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Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. The disease manifestation is associated with the proliferation and activation of lymphocytes and astrocytes, leading to demyelination and neuronal damage. Most of the current therapies are not completely effective, and few target the underlying pathophysiology of MS. T helper 9 (Th9)- and Th22-dominant cells have been proven to play a pathogenic role in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The goal of the present study was to investigate the therapeutic efficacy of J-113863, a novel CCR1 chemokine receptor, on PLP

Several studies have suggested that chemokine receptors are important mediators of inflammatory response in rheumatoid arthritis (RA). B cells are also known to play an important role in RA pathology. C-X-C chemokine receptor type 3 (CXCR3) is considered a potential therapeutic target in different inflammatory diseases; however, the mechanism remains unclear. Here, we evaluated the potentially protective effect of AMG487, a selective CXCR3 antagonist, in collagen-induced arthritis (CIA) mouse model. CIA mice were treated with AMG487 (5 mg/kg) every 48 h, from day 21 until day 41. We then investigated the effect of AMG487 on NF-κB p65-, NOS2-, MCP-1-, TNF-α-, IFN-γ, IL-4-, and IL-27-producing CD19+ B cells in the spleen through flow cytometry. We also evaluated the mRNA and protein expression levels of these molecules using RT-PCR and western blotting in the knee tissues. Our results revealed that AMG487-treated mice showed decreased NF-κB p65-, NOS2-, MCP-1-, and TNF-α-, and increased IL-4-, and IL-27-producing CD19+ B cells compared with the control mice. Additionally, AMG487 treatment significantly down regulated NF-κB p65, NOS2, TNF-α, and IFN-γ, and upregulated IL-4 and IL-27 mRNA and protein expression levels compared with the control. Thus, our study shows that AMG487 exerts its anti-arthritic effect by potently downregulating inflammatory B cell signaling. Based on our observations, we propose that AMG487 could serve as a potential novel therapeutic agent for inflammatory and autoimmune diseases, including RA.

Multiple sclerosis (MS) is an immunopathological disease that causes demyelination and recurrent episodes of T cell-mediated immune attack in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model of MS. The roles of T cells in MS/EAE have been well investigated, but little is known about the role of CCR5

Autism spectrum disorders (ASD) are neurobehavioral disabilities characterized by impaired social interactions, poor communication skills, and restrictive/repetitive behaviors. Cadmium is a common heavy metal implicated in ASD. In this study, we investigated the effects of Cd exposure on BTBR T+ Itpr3tf/J (BTBR) mice, an ASD model. We looked for changes in repetitive behaviors and sociability through experiments. We also explored the molecular mechanisms underlying the effects of Cd exposure, focusing on proinflammatory cytokines and pathways. Flow cytometry measured IL-17A-, IL-17F-, IL-21-, TNF-α-, STAT3-, and RORγt-expressing CD4+ T cells from the spleens of experimental mice. We then used RT-PCR to analyze IL-17A, IL-17F, IL-21, TNF-α, STAT3, and RORγ mRNA expression in the brain. The results of behavioral experiments showed that Cd exposure significantly increased self-grooming and marble-burying in BTBR mice while decreasing social interactions. Cd exposure also significantly increased the number of CD4+IL-17A+, CD4+IL-17F+, CD4+IL-21+, CD4+TNF-α+, CD4+STAT3+, and CD4+RORγt+ cells, while upregulating the mRNA expression of the six molecules in the brain. Overall, our results suggest that oral exposure to Cd aggravates behavioral and immune abnormalities in an ASD animal model. These findings have important implications for ASD etiology and provide further evidence of heavy metals contributing to neurodevelopmental disorders through proinflammatory effects.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder that are characterized by abnormal social interaction impairments in communication and repetitive and restricted activities or interests. Even though the exact etiology of ASD remains unknown. Lead (Pb) is a toxin known to harm many organs in the body, it is one of the most ubiquitous metal exposures which is associated with neurological deficits. Previous studies have shown that the exposure to Pb may play a role in ASD. BTBR T

Autism is a neurodevelopmental disorder characterized by deficits and qualitative impairments in communication and implicit skill learning. Its prevalence is higher than previous estimates, and treatments have limited efficacy and are costly. Here, we assessed the therapeutic potential of JNJ77777120 (JNJ), a histamine-4 receptor (H4R) antagonist, using BTBR T+ Itpr3tf/J (BTBR) mice, a confirmed model of autism, and C57BL/6J (C57) mice, a commonly chosen reference strain. We first examined the effects of JNJ treatment on BTBR mice exposed to gamma-rays (irradiation-exposed) using a three-chambered apparatus. We further investigated the possible molecular mechanisms through which JNJ administration modulates IL-17A-, RORγT-, IL-22-, T-bet-, STAT3-, ICOS-, and Foxp3-producing CD8+ T cells in the spleens of irradiation-exposed BTBR mice. The effects of JNJ administration on the mRNA and protein expression of IL-17A, RORγT, IL-22, T-bet, STAT-3, pSTAT3, IL-10, and Foxp3 in brain tissue were also explored. Results showed that JNJ treatment with irradiation exposure increased social interactions in BTBR mice compared to that in irradiation-exposed BTBR mice. Additionally, JNJ-treated and irradiation-exposed BTBR mice exhibited decreases in IL-17A-, RORγT-, IL-22-, T-bet-, and STAT3-producing CD8+ T cells and increases in ICOS- and Foxp3-producing CD8+ T cells. Moreover, JNJ treatment and irradiation exposure in BTBR mice regulated the mRNA and protein expression levels of IL-17A, RORγT, IL-22, T-bet, STAT3, pSTAT-3, IL-10, and Foxp3 in the brain tissue. These results suggest that JNJ is useful for the treatment of autism, as this H4R antagonist could block inflammatory cytokine production and transcription factor signaling.

Information regarding DNA repair in autism is limited to a few studies, which have reported inconsistent results. Therefore, we designed a study to determine whether DNA repair efficiency is altered in autism and to investigate whether the H4 ligand JNJ7777120 can enhance DNA repair efficiency in BTBR T+tf/J (BTBR) mice; we also attempted to elucidate the mechanism(s) underlying this amelioration. Evaluation of DNA damage using the comet assay on bone marrow cells showed increased levels of DNA damage in BTBR mice compared with age-matched control C57BL/6J mice. Conversely, BTBR animals pretreated with 20 mg/kg JNJ7777120 for five days exhibited significant decreases in DNA damage compared with that of control BTBR mice. Our results also indicated higher sensitivity of BTBR mice exposed to gamma rays to DNA damage generation. A marked difference was observed between BTBR and C57BL/6J mice at different sampling times after irradiation, with BTBR mice showing a higher percentage of DNA damage and slower repair rate than that of C57BL/6J mice. JNJ7777120 led to enhanced repair of the DNA damage induced by radiation when administered to BTBR mice five days prior to radiation. Additionally, oxidative stress in BTBR mice was significantly elevated with a reduced GSH/GSSG ratio; significant amelioration was subsequently observed in JNJ7777120-pretreated BTBR mice. Furthermore, repetitive behaviors were also attenuated in BTBR mice by JNJ7777120 treatment without altering locomotor activity. Our results suggest that JNJ7777120 can be developed for use as a therapeutic agent to enhance DNA repair efficiency in autism spectrum disorder.

Autism spectrum disorders is a complex neurodevelopmental disorder characterized by abnormal social interaction, defective communication, repetitive and stereotyped patterns of behaviors or interests. The BTBR T

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral abnormalities such as impairments in social function and deficits in communication. The etiology of autism is unknown in most cases, but many studies have pointed towards the immune system as a causative agent in autism. Specific studies implicated lymphocytes, natural killer (NK) cells, monocytes, cytokines, and specific transcription factors in the development of ASD. The protein Ki-67 is n expressed in the proliferating cells and is used as a tool in several disorders. Ki-67 plays a crucial role in many neurological diseases. However, Ki-67 role in ASD is not fully understood. In this study, we investigated the possible role of Ki-67 expression in autistic children. We compared Ki-67 production in CD3+, CD4+, CD8+, CXCR4+, CXCR7+, CD45R+, HLA-DR+, GATA3+, Helios+, and FOXP3+ peripheral blood mononuclear cells (PBMCs) in autistic children to typically developing (TD) controls using immunofluorescence staining. We also determined Ki-67 mRNA levels in PBMCs using RT–PCR. The results revealed that autistic children had significantly increased numbers of CD3+Ki-67+, CD4+Ki-67+, CD8+Ki-67+, CXCR4+Ki-67+, CXCR7+Ki-67+, CD45R+Ki-67+, HLA-DR+Ki-67+, CXCR4+GATA3+, GATA3+Ki-67+ cells and decreased Helios+Ki-67+ and FOXP3+Ki-67+ cells compared with TD controls. In addition, the autistic children showed upregulation of Ki-67 mRNA levels compared with TD controls. Further studies need to be carried out to assess the exact role of Ki-67 and its therapeutic potential in ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by impaired communication, impaired reciprocal social interaction, restricted sociability deficits, and the presence of stereotyped patterns of behaviors. Immune dysregulation has been suggested to play a possible etiological role in ASD. Recent studies have demonstrated that exposure to methylmercury chloride (MeHgCl) leads to abnormal gait, motor deficits, impaired hearing, and memory deficits; however, its effects on behavioral and immunological responses have not been adequately investigated in ASD. In this study, we investigated the effects of MeHgCl exposure on marble burying, self-grooming behaviors, sociability tests, and locomotor activities in BTBR T

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by deficits in social interaction, communication, and repetitive behaviors. BTBR T+ Itpr3tf/J (BTBR) mice, a preclinical autistic model featuring ASD symptoms as defined by social relations, was used in this study. We evaluated the potentially protective effect of D -Ala-peptide T-amide (DAPTA), a selective C-C chemokine receptor 5 (CCR5) antagonist, in BTBR mice. CCR5 is considered a potential therapeutic target in different neurodegenerative disorders. BTBR and C57 mice were intraperitoneally (i.p) treated with the DAPTA (0.01 mg/kg, i.p, once daily) for 7 days. We examined the effect of DAPTA by evaluating marble burying and administering repetitive behavior tests. We employed flow cytometry to assess the effect of DAPTA on CCR5+, CD4+CCR5+, CCR5+IL-6+, CCR5+IL-9+, CCR5+IL-17A+, CCR5+RORγT+, CCR5+IL-10+, and CCR5+Foxp3+ in spleen cells. We further explored the effects of DAPTA on IL-6, IL-9, IL-17A, RORγT, IL-10, and Foxp3 protein and mRNA expression levels in the brain tissues. DAPTA administration significantly decreased marble burying and repetitive behavior in BTBR mice. Additionally, DAPTA treatment inhibited CCR5+, CD4+CCR5+, CCR5+IL-6+, CCR5+IL-9+, CCR5+IL-17A+, CCR5+RORγT+, and upregulated CCR5+IL-10+, and CCR5+Foxp3+ production. We further observed that DAPTA downregulated IL-6, IL-9, IL-17A, and RORγT, and increased IL-10 and Foxp3 protein and mRNA expression. Therefore, our results suggest that DAPTA administration represents a potential treatment strategy for patients with ASD.

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

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory infiltration in association with demyelination in the central nervous system. Among the factors involved in the immunological mechanisms of MS, Th1, Th17, and Th22 cells play a critical role. In the present study, we investigated the role of CA-074, a potent Cathepsin B inhibitor, in MS progression, using the SJL/J mouse model of experimental autoimmune encephalomyelitis (EAE). Following induction of EAE, mice were administered CA-074 (10 mg/kg) intraperitoneally each day, beginning on day 14 and continuing until day 28, and were evaluated for clinical signs. We further investigated the effect of CA-074 on Th1 (T-bet/STAT4), Th17 (IL-17A/RORγT), Th22 (TNF-α/IL-22), and regulatory T (Treg/Foxp3) cells in the spleen, using flow cytometry. We also analyzed the effect of CA-074 on T-bet, IL-17A, RORγT, IL-22, and mRNA and protein levels using RT-PCR and western blot analysis for brain tissues. Cathepsin B expression were also assessed by western blot in the brain tissues. The severity of clinical scores decreased significantly in CA-074-treated mice compared with that in EAE control mice. Moreover, the percentage of CD4

Little is known about genetic and epigenetic alterations in autism spectrum disorder. Moreover, the efficiency of DNA repair in autism must be improved to correct these alterations. We examined whether 3-aminobenzamide (3-AB) could reverse these alterations. We conducted experiments to clarify the molecular mechanism underlying these ameliorations. An assessment of genetic and epigenetic alterations by a modified comet assay showed elevated levels of oxidative DNA strand breaks and DNA hypermethylation in BTBR T

Autism spectrum disorder (ASD) is a complex and multifactorial heterogeneous disorder. Previous investigations have revealed the association between the immune system and ASD, which is characterized by impaired communication skills. Inflammatory response through CD45 cells plays a key role in the pathogenesis of several autoimmune disorders; however, the molecular mechanism of CD45 cells in ASD is not clearly defined. In this study, we investigated the role of CD45 signaling in children with ASD. In this study, we aimed to investigate the possible involvement of CD45 cells expressing granulocyte-macrophage colony-stimulating factor and inflammatory transcription factors in ASD. Flow cytometric analysis, using peripheral blood mononuclear cells (PBMC), revealed the numbers of GM-CSF-, IFN-γ-, IL-6-, IL-9-, IL-22-, T-bet-, pStat3-, Helios-, and Stat6-producing CD45+ cells in children with ASD and children in the control group. We further evaluated the mRNA and protein expression levels of GM-CSF in PBMC by RT-PCR and western blotting analysis. Our results revealed that the children with ASD exhibited significantly higher numbers of CD45+GM-CSF+, CD45+IFN-γ+, CD45+IL-6+, CD45+IL-9+, CD45+IL-22+, CD45+T-bet+, and CD45+pStat3+ cells compared with the control group. We also found that the children with ASD showed a lower number of CD45+Helios+ and CD45+Stat6+ cells compared with the control group. Furthermore, the children with ASD showed higher GM-CSF mRNA and protein expression levels compared with the control group. These results indicated that CD45 could play an essential role in the immune abnormalities of ASD. Further investigation of the role of CD45 in neurodevelopment in ASD is warranted.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by deficits in social interaction, communication, and repetitive behaviors. BTBR T

The incidence, prevalence, and hospitalization rates associated with heart failure (HF) are projected to increase substantially in the world. Among all medications used clinically to treat HF, valsartan (VAL) and spironolactone (SPL) have been shown to reduce morbidity and mortality. Recently, a novel cardiac gene cardiotrophin-1 (CT-1) has been shown to play a crucial role in the pathogenesis of HF. However, the ability of VAL and SPL to modulate the expression of CT-1 has not been investigated yet. Therefore, healthy and isoproterenol (ISO)-induced hypertrophy adult male Wistar albino rats were treated with either VAL or SPL for 14 days. Thereafter, cardiac markers of cardiotoxicity and hypertrophy, creatine kinase, heart weight/body weight ratio, and atrial natriuretic peptide mRNA levels were measured. In addition, CT-1 mRNA and protein levels were determined by real-time polymerase chain reaction and Western blot analysis. Our results showed that the increases in all HF markers, creatine kinase, heart weight/body weight ratio, and atrial natriuretic peptide mRNA levels in ISO-treated rats were significantly restored to their normal levels by VAL and SPL. In addition, induction of cardiac hypertrophy by ISO caused remarkable induction in CT-1 mRNA and protein expression levels by approximately 3.5- and 3-fold, respectively. Importantly, VAL and SPL significantly decreased the induction of CT-1 gene at the mRNA and protein levels in heart hypertrophied rats. On the other hand, treatment of cardiac-derived rat myoblast H9c2 cells with VAL and SPL significantly decreased angiotensin II-induced CT-1 mRNA levels through transcriptional mechanism, as demonstrated by the effect of transcription inhibitor, actinomycin D. In conclusion, VAL and SPL exhibited their cardioprotective effect through inhibiting the expression of CT-1 gene in cardiac hypertrophied rats.