the demyelination of neurons and the subsequent degeneration of the central nervous system (CNS). The infiltration of leukocytes of both myeloid and lymphoid origins from the systemic circulation into the CNS triggers autoimmune reactions through the release of multiple mediators. These mediators include oxidants, pro-inflammatory cytokines, and chemokines which ultimately cause the characteristic plaques observed in MS. Thioredoxin reductase (TrxR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling plays a crucial role in the regulation of inflammation by modulating the transcription of antioxidants and the suppression of inflammatory cytokines. The gold compound auranofin (AFN) is known to activate Nrf2 through the inhibition of TrxR; however, the effects of this compound have not been explored in a mouse model of relapsing-remitting MS (RRMS). Therefore, this study explored the influence of AFN on clinical features, TrxR/Nrf2 signaling [heme oxygenase 1 (HO-1), superoxide dismutase 1 (SOD-1)] and oxidative/inflammatory mediators [IL-6, IL-17A, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), nitrotyrosine] in peripheral immune cells and the CNS of mice with the RR type of EAE. Our results showed an increase in TrxR activity and a decrease in Nrf2 signaling in SJL/J mice with RR-EAE. The treatment with AFN caused the amelioration of the clinical features of RR-EAE through the elevation of Nrf2 signaling and the subsequent upregulation of the levels of antioxidants as well as the downregulation of oxidative/pro-inflammatory mediators in peripheral immune cells and the CNS. These data suggest that AFN may be beneficial in the treatment of RRMS.

Autism spectrum disorder (ASD) is a complex developmental disorder in children that results in abnormal communicative and verbal behaviors. Exposure to heavy metals plays a significant role in the pathogenesis or progression of ASD. Mercury compounds pose significant risk for the development of ASD as children are more exposed to environmental toxicants. Increased concentration of mercury compounds has been detected in different body fluids/tissues in ASD children, which suggests an association between mercury exposure and ASD. Thioredoxin1 (Trx1) and thioredoxin reductase1 (TrxR1) redox system plays a crucial role in detoxification of oxidants generated in different immune cells. However, the effect of methylmercury and the Nrf2 activator sulforaphane on the Trx1/TrxR1 antioxidant system in neutrophils of ASD subjects has not been studied previously. Therefore, this study examined the effect of methylmercury on Trx1/TrxR1 expression, TrxR activity, nitrotyrosine, and ROS in neutrophils of ASD and TDC subjects. Our study shows that Trx1/TrxR1 protein expression is dysregulated in ASD subjects as compared to the TDC group. Further, methylmercury treatment significantly inhibits the activity of TrxR in both ASD and TDC groups. Inhibition of TrxR by mercury is associated with upregulation of the Trx1 protein in TDC neutrophils but not in ASD neutrophils. Furthermore, ASD neutrophils have exaggerated ROS production after exposure to methylmercury, which is much greater in magnitude than TDC neutrophils. Sulforaphane reversed methylmercury-induced effects on neutrophils through Nrf2-mediated induction of the Trx1/TrxR1 system. These observations suggest that exposure to the environmental toxicant methylmercury may elevate systemic oxidative inflammation due to a dysregulated Trx1/TrxR1 redox system in the neutrophils of ASD subjects, which may play a role in the progression of ASD.

Lipopolysaccharides (LPS), the lipid component of gram-negative bacterial cell wall, is recognized as the key factor in acute lung inflammation and is found to exhibit severe immunologic reactions. Phosphodiesterase-4 (PDE-4) inhibitor: "apremilast (AP)" is an immune suppressant and anti-inflammatory drug which introduced to treat psoriatic arthritis. The contemporary experiment designed to study the protective influences of AP against LPS induced lung injury in rodents. Twenty-four (24) male experimental Wistar rats selected, acclimatized, and administered with normal saline, LPS, or AP + LPS respectively from 1 to 4 groups. The lung tissues were evaluated for biochemical parameters (MPO), Enzyme Linked Immunosorbent Assay (ELISA), flowcytometry assay, gene expressions, proteins expression and histopathological examination. AP ameliorates the lung injuries by attenuating immunomodulation and inflammation. LPS exposure upregulated IL-6, TNF-α, and MPO while downregulating IL-4 which were restored in AP pretreated rats. The changes in immunomodulation markers by LPS were reduced by AP treatment. Furthermore, results from the qPCR analysis represented an upregulation in IL-1β, MPO, TNF-α, and p38 whereas downregulated in IL-10 and p53 gene expressions in disease control animals while AP pretreated rats exhibited significant reversal in these expressions. Western blot analysis suggested an upregulation of MCP-1, and NOS-2, whereas HO-1, and Nrf-2 expression were suppressed in LPS exposed animals, while pretreatment with AP showed down regulation in the expression MCP-1, NOS-2, and upregulation of HO-1, and Nrf-2 expression of the mentioned intracellular proteins. Histological studies further affirmed the toxic influences of LPS on the pulmonary tissues. It is concluded that, LPS exposure causes pulmonary toxicities via up regulation of oxidative stress, inflammatory cytokines and stimulation of IL-1β, MPO, TNF-α, p38, MCP-1, and NOS-2 while downregulation of IL-4, IL-10, p53, HO-1, and Nrf-2 at different expression level. Pretreatment with AP controlled the toxic influences of LPS by modulating these signaling pathways., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Autism spectrum disorder (ASD) is a multifaceted developmental condition that first appears in infancy. The condition is characterized by recurrent patterns in behavior and impairments in social and vocalization abilities. Methylmercury is a toxic environmental pollutant, and its derivatives are the major source of organic mercury to human beings. Inorganic mercury, which is released from a variety of pollutants into oceans, rivers, and streams, is transformed into methylmercury by bacteria and plankton in the water, which later builds up in fish and shellfish, and then enters humans through the consumption of fish and shellfish and increases the risk of developing ASD by disturbing the oxidant-antioxidant balance. However, there has been no prior research to determine the effect of juvenile exposure of methylmercury chloride on adult BTBR mice. Therefore, the current study evaluated the effect of methylmercury chloride administered during the juvenile stage on autism-like behavior (three-chambered sociability, marble burying, self-grooming tests) and oxidant-antioxidant balance (specifically Nrf2, HO-1, SOD-1, NF-kB, iNOS, MPO, and 3-nitrotyrosine) in the peripheral neutrophils and cortex of adult BTBR and C57BL/6 (B6) mice. Our results show that exposure to methylmercury chloride at a juvenile stage results in autism-like symptoms in adult BTBR mice which are related to a lack of upregulation of the Nrf2 signaling pathway as demonstrated by no significant changes in the expression of Nrf2, HO-1, and SOD-1 in the periphery and cortex. On the other hand, methylmercury chloride administration at a juvenile stage increased oxidative inflammation as depicted by a significant increase in the levels of NF-kB, iNOS, MPO, and 3-nitrotyrosine in the periphery and cortex of adult BTBR mice. This study suggests that juvenile exposure to methylmercury chloride contributes to the worsening of autism-like behavior in adult BTBR mice through the disruption of the oxidant-antioxidant balance in the peripheral compartment and CNS. Strategies that elevate Nrf2 signaling may be useful to counteract toxicant-mediated worsening of ASD and may improve quality of life.

Asthma affects millions of people worldwide and is one of the most common inflammatory airway diseases. Asthma phenotypes are quite complex and categorized as eosinophilic, mixed granulocytic (presence of both eosinophils and neutrophils in the airways) and neutrophilic. Mixed granulocytic asthma requires large doses of inhaled corticosteroids, which are often insufficient in controlling airway inflammation. Therefore, there is a medical need to test newer therapies to control granulocytic inflammation. Lymphocyte specific protein tyrosine kinase (LCK) signaling has gained momentum in recent years as a molecular target in inflammatory diseases such as asthma. LCK is expressed in lymphocytes and is required for inflammatory intracellular signaling in response to antigenic stimulation. Therefore, efficacy of LCK inhibitor, A770041 was tested in cockroach (CE)-induced corticosteroid insensitive murine model of asthma. The effect of LCK inhibitor was investigated on granulocytic airway inflammation, mucus production, p-LCK and downstream signaling molecules such as p-PLCγ, GATA3, p-STAT3 in CD4+ T cells. Moreover, its effects were also studied on Th2/Th17 related cytokines and oxidative stress parameters (iNOS/nitrotyrosine) in neutrophils/macrophages. Our study shows that CE-induced p-LCK levels are concomitant with increased neutrophilic/eosinophilic inflammation and mucus hypersecretion which are significantly mitigated by A770041 treatment. A770041 also caused marked attenuation of CE-induced pulmonary levels of IL-17A levels but not completely. However, A770041 in combination with dexamethasone caused complete downregulation of mixed granulocytic airway inflammation as well as Th2/Th17 related immune responses. These results suggest that combination of LCK inhibition along with corticosteroids may be pursued as an alternative strategy to completely treat mixed granulocytic asthma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Sepsis affects millions of people worldwide and is associated with multiorgan dysfunction that is a major cause of increased morbidity and mortality. Sepsis is associated with several morbidities, such as lung, liver, and central nervous system (CNS) dysfunction. Sepsis-associated CNS dysfunction usually leads to several mental problems including depression. IL-17A is one of the crucial cytokines that is expressed and secreted by Th17 cells. Th17 cells are reported to be involved in the pathogenesis of depression and anxiety in humans and animals. One of the protein tyrosine kinases that plays a key role in controlling the development/differentiation of Th17 cells is ITK. However, the role of ITK in sepsis-associated neuroinflammation and depression-like symptoms in mice has not been investigated earlier. Therefore, this study investigated the efficacy of the ITK inhibitor, BMS 509744, in sepsis-linked neuroinflammation (ITK, IL-17A, NF k B, iNOS, MPO, lipid peroxides, IL-6, MCP-1, IL-17A) and a battery of depression-like behavioral tests, such as sucrose preference, tail suspension, and the marble burying test. Further, the effect of the ITK inhibitor on anti-inflammatory signaling (Foxp3, IL-10, Nrf2, HO-1, SOD-2) was assessed in the CNS. Our data show that sepsis causes increased ITK protein expression, IL-17A signaling, and neuroinflammatory mediators in the CNS that are associated with a depression-like state in mice. ITK inhibitor-treated mice with sepsis show attenuated IL-17A signaling, which is associated with the upregulation of IL-10/Nrf2 signaling and the amelioration of depression-like symptoms in mice. Our data show, for the first time, that the ITK inhibition strategy may counteract sepsis-mediated depression through a reduction in IL-17A signaling in the CNS.

Asthmatic inflammation is not a single homogenous inflammation but may be categorized into several phenotypes/endotypes. Severe asthma is characterized by mixed granulocytic inflammation in which there is increased presence of neutrophilic numbers and unresponsiveness to corticosteroids. Neutrophilic oxidative stress and histone deacetylase 2 (HDAC2) dysregulation in the pulmonary compartment are thought to lead to corticosteroid insensitivity in severe asthma with mixed granulocytic inflammation. Bruton's tyrosine kinase (BTK) is a no-receptor tyrosine kinase which is expressed in innate immune cells such as neutrophils and dendritic cells (DCs) where it is incriminated in balancing of inflammatory signaling. We hypothesized in this study that BTK inhibition strategy could be utilized to restore corticosteroid responsiveness in mixed granulocytic asthma. Therefore, combined therapy of BTK inhibitor (ibrutinib) and corticosteroid, dexamethasone was administered in cockroach allergen extract (CE)-induced mixed granulocyte airway inflammation model in mice. Our data show that CE-induced neutrophilic inflammation was concomitant with HDAC2 expression and upregulation of p-NFkB expression in airway epithelial cells (AECs), myeloid cells and pulmonary tissue. Further, there were increased expression/release of inflammatory and oxidative mediators such as MUC5AC, TNF-α, GM-CSF, MCP-1, iNOS, nitrotyrosine, MPO, lipid peroxides in AECs/myeloid cells/pulmonary tissue. Dexamethasone alone significantly attenuated eosinophilic inflammation and inflammatory cytokines but was not able to control oxidative inflammation. Ibrutinib alone markedly reduced neutrophilic infiltration and oxidative inflammation, and restored HDAC2 without having any significant effect on eosinophilic inflammation. These data suggest that BTK inhibition strategy may be used in conjunction with dexamethasone to treat both neutrophilic and eosinophilic inflammation, i.e. mixed granulocytic asthma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) is a multidimensional disorder in which environmental, immune, and genetic factors act in concert to play a crucial role. ASD is characterized by social interaction/communication impairments and stereotypical behavioral patterns. Epigenetic modifications are known to regulate genetic expression through various mechanisms. One such mechanism is DNA methylation, which is regulated by DNA methyltransferases (DNMTs). DNMT transfers methyl groups onto the fifth carbon atom of the cytosine nucleotide, thus converting it into 5-methylcytosine (5mC) in the promoter region of the DNA. Disruptions in methylation patterns of DNA are usually associated with modulation of genetic expression. Environmental pollutants such as the plasticizer Di(2-ethylhexyl) phthalate (DEHP) have been reported to affect epigenetic mechanisms; however, whether DEHP modulates DNMT1 expression, DNA methylation, and inflammatory mediators in the neutrophils of ASD subjects has not previously been investigated. Hence, this investigation focused on the role of DNMT1 and overall DNA methylation in relation to inflammatory mediators (CCR2, MCP-1) in the neutrophils of children with ASD and typically developing healthy children (TDC). Further, the effect of DEHP on overall DNA methylation, DNMT1, CCR2, and MCP-1 in the neutrophils was explored. Our results show that the neutrophils of ASD subjects have diminished DNMT1 expression, which is associated with hypomethylation of DNA and increased inflammatory mediators such as CCR2 and MCP-1. DEHP further causes downregulation of DNMT1 expression in the neutrophils of ASD subjects, probably through oxidative inflammation, as antioxidant treatment led to reversal of a DEHP-induced reduction in DNMT1. These data highlight the importance of the environmental pollutant DEHP in the modification of epigenetic machinery such as DNA methylation in the neutrophils of ASD subjects.

Autism spectrum disorder (ASD) is a neuropsychiatric childhood disorder that affects social skill and language development, and is characterized by persistent stereotypic behaviors, restricted social interests, and impaired language/social skills. ASD subjects have dysregulated immune responses due to impairment in inflammatory and antioxidant signaling in immune cells, such as T cells. Thioredoxin reductase-1 (TrxR1) and thioredoxin-1 (Trx1) play a crucial role in the maintenance of redox equilibrium in several immune cells, including T cells. T-cell apoptosis plays a crucial role in the pathogenesis of several inflammatory diseases. However, it remains to be explored how the TrxR1/Trx1 redox couple affects T-cells apoptosis in ASD and typically developing control (TDC) groups. Therefore, this single-center cross-sectional study explored the expression/activity of TrxR1/Trx1, and Bcl2, 7-AAD/annexin V immunostaining in T cells of ASD ( n = 25) and TDC ( n = 22) groups. Further, effects of the LPS were determined on apoptosis in TDC and ASD T cells. Our data show that T cells have increased TrxR1 expression, while having decreased Trx1 expression in the ASD group. Further, TrxR enzymatic activity was also elevated in T cells of the ASD group. Furthermore, T cells of the ASD group had a decreased Bcl2 expression and an increased % of annexin V immunostaining. Treatment of T cells with LPS caused greater apoptosis in the ASD group than the TDC group, with same treatment. These data reveal that the redox couple TrxR1/Trx1 is dysregulated in T cells of ASD subjects, which is associated with decreased Bcl2 expression and increased apoptosis. This may lead to decreased survival of T cells in ASD subjects during chronic inflammation. Future studies should investigate environmental factors, such as gut dysbiosis and pollutants, that may cause abnormal immune responses in the T cells of ASD subjects due to chronic inflammation.

The complicated multiple sclerosis (MS) can exhibit subacute sight deterioration and can lead to total deprivation of vision. In the current work, we explored the therapeutic outcome of Cathepsin B inhibitor (CA-074) against retinopathy and optic neuritis (ON) caused by experimental autoimmune encephalomyelitis (EAE) induced by proteolipid protein peptide (PLP) in female SJL/J mice. A daily dose of 10 mg/kg CA-074 was administered to the EAE mice intraperitoneally for 14 days from day 14 post-immunization until day 28. The Western blot and immunofluorescence analyses show inflammation in the optic nerve through the elevation of iNOS and NFkB markers in EAE mice. Optic neuritis was reported which is a consequence of demyelination and axon injury, estimated with the reduction in myelin basic protein (MBP). The glial fibrillary acidic protein (GFAP) expression level was found to be elevated in the retina of EAE mice which confirmed the retinopathy. The administration of CA-074 ameliorated optic neuritis and retinopathy by reducing inflammation. The treatment with CA-074 also reduced the demyelination and axonal injuries in the EAE mice. The findings of this study have shown the protective effect of CA-074 in the case of retinopathy and ON inflicted by EAE in SJL/J mice., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier B.V. on behalf of King Saud University.)

Asthma is one of the most common inflammatory diseases affecting the airways. Approximately 300 million individuals suffer from asthma around the world. Allergic immune responses in the asthmatic airways are predominantly driven by Th2 cells and eosinophils. Lymphocyte-specific protein tyrosine kinase (LCK) is a non-receptor tyrosine kinase which regulates several key intracellular events through phosphorylation of its substrates. Some of the intracellular signaling pathways activated by LCK phosphorylation help in differentiation of Th2 cells which secrete allergic cytokines that amplify airway inflammation. Therefore, this investigative study was designed to determine the role of LCK in a cockroach extract (CE)-induced airway inflammation murine model of allergic asthma. Further, the effect of a pharmacological LCK inhibitor, A-770041, on allergic airway inflammation and key intracellular pathways in CD4+ T cells was assessed. Our data exhibit that there is an activation of LCK during allergic airway inflammation as depicted by increased p -LCK levels in CD4+ T cells. Activated LCK is involved in the activation of ITK, PLC-γ, GATA3, NF k B, and NFATc1. Activated LCK is also involved in the upregulation of Th2 related cytokines, such as IL-4/IL-5/IL-13 and oxidative stress, and the downregulation of Treg cells. Furthermore, utilization of LCK inhibitor causes the reduction in p -LCK, PLC-γ, GATA3, and NFATc1 as well as Th2 cytokines and oxidative stress. LCK inhibitor causes upregulation of Treg cells in allergic mice. LCK inhibitor also caused a reduction in CE-induced airway inflammation and mucus secretion. Therefore, the inhibition of LCK signaling could be a fruitful approach to adjust allergic airway inflammation through the attuning of Th2/Treg immune responses. This study could lead to the design of newer treatment options for better management of allergic inflammation in asthma.

Multiple sclerosis (MS) is characterized by chronic autoimmune inflammation of central nervous system (CNS), i.e. brain and spinal cord. Autoimmune inflammation of the CNS and periphery causes demyelination of axons ultimately leading to clinical symptoms such as gait imbalance, lack of coordination and paraplegia. Innate immune cells such as dendritic cells and neutrophils play a critical role in the initiation and progression of MS through upregulation of oxidants. Two prominent pathways that play important role in regulation of oxidant-antioxidant balance are nuclear factor-erythroid factor 2-related factor 2(Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Nrf2-mediated upregulation of antioxidants counteracts NF-κB-mediated oxidant generation. Therefore, this study evaluated the effects of nutraceutical drug, acetyl-11-keto-β-boswellic acid (AKBA) in relapsing remitting model of experimental autoimmune encephelomyelitis (EAE). Efficacy of AKBA was explored on clinical symptoms, Nrf2, hemeoxygenase-1 (HO-1), NF-κB, inducible nitric oxide synthase (iNOS) in CNS and periphery of SJL/J mice. Our results show that expression of p-NF-κB and iNOS is elevated, whereas expression of Nrf2 and HO-1 is decreased in CD11c + DCs and CNS, which is linked with appearance of clinical symptoms in immunized SJL/J mice. Treatment of immunized SJL/J mice with AKBA causes improvement of clinical symptoms and downregulation of inflammatory markers in CD11c + DCs (p-NF-κB, iNOS, and nitrotyrosine), and CNS (p-NF-κB, iNOS, nitrotyrosine,lipid peroxides, and total antioxidant capacity). Treatment of immunized SJL/J mice with AKBA also causes rectification of Nrf2 signaling in CD11c + DCs, and CNS. These results propose AKBA ameliorates EAE disease progression through rectification of Nrf2 signaling and attenuation of NF-κB pathway in RR model of EAE. Therefore, nutraceutical compound, AKBA may be therapeutically useful in RRMS., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Psoriasis is a chronic dermal inflammatory disease with a world-wide prevalence in which different immune/non-immune cells, e.g. T cells, macrophages, neutrophils, and keratinocytes play a decisive role. These immune cells interact among themselves by releasing multiple mediators which eventually cause characteristic psoriatic plaques in the skin. T cells are reported to be significant contributors to psoriatic inflammation through release of multiple cytokines which are controlled by several kinases, one of them being Lymphocyte-specific protein tyrosine kinase (Lck). Lck has been reported to be crucial for expression/production of several key inflammatory cytokines though modulation of several other kinases/transcription factors in T cells. Therefore, in this investigation, effect of Lck inhibitor, A-770041 was examined on PLCγ, p38MAPK, NFATc1, NFkB and STAT3, TNF-α, IFN-γ, Foxp3, IL-17A, in CD4+ T cells in imiquimod (IMQ)-induced psoriatic inflammation in mice. Results from the present study exhibit that p-Lck expression is enhanced in CD4+ T cells of IMQ-treated mice which is concomitant with enhanced clinical features of psoriatic inflammation (ear/back skin thickness, MPO activity, acanthosis/leukocytic infiltration) and molecular parameters (enhanced expression of p-Lck, p-PLCγ, p-p38-MAPK, NFATc1, p-NFkB, TNF-α, IFN-γ, p-STAT3, and IL-17A in CD4+ T cells). Inhibition of Lck signaling led to amelioration of clinical features of psoriasis through attenuation of Th1/Th17 immune responses and upregulation of Treg cells in IMQ-treated mice. In summary, current investigations reveal that Lck signaling is a crucial executor of inflammatory signaling in CD4+ T cells in the context of psoriatic inflammation. Therefore, Lck inhibition may be pursued as an effective strategy to counteract psoriatic inflammation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Lung injuries are attributed due to exposure to Drugs or chemicals. One of the important challenging situations for the clinicians is to manage treatments of different diseases with acute lung injury (ALI). The objective of this study was to investigate the possible protective mechanisms and action of a novel Phosphodiesterase-4 inhibitor "Apremilast" (AP) in lipopolysaccharide (LPS)-induced lung injury. Blood sample from each animals were collected in a vacuum blood collection tube. The rat lungs were isolated for oxidative stress assessment, western blot analysis and their mRNA expressions using RT-PCR. Exposure of LPS in rats causes significant increase in oxidative stress, activates the pro-inflammatory cytokines release like tissue necrotic factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), modulated gene expression, protein expression and histopathological changes which were reversed by administration of AP. Finding of the research enlighten the protective role of AP against LPS-induced ALI., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Autism spectrum disorder (ASD) is characterized by constellation of impaired behaviors that include deficits in social interaction/communication and the presence of restricted/repetitive behavioral patterns. Both genetic component and environmental factors are thought to play a key role in the initiation and progression of ASD. Several environmental factors such as heavy metals and plasticizers are known to affect the progression of ASD. One of the most common pollutants in the environment today is di-2-ethylhexyl phthalate (DEHP). DEHP is utilized as a plasticizer in several household and office materials which range from medical devices to plastic toys. Children usually get exposed to DEHP at an early age through use of plastic toys and other plastic materials. Nuclear factor erythroid 2 (NFE2)-relatedfactor-2 (Nrf2) is a master redox regulator as it controls transcription of several antioxidant genes. DEHP has been reported to cause dysregulation in Nrf2 signaling in vitro/in vivo and ASD subjects also exhibit oxidant-antioxidant imbalance.Therefore, this study attempted to delineate the effect of DEHP on Nrf2 signaling in neutrophils of ASD and typically developing healthy children (TDC) in vitro. Our data display that neutrophils of ASD subjects have dysregulated Nrf2 and hemeoxygenase-1 (HO-1) expression as compared to TDC subjects. DEHP treatment leads to elevation of oxidant stress in neutrophils of both ASD and TDC subjects, however TDC neutrophils have better antioxidant response to mitigate oxidative stress. This is depicted by enhancement of Nrf2/HO-1 signaling in TDC neutrophils in response to DEHP whereas ASD neutrophils fail to do so. These results suggest that plasticizer, DEHP may cause further dysregulation in Nrf2 signaling which may promote progression of ASD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Doxorubicin-mediated kidney impairment is a serious problem in cancer treatment. Accordingly, this work investigated the ability of geraniol to modulate doxorubicin-induced kidney damage using a rat model. Rats were randomly assigned to four groups: control, doxorubicin (20 mg/kg, intraperitoneal, i.p.), doxorubicin plus 100 mg/kg of geraniol, and doxorubicin plus 200 mg/kg of geraniol. A single doxorubicin injection triggered kidney impairment, as evidenced by the altered serum creatinine, blood urea nitrogen, and albumin values; it also caused histological changes in the kidney architecture. Additionally, doxorubicin enhanced lipid peroxidation while lowering reduced glutathione, catalase activity, and the expression of glutathione peroxidase and superoxide dismutase. Interestingly, pre-treatment with geraniol rescued doxorubicin-induced alterations in kidney antioxidant parameters, enzymatic activity, and the expression of inflammatory and apoptosis-mediating gene and proteins. Moreover, prophylactic treatment with geraniol preserved most kidney histological characteristics in a dose-dependent manner. These findings support that geraniol could protect against doxorubicin-mediated kidney dysfunction. However, further research is needed to clarify the mechanisms of geraniol's protective effects against doxorubicin-mediated kidney dysfunction.

B cells play multiple roles in preservation of healthy immune system including management of immune responses by expression of pro- and anti-inflammatory cytokines. Several earlier studies have documented that B cells express both pro-inflammatory cytokines such as IL-6, TNF-α as well as anti-inflammatory cytokines such as IL-10. However, it is yet to be examined whether these pro-/anti-inflammatory cytokines are expressed in B cells of children with autism spectrum disorder (ASD). Pathophysiology of ASD begins in early childhood and is characterized by repetitive/restricted behavioral patterns, and dysfunction in communal/communication skills. ASD pathophysiology also has a strong component of immune dysfunction which has been highlighted in numerous earlier publications. In this study, we specifically explored pro-/anti-inflammatory cytokines (IL-6, IL-17A, IFN-γ, TNF-α, IL-10) in B cells of ASD subjects and compared them typically developing control (TDC) children. Present study shows that inflammatory cytokines such as IL-6 and TNF-α are elevated in B cells of ASD subjects, while anti-inflammatory cytokine, IL-10 is decreased in ASD group when compared to TDC group. Further, TLR4 activation by its ligand, lipopolysaccharide (LPS) further upregulates inflammatory potential of B cells from ASD group by increasing IL-6 expression, whereas LPS has no significant effect on IL-10 expression in ASD group. Furthermore, LPS-induced inflammatory signaling of IL-6 in B cells of ASD subjects was partially mitigated by the pretreatment with NF-kB inhibitor. Present study propounds the idea that B cells could be crucial players in causing immune dysfunction in ASD subjects through an imbalance in expression of pro-/anti-inflammatory cytokines., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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., (© 2020 John Wiley & Sons Australia, Ltd.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest. All authors have approved the final article., (Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Sunitinib (SUN) is an oral tyrosine kinase inhibitor approved in 2006 as a first-line treatment for metastatic renal cell cancer. However, weak selectivity to kinase receptors and cardiotoxicity have limited the use of sunitinib. Rivaroxaban (RIVA) is a Factor Xa inhibitor with cardioprotective action. It inhibits atherosclerosis and numerous inflammatory cascades. The present study was designed to investigate the cardioprotective effects of RIVA in sunitinib-induced cardiotoxicity. Thirty male Wistar rats were divided into five groups. Group 1 was the normal control (control). Group 2 was administered i.p. SUN 25 mg kg -1 thrice weekly for 3 weeks. Groups 3 and 4 received the same treatment as Group 2 followed by the administration of RIVA 5 mg kg -1 day -1 and 10 mg kg -1 day -1 , respectively, for 3 weeks. Group 5 received only 10 mg kg -1 day -1 RIVA for 3 weeks. Serum levels of Ca 2+ , Mg 2+ , Fe 3+ /Fe 2+ , lipid profiles, and cardiac enzymes were measured. Cardiac tissues were isolated for the measurements of oxidant/antioxidant balance gene and protein expressions. Relative to the controls, the administration of SUN significantly altered serum levels of (Ca 2+ , Mg 2+ , Fe 3+ /Fe 2+ , lipid profiles, and cardiac enzymes), intracellular antioxidant enzymes, and the expression levels of the genes encoding certain proteins. RIVA treatment significantly restored these parameters to near-normal levels. RIVA treatment significantly mitigated SUN-induced cardiac injuries by restoring antioxidant enzyme levels and attenuating the proinflammatory cascades resulting from SUN-induced cardiac injuries.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

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, H 2 O 2 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., Competing Interests: Declaration of competing interest All of the authors declare no conflict of interest of any kind., (Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (© 2020 The Authors.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 ( P  < 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 ( P  < 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.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Autism is a neurodevelopmental disorder that affects social cognitive abilities resulting in communication or sensory deficits, and stereotyped behaviors in millions of people worldwide. Oxidant-antioxidant imbalance contributes significantly to the neurobehavioral dysregulations and severity of symptoms in patients with autism, however it has not been explored earlier whether it affects autism-like behavior directly. Therefore, we investigated oxidant-antioxidant balance in peripheral immune cells (neutrophils and CD3+ T cells) and cerebellum of BTBR T + tf/J (BTBR) mice which show autism-like behavior and the social C57BL/6 J (C57) mice. Further, we utilized buthionine sulfoximine (BSO), a glutathione depleting agent to assess the impact of oxidant-antioxidant dysregulation on autism-like behavior. Our study shows that BTBR mice have increased lipid/protein oxidation products in cerebellum and neutrophils/CD3+ T cells along with increased NADPH oxidase (NOX2) and inducible nitric oxide synthase (iNOS) expression. This was concurrent with lower levels of glutathione and enzymatic antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the cerebellum and peripheral immune cells. BSO administration led to further lowering of glutathione with a concurrent upregulation of iNOS, and NOX2 in cerebellum and peripheral immune cells. However, there was deficiency of an adaptive antioxidant response which was associated with exaggerated repetitive behaviors in BTBR mice. On the other hand, C57 mice also had increased oxidative stress after BSO treatment, however there was an enzymatic antioxidant response both in cerebellum and periphery. Overall, this study suggests that BTBR mice have increased oxidative stress with a deficient enzymatic antioxidant response that is associated with autism-like repetitive behaviors., (Copyright © 2018 Elsevier Inc. All rights reserved.)