Adenosine receptors (ARs) function in the body’s response to conditions of pathology and stress associated with a functional imbalance, such as in the supply and demand of energy/oxygen/nutrients. Extracellular adenosine concentrations vary widely to raise or lower the basal activation of four subtypes of ARs. Endogenous adenosine can correct an energy imbalance during hypoxia and other stress, for example, by slowing the heart rate by A₁AR activation or increasing the blood supply to heart muscle by the A_2AAR. Moreover, exogenous AR agonists, antagonists, or allosteric modulators can be applied for therapeutic benefit, and medicinal chemists working toward that goal have reported thousands of such agents. Thus, numerous clinical trials have ensued, using promising agents to modulate adenosinergic signaling, most of which have not succeeded. Currently, short-acting, parenteral agonists, adenosine and Regadenoson, are the only AR agonists approved for human use. However, new concepts and compounds are currently being developed and applied toward preclinical and clinical evaluation, and initial results are encouraging. This review focuses on key compounds as AR agonists and positive allosteric modulators (PAMs) for disease treatment or diagnosis. AR agonists for treating inflammation, pain, cancer, non-alcoholic steatohepatitis, angina, sickle cell disease, ischemic conditions and diabetes have been under development. Multiple clinical trials with two A₃AR agonists are ongoing.

Background: Chikungunya (CHIK) is currently endemic in South and Central India and exist as co-infections with dengue in Northern India. In 2010, New Delhi witnessed an outbreak of CHIK in the months October-December. This was the first incidence of a dominant CHIK outbreak in Delhi and prompted us to characterize the Delhi virus strains. We have also investigated the evolution of CHIK spread in India. Findings: Clinical samples were subjected to RT-PCR to detect CHIK viral RNA. The PCR amplified products were sequenced and the resulting sequences were genetically analyzed. Phylogenetic analysis based on partial sequences of the structural proteins E1 and E2 revealed that the viruses in the latest outbreak exhibited ECSA lineage. Two novel mutations, E1 K211E and E2 V264A were observed in all Delhi isolates. In addition, CHIKV sequences from eight states in India were analyzed along with Delhi sequences to map the genetic diversity of CHIKV within the country. Estimates of average evolutionary divergence within states showed varying divergence among the sequences both within the states and between the states. We identified distinct molecular signatures of the different genotypes of CHIKV revealing emergence of a new signature in the New Delhi clade. Statistical analyses and construction of evolutionary path of the virus within the country revealed gradual spread of one specific strain all over the country. Conclusion: This study has identified unique mutations in the E1 and E2 genes and has revealed the presence of ancestral CHIKV population with maximum diversity circulating in Maharashtra. The study has further revealed the trend of CHIK spread in India since its first report in 1963 and its subsequent reappearance in 2005.

Application of genomics and Next Generation sequencing has led to the identification of new class of cellular functional molecules, namely, small RNAs. Of the several classes of ncRNAs (non-coding RNA), microRNAs have been demonstrated to exert determinative influence on various cellular processes. It is becoming abundantly clear that host/vector/pathogen encoded microRNAs impact eventual pathogenesis. In this context, the participation of vector based microRNAs in disease transmission and pathogen development is being investigated intensively. A few studies have highlighted the role of vector encoded microRNAs in pathogen infection. We conducted this study to evaluate the role of host miRNAs upon CHIKV (Chikungunya Virus) infection in an important vector, Aedes albopictus. We identified 88 and 79 known miRNAs in uninfected and CHIKV infected Ae. albopictus Singh's cell line respectively. We further identified nine novel miRNAs in Ae. albopictus. Comparison of the two libraries revealed differential expression of 77 common miRNAs between them. CHIKV infection specifically altered the miRNA profile of a specific set of eight miRNAs. Putative targets of these regulated miRNAs were identified and classified into their pathways. In our study we have identified and described the profiles of various miRNAs upon CHIKV infection in Ae. albopictus. This investigation provides an insight about cellular modification by miRNAs during CHIKV infection and the results provide leads for identifying potential candidates for vector based antiviral strategies. Small, non-coding, RNAs such as microRNAs (miRNA) of length 18–24 nucleotide are reported in wide range of organisms and known to play a determinative role in regulation of various cellular processes. They have also reported to have regulatory roles during pathogen infection, maturation and transmission. Chikungunya virus is an important alphavirus transmitted through two important vectors, Aedes aegypti and Ae. albopictus. While Ae. aegypti has been the preferred vector for transmission of this virus, recently, Ae. albopictus has gained notoriety for disease transmission. Using Illumina platform, we sequenced the small RNA population an Aedes albopictus cell line infected with chikungunya virus. We studied the expression modulation of miRNAs upon CHIKV infection and found distinct set of miRNAs regulated in Aedes upon CHIKV infection. We further predicted the targets of these miRNAs and performed pathway analysis of these targets. The cellular functional targets of some of these miRNAs overlapped suggesting aggressive participation of the targeted pathways in establishing CHIKV infection.

Significance: The prevalence of obesity and type 2 diabetes (T2D) has increased worldwide. Obesity is correlated with unfavorable adipose tissue modifications that lead to metabolic dysregulation. Here, we show that P2Y ₆ R deficiency in adipocytes protects from diet-induced obesity due to enhanced energy expenditure, reduced inflammation, and white adipose tissue browning. Further, adipocytes lacking P2Y ₆ R show reduced JNK expression and activity, contributing to the improved phenotype. This proof-of-concept study strongly suggests that P2Y ₆ R antagonists may be beneficial for the treatment of obesity and T2D.

An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic G_s–linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic G_i signaling. Specifically, we used a chemogenetic approach to selectively activate G_i-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic G_i signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased G_i signaling stimulated glucose release in human hepatocytes. A lack of functional G_i-type G proteins in hepatocytes reduced blood glucose levels and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Additionally, we delineated a signaling cascade that links hepatic G_i signaling to ROS production, JNK activation, and a subsequent increase in HGP. Taken together, our data support the concept that drugs able to block hepatic G_i–coupled GPCRs may prove beneficial as antidiabetic drugs.