IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells

Myokines are specialized cytokines that are secreted from skeletal muscle (SKM) in response to metabolic stimuli, such as exercise. Interleukin-15 (IL-15) is a myokine with potential to reduce obesity and increase lean mass through induction of metabolic processes. It has been previously shown that IL-15 acts to increase glucose uptake in SKM cells. However, the downstream signals orchestrating the link between IL-15 signaling and glucose uptake have not been fully explored. Here we employed the mouse SKM C2C12 cell line to examine potential downstream targets of IL-15-induced alterations in glucose uptake. Following differentiation, C2C12 cells were treated overnight with 100 ng/ml of IL-15. Activation of factors associated with glucose metabolism (Akt and AMPK) and known downstream targets of IL-15 (Jak1, Jak3, STAT3, and STAT5) were assessed with IL-15 stimulation. IL-15 stimulated glucose uptake and GLUT4 translocation to the plasma membrane. IL-15 treatment had no effect on phospho-Akt, phospho-Akt substrates, phospho-AMPK, phospho-Jak1, or phospho-STAT5. However, with IL-15, phospho-Jak3 and phospho-STAT3 levels were increased along with increased interaction of Jak3 and STAT3. Additionally, IL-15 induced a translocation of phospho-STAT3 from the cytoplasm to the nucleus. We have evidence that a mediator of glucose uptake, HIF1α, expression was dependent on IL-15 induced STAT3 activation. Finally, upon inhibition of STAT3 the positive effects of IL-15 on glucose uptake and GLUT4 translocation were abolished. Taken together, we provide evidence for a novel signaling pathway for IL-15 acting through Jak3/STAT3 to regulate glucose metabolism

IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells

Myokines are specialized cytokines that are secreted from skeletal muscle (SKM) in response to metabolic stimuli, such as exercise. Interleukin-15 (IL-15) is a myokine with potential to reduce obesity and increase lean mass through induction of metabolic processes. It has been previously shown that IL-15 acts to increase glucose uptake in SKM cells. However, the downstream signals orchestrating the link between IL-15 signaling and glucose uptake have not been fully explored. Here we employed the mouse SKM C2C12 cell line to examine potential downstream targets of IL-15-induced alterations in glucose uptake. Following differentiation, C2C12 cells were treated overnight with 100 ng/ml of IL-15. Activation of factors associated with glucose metabolism (Akt and AMPK) and known downstream targets of IL-15 (Jak1, Jak3, STAT3, and STAT5) were assessed with IL-15 stimulation. IL-15 stimulated glucose uptake and GLUT4 translocation to the plasma membrane. IL-15 treatment had no effect on phospho-Akt, phospho-Akt substrates, phospho-AMPK, phospho-Jak1, or phospho-STAT5. However, with IL-15, phospho-Jak3 and phospho-STAT3 levels were increased along with increased interaction of Jak3 and STAT3. Additionally, IL-15 induced a translocation of phospho-STAT3 from the cytoplasm to the nucleus. We have evidence that a mediator of glucose uptake, HIF1α, expression was dependent on IL-15 induced STAT3 activation. Finally, upon inhibition of STAT3 the positive effects of IL-15 on glucose uptake and GLUT4 translocation were abolished. Taken together, we provide evidence for a novel signaling pathway for IL-15 acting through Jak3/STAT3 to regulate glucose metabolism

Effectiveness of Insecticide Spraying and Culling of Dogs on the Incidence of Leishmania infantum Infection in Humans: A Cluster Randomized Trial in Teresina, Brazil

Background: To evaluate the effect of insecticide spraying for vector control and elimination of infected dogs on the incidence of human infection with L. infantum, a randomized community intervention trial was carried out in the city of Teresina, Brazil. Methods/Principal Findings Within each of ten localities in the city, four blocks were selected and randomized to 4 interventions: 1) spraying houses and animal pens with insecticide; 2) eliminating infected dogs; 3) combination of spraying and eliminating dogs, and 4) nothing. The main outcome is the incidence of infection assessed by the conversion of the Montenegro skin test (MST) after 18 months of follow-up in residents aged ≥1 year with no previous history of visceral leishmaniasis (VL). Reactions were measured at 48–72 h, induration of ≥5 mm considered positive. Interventions were executed after the baseline interview and repeated 6 and 12 months later. The effects of each type of intervention scheme on the incidence of infection were assessed by calculating relative risks and 95% confidence intervals using Poisson population-averaged regression models with robust variance. Among the 1105 participants, 408 (37%) were MST positive at baseline. Of the 697 negatives, only 423 (61%) were reexamined at the end of the follow-up; 151 (36%) of them converted to a positive MST. Only dog culling had some statistically significant effect on reducing the incidence of infection, with estimates of effectiveness varying between 27% and 52%, depending on the type of analysis performed. Conclusions/Significance: In light of the continuous spread of VL in Brazil despite the large scale deployment of insecticide spraying and dog culling, the relatively low to moderate effectiveness of dog culling and the non-significant effect of insecticide spraying on the incidence of human infection, we conclude that there is an urgent need for revision of the Brazilian VL control program

Mitochondrial DNA mutations in preneoplastic lesions of the gastrointestinal tract: A biomarker for the early detection of cancer

BACKGROUND: Somatic mutations of mitochondrial DNA (mtDNA) are common in many human cancers. We have described an oligonucleotide microarray ("MitoChip") for rapid sequencing of the entire mitochondrial genome (Zhou et al, J Mol Diagn 2006), facilitating the analysis of mtDNA mutations in preneoplastic lesions. We examined 14 precancerous lesions, including seven Barrett esophagus biopsies, with or without associated dysplasia; four colorectal adenomas; and three inflammatory colitis-associated dysplasia specimens. In all cases, matched normal tissues from the corresponding site were obtained as germline control. MitoChip analysis was performed on DNA obtained from cryostat-embedded specimens. RESULTS: A total of 513,639 bases of mtDNA were sequenced in the 14 samples, with 490,224 bases (95.4%) bases assigned by the automated genotyping software. All preneoplastic lesions examined demonstrated at least one somatic mtDNA sequence alteration. Of the 100 somatic mtDNA alterations observed in the 14 cases, 27 were non-synonymous coding region mutations (i.e., resulting in an amino acid change), 36 were synonymous, and 37 involved non-coding mtDNA. Overall, somatic alterations most commonly involved the COI, ND4 and ND5 genes. Notably, somatic mtDNA alterations were observed in preneoplastic lesions of the gastrointestinal tract even in the absence of histopathologic evidence of dysplasia, suggesting that the mitochondrial genome is susceptible at the earliest stages of multistep cancer progression. CONCLUSION: Our findings further substantiate the rationale for exploring the mitochondrial genome as a biomarker for the early diagnosis of cancer, and confirm the utility of a high-throughput array-based platform for this purpose from a clinical applicability standpoint

Content of basil essential oil on a loam texture soil under water regimes and different harvest stages

The essential oil of basil (Ocimum basilicum L.) has high economic value and is produced in the plant by secondary metabolism. Its quantity and composition tend to vary as a response of the plant to stress situations due to changes in the environment and phenological phase. This work aimed to evaluate the development, the chemical composition, content, and the yield of essential oil of basil rich in Linalool, as a function of the soil water tensions and the harvest stages, in a loam texture soil. The experiment was carried out in a greenhouse and consisted of three harvest times (BF - beginning of flowering,  FF - full flowering,  and EF - end of flowering) and five values of soil water tension to define when to irrigate (20, 30, 40, 50, and 60 kPa), totalizing 15 treatments. The irrigation in the soil water tension of 60 kPa generated a reduction in the content and the yield of essential oils compared with 20 kPa, only in the FF harvest stage. However, it did not modify the composition of the essential oil. Regardless of the soil water tension to define irrigation, the highest levels and yields of essential oil were found in the EF harvest stage. Harvest stages did not change the composition of the essential oil or the content of Linalool. In turn, the contents of the components Cineol, Camphor, ∝-Terpeneol, and Isobornyl acetate increased with the harvesting period from BF to EF. Eugenol had the opposite trend, reducing the content from BF to EF. Linalool, a component in greater proportion in essential oil, showed a higher content in soil water tensions up to 50 kPa, decreasing only by 60 kPa. In loam textured soils, it is recommended that basil producers, who aim to extract Linalool, irrigate when the soil water tension reaches up to 50 kPa, with the harvest at any stage of flowering