Immunomodulatory properties of silver nanoparticles contribute to anticancer strategy for murine fibrosarcoma

The use of nanotechnology in nanoparticle-based cancer therapeutics is gaining impetus due to the unique biophysical properties of nanoparticles at the quantum level. Silver nanoparticles (AgNPs) have been reported as one type of potent therapeutic nanoparticles. The present study is aimed to determine the effect of AgNPs in arresting the growth of a murine fibrosarcoma by a reductive mechanism. Initially, a bioavailability study showed that mouse serum albumin (MSA)-coated AgNPs have enhanced uptake; therefore, toxicity studies of AgNP-MSA at 10 different doses (1–10 mg/kg b.w.) were performed in LACA mice by measuring the complete blood count, lipid profile and histological parameters. The complete blood count, lipid profile and histological parameter results showed that the doses from 2 to 8 mg (IC₅₀: 6.15 mg/kg b.w.) sequentially increased the count of leukocytes, lymphocytes and granulocytes, whereas the 9- and 10-mg doses showed conclusive toxicity. In an antitumor study, the incidence and size of fibrosarcoma were reduced or delayed when murine fibrosarcoma groups were treated by AgNP-MSA. Transmission electron micrographs showed that considerable uptake of AgNP-MSA by the sentinel immune cells associated with tumor tissue and a morphologically buckled structure of the immune cells containing AgNP-MSA. Because the toxicity studies revealed a relationship between AgNPs and immune function, the protumorigenic cytokines TNF-α, IL-6 and IL-1β were also assayed in AgNP-MSA-treated and non-treated fibrosarcoma groups, and these cytokines were found to be downregulated after treatment with AgNP-MSA.     

IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

Psoriasis vulgaris (PV) results from activation of IL‐23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin‐derived pro‐inflammatory cytokines, IL‐36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL‐23 and IL‐36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL‐23‐induced mouse model of psoriasiform dermatitis by functional inhibition of IL‐36 receptor (IL‐36R) was interrogated. Anti‐mouse IL‐36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL‐36α‐induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL‐36α systemic injection in mice. In addition, anti‐IL‐36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL‐36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL‐36 signalling in IL‐23/Th17 pathway, the ability of anti‐IL‐36R mAbs to inhibit skin inflammation in an IL‐23 ear injection model was assessed. Inhibiting the IL‐36 pathway resulted in significant attenuation of skin thickening and psoriasis‐relevant gene expression. Taken together, these data suggest a role for IL‐36 signalling in the IL‐23/Th17 signalling axis in PV.     

Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis

Background  

Interleukin-17A (IL-17A) is the founding member of a novel family of inflammatory cytokines that plays a critical role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). IL-17A signals through its receptor, IL-17RA, which is expressed in many peripheral tissues; however, expression of IL-17RA in the central nervous system (CNS) and its role in CNS inflammation are not well understood.     

Evaluation of the role of LRRK2 gene in Parkinson's disease in an East Indian cohort

Leucine rich repeat kinase 2 (LRRK2) gene defects cause Parkinson's disease (PD). Recently, LRRK2 has also been shown by genome wide association (GWA) studies to be a susceptibility gene for the disease. In India mutations in LRRK2 is a rare cause of PD. We, therefore, genotyped 64 SNPs across LRRK2 in 161 control samples and finally studied 6 haplotype tagging SNPs for association-based study on 300 cases and 446 ethnically matched controls to explore the potential role of LRRK2 as a susceptibility gene in PD for East Indians. We did not find any significant allele/ genotype or haplotype associations with PD suggesting that common genetic variants within LRRK2 play limited role in modulating PD among East Indians. In addition, we also screened for the common mutations (viz. p.R1441C, p.R1441G, p.R1441H, p.Y1699C, p.G2019S), and a risk variant common among Asians (p.G2385R) but did not observe any of the above mentioned variants in our cohort. Our study, therefore, strongly suggests that LRRK2 has minimal role as a candidate and susceptibility gene in PD pathogenesis among East Indians.