Dapagliflozin Does Not Protect against Adriamycin-Induced Kidney Injury in Mice

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors target SGLT2 in renal proximal tubules and promote glycosuria in type 2 diabetes mellitus in humans and animal models, resulting in reduced blood glucose levels. Although clinical trials have shown that SGLT2 inhibitors attenuate the progression of chronic kidney disease, there have been concerns regarding SGLT2-induced acute kidney injury. In this study, we investigated the effect of SGLT2 inhibitors on adriamycin-induced kidney injury in mice. Methods: Seven-week-old balb/c mice were injected with adriamycin 11.5 mg/kg via the tail vein. Additionally, dapagliflozin was administered via gavage for 2 weeks. The mice were divided into five groups: vehicle, dapagliflozin 3 mg/kg, adriamycin, adriamycin plus dapagliflozin 1 mg/kg, and adriamycin plus dapagliflozin 3 mg/kg. Results: Adriamycin injection reduced the body weight and food and water intakes. Dapagliflozin also decreased the body weight and food and water intakes. Fasting blood glucose and urine volume were not altered by either adriamycin or dapagliflozin. Once adriamycin-induced kidney injury had developed, there were no differences in systolic blood pressure among the groups. Dapagliflozin did not alleviate proteinuria in adriamycin-induced kidney injury. Adriamycin induced significant glomerular and interstitial injury, but dapagliflozin did not attenuate these changes in renal injury. Interestingly, SGLT2 expressions were different between the cortex and medulla of kidneys by dapagliflozin treatment. Dapagliflozin increased SGLT2 expression in medulla, not in cortex. Conclusion: Dapagliflozin had no effect on proteinuria or inflammatory changes such as glomerular and tubular damages in adriamycin-induced kidney injury. Our study suggests that dapagliflozin does not protect against adriamycin-induced kidney injury. More experimental studies regarding the effects of SGLT2 inhibitors on various kidney diseases are needed to clarify the underlying mechanisms

A role of DNA-dependent protein kinase for the activation of AMP-activated protein kinase in response to glucose deprivation

AbstractThe catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) plays an essential role in double-strand break repair by initially recognizing and binding to DNA breaks. Here, we show that DNA-PKcs interacts with the regulatory γ1 subunit of AMP-activated protein kinase (AMPK), a heterotrimeric enzyme that has been proposed to function as a “fuel gauge” to monitor changes in the energy status of cells and is controlled by the upstream kinases LKB1 and Ca2+/calmodulin-dependent kinase kinase (CaMKK). In co-immunoprecipitation analyses, DNA-PKcs and AMPKγ1 interacted physically in DNA-PKcs-proficient M059K cells but not in DNA-PKcs-deficient M059J cells. Glucose deprivation-stimulated phosphorylation of AMPKα on Thr172 and of acetyl-CoA carboxylase (ACC), a downstream target of AMPK, is substantially reduced in M059J cells compared with M059K cells. The inhibition or down-regulation of DNA-PKcs by the DNA-PKcs inhibitors, wortmannin and Nu7441, or by DNA-PKcs siRNA caused a marked reduction in AMPK phosphorylation, AMPK activity, and ACC phosphorylation in response to glucose depletion in M059K, WI38, and IMR90 cells. In addition, DNA–DNA-PKcs−/− mouse embryonic fibroblasts (MEFs) exhibited decreased AMPK activation in response to glucose-free conditions. Furthermore, the knockdown of DNA-PKcs led to the suppression of AMPK (Thr172) phosphorylation in LKB1-deficient HeLa cells under glucose deprivation. Taken together, these findings support the positive regulation of AMPK activation by DNA-PKcs under glucose-deprived conditions in mammalian cells

Rhino-Orbito-Cerebral Mucormycosis in an Immunocompromised Patient

Rhino-orbito-cerebral mucormycosis (ROCM) is an invasive fungal infection that usually occurs in immunocompromised patients. It is aggressive and has a high risk of mortality. With unclear guidelines, ROCM is treated in various ways. We present a patient who underwent kidney transplant and who treated for ROCM without major complications

5′-Triphosphate-RNA-independent activation of RIG-I via RNA aptamer with enhanced antiviral activity

RIG-I is a cytosolic receptor for non-self RNA that mediates immune responses against viral infections through IFNα/β production. In an attempt to identify novel tools that modulate IFNα/β production, we used SELEX technology to screen RNA aptamers that specifically target RIG-I protein. Most of the selected RIG-I aptamers contained polyU motifs in the second half regions that played critical roles in the activation of RIG-I-mediated IFNβ production. Unlike other known ligands, RIG-I aptamer bound and activated RIG-I in a 5′-triphosphate-independent manner. The helicase and RD domain of RIG-I were used for aptamer binding, but intact RIG-I protein was required to exert aptamer-mediated signaling activation. Furthermore, replication of NDV, VSV and influenza virus in infected host cells was efficiently blocked by pre- or post-treatment with RIG-I aptamer. Based on these data, we propose that RIG-I aptamer has strong potential to be an antiviral agent that specifically boosts the RIG-I-dependent signaling cascade

The relationship between eosinophilia and bronchopulmonary dysplasia in premature infants at less than 34 weeks' gestation

PurposeEosinophilia is common in premature infants, and its incidence increases with a shorter gestation period. We investigated the clinical significance of eosinophilia in premature infants born at 3% of the total leukocytes. Perinatal parameters and clinical parameters were also analyzed.ResultsOf the 261 infants born at <34 weeks gestation, 22.4% demonstrated eosinophilia at birth. The eosinophil percentage peaked in the fourth postnatal week at 7.5%. The incidence of severe eosinophilia increased after birth up to the fourth postnatal week when 8.8% of all patients had severe eosinophilia. Severity of eosinophilia was positively correlated with a lower gestational age, birth weight, and Apgar score. Respiratory distress syndrome, bronchopulmonary dysplasia, nephrocalcinosis, intraventricular hemorrhage, and sepsis were associated with a higher eosinophil percentage. The eosinophil percentage was significantly higher in infants with bronchopulmonary dysplasia from the first postnatal week and the percentage was the highest in the fourth postnatal week, with the maximal difference being 4.1% (P<0.001).ConclusionEosinophilia is common in premature infants and reaches peak incidence and severity in the fourth postnatal week. The eosinophil percentage was significantly higher in bronchopulmonary dysplasia patients from the first postnatal week. Severe eosinophilia was significantly associated with the incidence of bronchopulmonary dysplasia even after adjusting for other variables

KMT-2016-BLG-1107: A New Hollywood-Planet Close/Wide Degeneracy

We show that microlensing event KMT-2016-BLG-1107 displays a new type of degeneracy between wide-binary and close-binary Hollywood events in which a giant-star source envelops the planetary caustic. The planetary anomaly takes the form of a smooth, two-day "bump" far out on the falling wing of the light curve, which can be interpreted either as the source completely enveloping a minor-image caustic due to a close companion with mass ratio $q=0.036$, or partially enveloping a major-image caustic due to a wide companion with $q=0.004$. The best estimates of the companion masses are both in the planetary regime ($3.3^{+3.5}_{-1.8}\,M_{\rm jup}$ and $0.090^{+0.096}_{-0.037}\,M_{\rm jup}$) but differ by an even larger factor than the mass ratios due to different inferred host masses. We show that the two solutions can be distinguished by high-resolution imaging at first light on next-generation ("30m") telescopes. We provide analytic guidance to understand the conditions under which this new type of degeneracy can appear.Comment: 23 pages, 7 figures, accepted for publication in A

KMT-2018-BLG-1990Lb: A Nearby Jovian Planet From A Low-Cadence Microlensing Field

We report the discovery and characterization of KMT-2018-BLG-1990Lb, a Jovian planet $(m_p=0.57_{-0.25}^{+0.79}\,M_J)$ orbiting a late M dwarf $(M=0.14_{-0.06}^{+0.20}\,M_\odot)$, at a distance (D_L=1.23_{-0.43}^{+1.06}\,\kpc), and projected at $2.6\pm 0.6$ times the snow line distance, i.e., a_{\rm snow}\equiv 2.7\,\au (M/M_\odot), This is the second Jovian planet discovered by KMTNet in its low cadence ($0.4\,{\rm hr}^{-1}$) fields, demonstrating that this population will be well characterized based on survey-only microlensing data.Comment: 24 pages, 7 figures, 4 table

Fibrinogen Yecheon: Congenital Dysfibrinogenemia with Gamma Methionine-310 to Threonine Substitution

This case study reports a rare fibrinogen variant, γ Met310Thr mutation, for the first time in Korea. The case shows a point mutation from T to C in the 1,007th nucleotide of the FGG gene. This report describes a variant fibrinogen, hereinafter called "fibrinogen Yecheon", using the name after the town where the patient was living at the time of diagnosis. Fibrinogen Yecheon has a de novo heterozygous point mutation of FGG resulting in γ Met310Thr and subsequent extra N-glycosylation at γ Asn308. Extra N-glycosylated fibrinogen is considered a main inhibitor of normal fibrinogen activity