Plasticity in Interferon Responses Modulates T-Cell Immunity in Parasitic Infections: Periphery to Thymus

Parasitic infections are the major threat prevalent in tropical and subtropical regions throughout the world. Different parasitic infections take a huge toll on mortality and morbidity at global level. Different parasites invade the host system, multiply inside host cells of their choice and sabotage defense mechanisms to overpower the host. T-cell immunity is majorly affected in different parasitic diseases such that the peripheral T-cell immune response is altered along with lesser explored thymic changes. Direct and/or indirect effect of parasitic infection leads to alterations in T-cell development, differentiation and activation resulting in deregulated T-cell immune mechanisms. Cytokines of interferon family play a significant role in determining the disease outcome and severity. Therefore, in this chapter, we here provide a detailed overview of the functional role played by IFNs during parasitic diseases in terms of their influence on peripheral T-cell activation and tolerance along with lesser explored impact on developing T cells in the thymus with altered microenvironmental niches

Pathogenic Role of iNOs+ M1 Effector Macrophages in Fibromyalgia

Fibromyalgia (FM) or Fibromyalgia Syndrome (FMS) is a neurodegenerative disorder causing musculoskeletal pain, tenderness, stiffness, fatigue, and sleep disorder in the body. It is one of the most common chronic pain conditions, affecting about 6% of the world population. Being refractory, till date, no specific treatment of this disease is available. Accumulating evidences over the last few decades indicate that proinflammatory macrophages, cytokines, & chemokines as the key players in this disease. Recent findings suggest activation of Microglial cells and associated pro-inflammatory signals as one of the major causes of chronic pain in patients suffering from fibromyalgia. Increased density of iNOs/CD68+ M1 effector macrophages has been associated with neuropathic pain models. In light of this, depletion of these pro-inflammatory macrophages has been shown to reduce sensitivity to neuropathic pain. On the other hand, modulating pattern of AGEs (Advanced Glycation End-Products) can also contribute to inactivation of macrophages. These findings strongly suggest that macrophages are critical in both inflammatory and neuropathic pain. Therefore, this chapter highlights the impact of macrophage plasticity in various immunopathological aspects of fibromyalgia

A panel of blood-based circulatory miRNAs with diagnostic potential in patients with psoriasis

Psoriasis is a chronic inflammatory skin disease with keratinocyte hyperproliferation and T cells as key mediators of lesional and systemic inflammatory changes. To date, no suitable differential biomarkers are available for the disease diagnosis. More recently, microRNAs have been identified as critical regulators of lesional and systemic immune changes in psoriasis with diagnostic potential. We have performed expression profiling of T cell-specific miRNAs in 38 plasma samples from psoriasis vulgaris patients and an equal number of age- and gender-matched healthy subjects. Our findings have identified a panel of five blood-based circulatory miRNAs with a significant change in their expression levels, comprising miR-215, miR-148a, miR-125b-5p, miR-223, and miR-142-3p, which can differentiate psoriasis vulgaris patients from healthy individuals. The receiver operating characteristic (ROC) curves for all five miRNAs individually and in combination exhibited a significant disease discriminatory area under the curve with an AUC of 0.762 and a p < 0.0001 for all the miRNAs together. Statistically, all five miRNAs in combination depicted the best-fit model in relation to disease severity (PASI) compared with individual miRNAs, with the highest R2 value of 0.94 and the lowest AIC score of 131.8. Each of the miRNAs also exhibited a significant association with at least one of the other miRNAs in the panel. Importantly, the five miRNAs in the panel regulate one or more immune-inflammation pathways based on target prediction, pathway network analysis, and validated roles in the literature. The miRNA panel provides a rationalized combination of biomarkers that can be tested further on an expanded cohort of patients for their diagnostic value

Novel GC-rich DNA-binding compound produced by a genetically engineered mutant of the mithramycin producer Streptomyces argillaceus exhibits improved transcriptional repressor activity: implications for cancer therapy

The aureolic acid antibiotic mithramycin (MTM) binds selectively to GC-rich DNA sequences and blocks preferentially binding of proteins, like Sp1 transcription factors, to GC-rich elements in gene promoters. Genetic approaches can be applied to alter the MTM biosynthetic pathway in the producing microorganism and obtain new products with improved pharmacological properties. Here, we report on a new analog, MTM SDK, obtained by targeted gene inactivation of the ketoreductase MtmW catalyzing the last step in MTM biosynthesis. SDK exhibited greater activity as transcriptional inhibitor compared to MTM. SDK was a potent inhibitor of Sp1-dependent reporter activity and interfered minimally with reporters of other transcription factors, indicating that it retained a high degree of selectivity toward GC-rich DNA-binding transcription factors. RT–PCR and microarray analysis showed that SDK repressed transcription of multiple genes implicated in critical aspects of cancer development and progression, including cell cycle, apoptosis, migration, invasion and angiogenesis, consistent with the pleiotropic role of Sp1 family transcription factors. SDK inhibited proliferation and was a potent inducer of apoptosis in ovarian cancer cells while it had minimal effects on viability of normal cells. The new MTM derivative SDK could be an effective agent for treatment of cancer and other diseases with abnormal expression or activity of GC-rich DNA-binding transcription factors

Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks

DNA interstrand crosslinks (ICLs) are among the most cytotoxic types of DNA damage, thus ICL-inducing agents such as psoralen, are clinically useful chemotherapeutics. Psoralen-modified triplex-forming oligonucleotides (TFOs) have been used to target ICLs to specific genomic sites to increase the selectivity of these agents. However, how TFO-directed psoralen ICLs (Tdp-ICLs) are recognized and processed in human cells is unclear. Previously, we reported that two essential nucleotide excision repair (NER) protein complexes, XPA–RPA and XPC–RAD23B, recognized ICLs in vitro, and that cells deficient in the DNA mismatch repair (MMR) complex MutSβ were sensitive to psoralen ICLs. To further investigate the role of MutSβ in ICL repair and the potential interaction between proteins from the MMR and NER pathways on these lesions, we performed electrophoretic mobility-shift assays and chromatin immunoprecipitation analysis of MutSβ and NER proteins with Tdp-ICLs. We found that MutSβ bound to Tdp-ICLs with high affinity and specificity in vitro and in vivo, and that MutSβ interacted with XPA–RPA or XPC–RAD23B in recognizing Tdp-ICLs. These data suggest that proteins from the MMR and NER pathways interact in the recognition of ICLs, and provide a mechanistic link by which proteins from multiple repair pathways contribute to ICL repair

Guanine Holes Are Prominent Targets for Mutation in Cancer and Inherited Disease

Albino Bacolla, Guliang Wang, Aklank Jain, Karen M. Vasquez, Division of Pharmacology and Toxicology, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, Texas, United States of AmericaAlbino Bacolla, Nuri A. Temiz, Ming Yi, Joseph Ivanic, Regina Z. Cer, Duncan E. Donohue, Uma S. Mudunuri, Natalia Volfovsky, Brian T. Luke, Robert M., Stephens, Jack R. Collins, Advanced Biomedical Computing Center, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of AmericaEdward V. Ball, David N. Cooper, Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United KingdomSingle base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G•C bp in the context of all 64 5′-NGNN-3′ motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines (ionization potentials). Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease.This work was supported by grants from the NIH (CA097175 and CA093729) to KMV, NCI/NIH contract HHSN261200800001E to AB and the Frederick National Laboratory for Cancer Research, and CBIIT/caBIG ISRCE yellow task #09-260 to the Frederick National Laboratory for Cancer Research. DNC and EVB received financial support from BIOBASE GmbH through a license agreement (for HGMD) with Cardiff University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.PharmacyEmail: [email protected]

Role of Sphingosine-1-Phosphate in Mast Cell Functions and Asthma and Its Regulation by Non-Coding RNA

Sphingolipid metabolites are emerging as important signaling molecules in allergic diseases specifically asthma. One of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), is involved in cell differentiation, proliferation, survival, migration, and angiogenesis. In the allergic diseases, alteration of S1P levels influences the differentiation and responsiveness of mast cells (MCs). S1P is synthesized by two sphingosine kinases (SphKs), sphingosine kinase 1, and sphingosine kinase 2. Engagement of IgE to the FcεRI receptor induces the activation of both the SphKs and generates S1P. Furthermore, SphKs are also essential to FcεRI-mediated MC activation. Activated MCs export S1P into the extracellular space and causes inflammatory response and tissue remodeling. S1P signaling has dual role in allergic responses. Activation of SphKs and secretion of S1P are required for MC activation; however, S1P signaling plays a vital role in the recovery from anaphylaxis. Several non-coding RNAs have been shown to play a crucial role in controlling the MC-associated inflammatory and allergic responses. Thus, S1P signaling pathway and its regulation by non-coding RNA could be explored as an exciting potential therapeutic target for asthma and other MC-associated diseases

Atypical leishmaniasis: A global perspective with emphasis on the Indian subcontinent.

BACKGROUND:Among the neglected tropical diseases, leishmaniasis continues to be prevalent in many tropical and subtropical countries despite international, national, and local efforts towards its control and elimination over the last decade. This warrants a critical evaluation of such factors as under-reporting, asymptomatic infections, post kala azar dermal leishmaniasis (PKDL) cases, and drug resistance. In this review, we highlight lesser-understood atypical presentations of the disease involving atypical parasite strains against a background of classical leishmaniasis with a focus on the Indian subcontinent. METHODS AND FINDINGS:A literature review based on endemic areas, the nature of disease manifestation, and underlying causative parasite was performed with data collected from WHO reports for each country. Searches on PubMed included the term ''leishmaniasis" and "leishmaniasis epidemiology" alone and in combination with each of the endemic countries, Leishmania species, cutaneous, visceral, endemic, non-endemic, typical, classical, atypical, and unusual with no date limit and published in English up to September 2017. Our findings portray a scenario with a wider distribution of the disease in new endemic foci, with new discoveries of parasite-driven atypical disease manifestations in different regions of the world. Unlike the classical picture, some Leishmania species are associated with more than one disease presentation, e.g., the L. donovani complex, generally associated with the visceral form, is now also associated with a cutaneous disease presentation, while L. tropica species complex, known to cause cutaneous disease, can cause viscerotropic disease. This phenomenon points towards the discovery of novel parasite variants as etiologic agents of atypical disease manifestations and represents an excellent opportunity to identify and study genes that control disease virulence and tropism. CONCLUSIONS:The increased recognition of atypical leishmaniasis as an outcome of parasite variants has major implications for leishmaniasis control and elimination. Identifying molecular correlates of parasite isolates from distinct regions associated with different disease phenotypes is required to understand the current epidemiology of leishmaniasis in regions with atypical disease