Explore the vast range of titles available.

Development of a novel agent against life-threatening sepsis requires the in-depth understanding of the relevant pathophysiology and therapeutic targets. Given the function of microRNAs (miRNAs) as potent oligonucleotide therapeutics, here we investigated the pathophysiological role of exogenously applied miRNA in sepsis-induced multiple organ injury. In vitro, miR-16, miR-126, miR-146a, and miR-200b suppressed the production of pro-inflammatory cytokines in RAW264.7 macrophage cells after lipopolysaccharide (LPS) stimulation. Of these, miR-146a displayed the most highly suppressive effect, wherein the transcriptional activity of nuclear factor kappa B (NF-κB) was decreased via targeting of interleukin 1 receptor-associated kinase 1 and tumor necrosis receptor-associated factor 6. Sepsis was induced in mice via cecal ligation and puncture (CLP) and an intravenous injection of a complex of miR-146a-expressing plasmid and polyethyleneimine. Treatment with this complex significantly decreased the level of serum inflammatory cytokines, attenuated organ injury including kidney injury, and led to increased survival from polymicrobial sepsis induced by CLP. miR-146a-expressing plasmid was abundantly distributed in splenic macrophages, but not in renal parenchymal cells. CLP mice treated with miR-146a displayed significantly decreased NF-κB activation and splenocyte apoptosis. Splenectomy diminished the anti-inflammatory effects of miR-146a. The collective results support the conclusion that the induction of miR-146a expression in splenic macrophages prevents excessive inflammation and sepsis-induced multiple organ injury. This study establishes a novel and critical pathophysiological role for splenic macrophage interference in sepsis-related organ injury.

Lupus nephritis (LN) is a life-threatening complication of systemic lupus erythematosus. The 2003 pathological classification of LN was revised in 2016; it quantitatively evaluates the interstitium in addition to the glomeruli. We performed a retrospective multi-centre cohort study and investigated the utility of the 2016 classification—including the activity index (AI), chronicity index (CI), and each pathological component to predict complete remission or renal function decline, defined as 1.5-fold increase in serum creatinine levels—and compare with that of the 2003 classification. Ninety-one consecutive adult patients with first-onset class III/IV LN who were newly prescribed any immunosuppressants were enrolled and followed up for a median of 51 months from January 2004. Cox regression analysis demonstrated the subclasses based on the 2003 classification, which mainly evaluate glomerular lesions, were not associated with clinical outcomes. After adjustments for estimated glomerular filtration rate and urinary protein levels, higher CI and higher interstitial fibrosis and lower hyaline deposit scores were associated with renal functional decline. Similarly, higher CI and interstitial inflammation scores were associated with failure to achieve complete remission. Therefore, the 2016 classification can predict the clinical outcomes more precisely than the 2003 classification.

BackgroundA Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown a one-to-one male-to-female mortality ratio, notwithstanding the statistically longer life expectancy of women in the general population. This finding contrasts with the recent report that Japanese women on dialysis treatment have a more favorable longevity. Accordingly, we further investigated the clinical procedures and outcomes to clarify the sex differences in Japanese patients undergoing dialysis treatment.MethodsSubjects were incident dialysis patients who participated in a multicenter prospective cohort study from October 2011 to September 2013. The all-cause mortality was analyzed by a Cox proportional hazard regression model and studied separately in women and men with or without cardiovascular disease (CVD) at baseline.ResultsOverall, 492 (32.3%) of the 1520 test subjects were women. All-cause mortality was higher in men (28.6%) than in women (19.9%, p < 0.001). Female sex (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.54–0.90) and history of CVD (HR: 1.51, 95% CI: 1.18–1.95) were independent predictors of all-cause mortality. In patients without CVD, female gender was strong independent contributor (HR = 0.46, 95% CI: 0.30–0.70, p < 0.001). In contrast, patients with CVD showed no difference in survival between the sexes (HR: 0.92, 95% CI: 0.67–1.24, p = 0.597).ConclusionOur study demonstrated that women undergoing chronic dialysis therapy had a lower mortality risk than men. However, complication with CVD canceled out the survival advantage in Japanese women on chronic dialysis. We should reevaluate the risk of women with CVD undergoing dialysis and apply the optimal care for CVD.

Preeclampsia is a hypertensive disorder of pregnancy and is due to abnormal placentation. The pathogenesis remains unclear. Fructose is biologically distinct from glucose and has a critical role in fetal growth in early pregnancy. Many species, including humans, produce fructose in their placenta during the first trimester to assist fetal growth and survival during a time when hypoxia is significant. Fructose is preferred over glucose in hypoxic tissues, and in the developing fetus, fructose has a critical role in stimulating the production of nucleic acids, lipids and glycosaminoglycans. Fructose production normally decreases significantly following the establishment of maternal-fetal circulation following placentation. However, if there is impaired placentation, local hypoxia will continue to drive fructose production. Excessive fructose metabolism drives endothelial dysfunction, oxidative stress, elevated blood pressure, insulin resistance, fatty liver, and a rise in uric acid and vasopressin levels, all of which are features of the preeclamptic state. In addition to fructose production, dietary fructose, for example, from soft drinks, would be additive and has been reported to be a strong independent risk factor for preeclampsia. Uric acid-associated endothelial dysfunction disturbs the invasion of the spiral artery, leading to placental ischemia and further placental hypoxia. Here, we summarize the previous literature regarding the physiological and pathological roles of fructose in pregnancy and propose studies to further investigate the pathogenesis of preeclampsia. Fructose might be a Clue to the Origin of Preeclampsia Insights from Nature and Evolution Preeclampsia is a hypertensive disorder of pregnancy. The pathogenesis remains unclear. Fructose has a critical role in fetal growth in early pregnancy, and might be a key role to developing preeclampsia. Here, we summarize the previous literatures regarding the physiological andpathological roles of fructose in pregnancy to propose studies to further investigate the pathogenesis of preeclampsia.

Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in laboratory animals and humans. The first enzyme in fructose metabolism is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is expressed primarily in liver, intestine, and kidney and has high affinity for fructose, resulting in rapid metabolism and marked ATP depletion. In contrast, fructokinase A is widely distributed, has low affinity for fructose, and has less dramatic effects on ATP levels. By reducing the amount of fructose for metabolism in the liver, fructokinase A protects against fructokinase C-mediated metabolic syndrome. These studies provide insights into the mechanisms by which fructose causes obesity and metabolic syndrome.

Serum presepsin levels are elevated during sepsis and are widely employed in clinical practice. However, the association between urinary presepsin and kidney diseases remains elusive. Given that monocytes/macrophages, primary presepsin producers, are closely associated with the pathophysiology of nephritis, we explored the potential of urinary presepsin as a kidney disease biomarker. In a cross-sectional study involving patients who underwent kidney biopsy (n = 463 patients; 43% female, median age 58 years), the median urinary presepsin/creatinine levels were 590 (interquartile range [IQR], 244–1276), 1023 (IQR, 491–2749), 1429 (IQR, 644–2725), and 3518 (IQR, 2084–6321) ng/g creatinine, indicating minimal (< 5%), mild (5–25%), moderate (26–50%), and severe (> 50%) interstitial inflammatory cell infiltration in biopsy samples, respectively. The area under the curve of urinary presepsin/creatinine (0.81) had a higher accuracy for distinguishing severe interstitial inflammatory cell infiltration than that of the N-acetyl-β-D-glucosaminidase/creatinine (0.70) ( P  = 0.003). The tubulointerstitial nephritis group had the highest urinary presepsin/creatinine level. Immunofluorescence staining revealed that monocytes and macrophages predominantly expressed presepsin in the kidney interstitium, with the stained area positively and significantly correlated with presepsin/creatinine values (r = 0.57, P  = 0.02). Urinary presepsin could be a biomarker for directly assessing monocyte/macrophage infiltration in kidney disease.

Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase-deficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome. Consumption of high amounts of glucose leads to the development of insulin resistance and metabolic syndrome. Here, Lanaspa et al. show that the hepatic conversion of glucose into fructose is a key step in the development of glucose-induced metabolic syndrome and fatty liver in mice.

Background Extracellular vesicles (EVs) have received considerable attention as ideal biomarkers for kidney diseases. Most reports have focused on urinary EVs, that are mainly derived from the cells in the urinary tract. However, the detection and the application of kidney-derived EVs in plasma remains uncertain. Methods We examined the kidney-derived small EVs (sEVs) in plasma that were supposedly released from renal mesangial and glomerular endothelial cells, using clinical samples from healthy controls and patients with kidney transplants. Plasma from healthy controls underwent ultracentrifugation, followed by on-bead flow cytometry, targeting α8 integrin, an antigen-specific to mesangial cells. To confirm the presence of kidney-derived sEVs in peripheral blood, plasma from ABO-incompatible kidney transplant recipients was ultracentrifuged, followed by western blotting for donor blood type antigens. Results Immunohistochemistry and immunoelectron microscopy confirmed α8 integrin expression in kidney mesangial cells and their sEVs. The CD9-α8 integrin double-positive sEVs were successfully detected using on-bead flow cytometry. Western blot analysis further revealed transplanted kidney-derived sEVs containing blood type B antigens in non-blood type B recipients, who had received kidneys from blood type B donors. Notably, a patient experiencing graft kidney loss exhibited diminished signals of sEVs containing donor blood type antigens. Conclusion Our findings demonstrate the potential usefulness of kidney-derived sEVs in plasma in future research for kidney diseases.

Acute T cell-mediated rejection (ATCMR) is a severe negative outcome of kidney transplantation; however, it currently has no reliable marker in Japan. This cross-sectional study was conducted at the Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital from 2016 to 2018 to determine whether plasma or urinary Basigin/CD147 is an effective marker of ATCMR. Plasma and urinary samples were obtained when episode graft biopsies were performed. Forty-six kidney transplant recipients received graft biopsies. Three of them missed plasma and urinary samples and three in ATCMR were on postrejection treatment. Graft biopsy results revealed ATCMR in 12 of them, calcineurin inhibitor nephrotoxicity (CIN) in nine, chronic active antibody-mediated rejection (CAAMR) in nine, BK nephropathy, recurrence IgA nephropathy, necrotic glomerulonephritis, and infection-related glomerulonephritis in one each, and other complications in six. The urinary Basigin/CD147 levels of patients in the ATCMR group [759.4 (490.0, 843.0)] pg/gCre were significantly higher than the levels of patients in the CAAMR [247.0 (157.1, 288.8)] and CIN groups [379.1 (264.7, 456.7)] pg/gCre (  < 0.001). No statistical difference in plasma Basigin/CD147 levels was observed between those groups. At a urinary Basigin/CD147 of 631.5 µg/gCre, 75% sensitivity and 84% specificity with an area under the curve of 0.80 were attained for the diagnosis of graft rejection. Urinary Basigin/CD147 may be a potential marker for ATCMR in kidney transplant recipients. Further studies will be needed to clarify the effectiveness of Basigin/CD147.

Background Combinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression (“neighborhood” miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive. Results Here, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites (“seed overlap” miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, “seed overlap” miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive “seed overlap” is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes—those conserved among eutherian mammals and from human to Coelacanth , and the latter, including KLF4-cotargeting sites, has a stronger association with both “seed overlap” and “neighborhood” miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes. Conclusions Our study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases.