No abstract

Graphical Abstract Highlights d Anticipatory hepatic fed miRNAs are essential to attenuating fasting response d RISC association of miRNA-mRNA pairs oscillates during fed-fast cycles in the liver d Convergent additive action of miRNAs governs metabolic and mitochondrial homeostasis d Scavenging fed miRNAs impairs refed transition and affects whole-body energetics SUMMARY Inability to mediate fed-fast transitions in the liver is known to cause metabolic dysfunctions and diseases. Intuitively, a failure to inhibit futile translation of state-specific transcripts during fed-fast cycles would abrogate dynamic physiological transitions.Here, we have discovered hepatic fed microRNAs that target fasting-induced genes and are essential for a refed transition. Our findings highlight the role of these fed microRNAs in orchestrating system-level control over liver physiology and whole-body energetics. By targeting SIRT1, PGC1a, and their downstream genes, fed microRNAs regulate metabolic and mitochondrial pathways. MicroRNA expression, processing, and RISC loading oscillate during these cycles and possibly constitute an anticipatory mechanism. Fed-microRNA oscillations are deregulated during aging. Scavenging of hepatic fed microRNAs causes uncontrolled gluconeogenesis and failure in the catabolic-to-anabolic switching upon feeding, which are hallmarks of metabolic diseases. Besides identifying mechanisms that enable efficient physiological toggling, our study highlights fed microRNAs as candidate therapeutic targets.

Graphene oxide-silver nanocomposite (GO-Ag) was fabricated via the sonochemical method, which shows unique physiochemical properties. Graphene oxide (GO) and silver nanoparticles (AgNPs) were synthesized by modified Hummer's and Chemical reduction methods, respectively. The synthesized nanocomposite was characterized using powder X-ray diffraction, Raman spectroscopy, and Fourier-transform infrared spectroscopy. The surface morphology of synthesized nanoparticles was studied using scanning electron microscopy and transmission electron microscopy. The thermoluminescence property of the nanocomposite was analyzed by irradiating the samples in gamma radiation at 1 kGy. Electrochemical reversibility of the GO-Ag nanocomposite was examined by cyclic voltammetry. The photocatalytic application of the nanocomposite was studied using degradation of methylene blue dye. Results reveal that doping of AgNPs on the GO surface not only improves its dye degradation property but also enhances its thermoluminescence property. This knowledge will be helpful in determining the antibacterial property of the GO-Ag nanocomposite in the future.

Background: 1,4-Naphthoquinone analogs, such as plumbagin, are toxic compounds due to their redox cycling and thiolreactive properties. Results: The p300 inhibitor PTK1, a plumbagin derivative with greatly reduced toxicity, was synthesized and characterized. Conclusion: PTK1 is a reversible, non-competitive inhibitor of p300 KAT activity with reduced toxicity. Significance: These studies provide insight into naphthoquinone-mediated KAT inhibition and describe the synthesis of a therapeutically important, non-toxic inhibitor.

BackgroundIn vector-borne diseases such as leishmaniasis, the sand fly midgut is considered to be an important site for vector-parasite interaction. Digestive enzymes including serine peptidases such as trypsin and chymotrypsin, which are secreted in the midgut are one of the obstacles for Leishmania in establishing a successful infection. The presence of some natural inhibitors of serine peptidases (ISPs) has recently been reported in Leishmania. In the present study, we deciphered the role of these ISPs in the survival of Leishmania donovani in the hostile sand fly midgut environment.Methods In silico and co-immunoprecipitation studies were performed to observe the interaction of L. donovani ISPs with trypsin and chymotrypsin. Zymography and in vitro enzyme assays were carried out to observe the inhibitory effect of purified recombinant ISPs of L. donovani (rLdISPs) on trypsin, chymotrypsin and the sand fly midgut peptidases. The expression of ISPs in the amastigote to promastigote transition stages were studied by semi-quantitative RT-PCR and Western blot. The role of LdISP on the survival of ISP overexpressed (OE) and ISP knocked down (KD) Leishmania parasites inside the sand fly gut was investigated by in vitro and in vivo cell viability assays.ResultsWe identified two ecotin-like genes in L. donovani, LdISP1 and LdISP2. In silico and co-immunoprecipitation results clearly suggest a strong interaction of LdISP molecules with trypsin and chymotrypsin. Zymography and in vitro enzyme assay confirmed the inhibitory effect of rLdISP on trypsin, chymotrypsin and the sand fly midgut peptidases. The expression of LdISP2 was found to be strongly associated with the amastigote to promastigote phase transition. The activities of the digestive enzymes were found to be significantly reduced in the infected sand flies when compared to uninfected. To our knowledge, our study is the first report showing the possible reduction of chymotrypsin activity in L. donovani infected sand flies compared to uninfected. Interestingly, during the early transition stage, substantial killing was observed in ISP2 knocked down (ISP2KD) parasites compared to wild type (WT), whereas ISP1 knocked down (ISP1KD) parasites remained viable. Therefore, our study clearly indicates that LdISP2 is a more effective inhibitor of serine peptidases than LdISP1.ConclusionOur results suggest that the lack of ISP2 is detrimental to the parasites during the early transition from amastigotes to promastigotes. Moreover, the results of the present study demonstrated for the first time that LdISP2 has an important role in the inhibition of peptidases and promoting L. donovani survival inside the Phlebotomus argentipes midgut.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-017-2239-9) contains supplementary material, which is available to authorized users.