APOL1 risk alleles associate with chronic kidney disease in African Americans, but the mechanisms remain to be fully understood. We show that APOL1 risk alleles activate protein kinase R (PKR) in cultured cells and transgenic mice. This effect is preserved when a premature stop codon is introduced to APOL1 risk alleles, suggesting that APOL1 RNA but not protein is required for the effect. Podocyte expression of APOL1 risk allele RNA, but not protein, in transgenic mice induces glomerular injury and proteinuria. Structural analysis of the APOL1 RNA shows that the risk variants possess secondary structure serving as a scaffold for tandem PKR binding and activation. These findings provide a mechanism by which APOL1 variants damage podocytes and suggest novel therapeutic strategies.

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.

The relationships between depression and gut microbiota, particularly those involving the immune system, have become a major focus of recent research. Here, we analyzed changes in gut microbiota and their sulfur metabolites in the feces of a depression rat model using the modified 14-day social defeat stress (SDS) paradigm. Our results showed that SDS increased fecal Lactobacillus reuteri in correlation with ergothioneine levels at around day 11, which continued for at least 1 month following SDS administration. In vitro study further revealed that L. reuteri is capable of producing ergothioneine. Although the known anti-inflammatory and anti-oxidative actions of ergothioneine suggested that the increased fecal ergothioneine levels may be related to intestinal anti-inflammatory defense mechanisms, no change was observed in the plasma ergothioneine levels during the same observation period, indicating that the defense mechanisms may not be sufficiently reflected in the body. As ergothioneine is a natural ingredient that is absorbed mainly from the upper gastrointestinal tract, we hypothesized that oral ergothioneine may exert antidepressant effects. As expected, oral administration of ergothioneine prior to and during the SDS paradigm had a preventative effect on SDS-induced depressive behaviors, such as social avoidance and depression-like sleep abnormalities, particularly those of rapid eye movement sleep. These findings indicate that ergothioneine, a metabolite of L. reuteri, may be a common substance in the microbiota-gut-brain axis that prevents stress-induced sleep disturbances, especially those associated with depression. Recent research has reported the influence of gut microbiota on cerebral function (i.e., the microbiota-gutbrain axis) 4-9. For example, depressive behaviors develop in germ-free rodents following fecal transplants from human patients with MDD 10,11. On the other hand, decreases in MDD-like behaviors occurred following the administration of prebiotics in mice subjected to mild

BackgroundEpidemiological studies have reported a link between serum LBP (lipopolysaccharide‐binding protein) levels and lifestyle‐related diseases. However, there have been no longitudinal studies investigating the association of serum LBP levels and the incidence of cardiovascular disease (CVD) in general populations.Methods and ResultsA total of 2568 community‐dwelling Japanese individuals 40 years and older without prior CVD were followed for 10 years (2002–2012). Serum LBP levels were divided into quartiles (quartile 1: 2.20–9.68 μg/mL; quartile 2: 9.69–10.93 μg/mL; quartile 3: 10.94–12.40 μg/mL; quartile 4: 12.41–24.34 μg/mL). The hazard ratios (HRs) and their 95% CIs for the incidence of CVD were computed using a Cox proportional hazards model. During the follow‐up period, 180 individuals developed CVD. The age‐ and sex‐adjusted cumulative incidence of CVD increased significantly with higher serum LBP levels (P for trend=0.005). Individuals with higher serum LBP levels had a significantly greater risk of the development of CVD after adjusting for conventional cardiovascular risk factors (quartile 1: HR, 1.00 [reference]; quartile 2: HR, 1.04 [95% CI, 0.60–1.78]; quartile 3: HR, 1.52 [95% CI, 0.92–2.51]; and quartile 4: HR, 1.90 [95% CI, 1.17–3.09]; P for trend=0.01). This association remained significant after additional adjustment for homeostasis model assessment of insulin resistance (P for trend=0.01). However, when additional adjustment was made for high‐sensitivity C‐reactive protein, the association was attenuated to the nonsignificant level (P for trend=0.08).ConclusionsThe present findings suggest that higher serum LBP levels are associated with increased risk of the development of CVD in the general Japanese population. Low‐grade endotoxemia may contribute to the pathogenesis of CVD through chronic systemic inflammation.

The aim of this study is to report a possible implication of augmented vasogenic leakage in the mechanism of prolonged aura in sporadic hemiplegic migraine. A 35-year-old woman with sporadic hemiplegic migraine presented with headache followed by right arm weakness, right visual field defect, aphasia and confusion that persisted for 1 week. During the acute stage, focal hyperaemia was seen in the left cerebral hemisphere corresponding to persistent aura symptoms. Augmented vasogenic leakage was demonstrated on delayed enhanced fluid-attenuated inversion recovery image. Magnetic resonance angiography showed dilation of the left middle cerebral artery. During the convalescent stage, such abnormal findings were not seen. Based on these results, we speculate that augmented vasogenic leakage from the leptomeningeal vessels, probably associated with activation of the trigeminovascular system, may delay the recovery of hemiplegic migraine aura.