No abstract

Background: Recent studies revealed that lysophospholipids (LPLs) and related molecules, such as autotaxin (ATX) and phosphatidylserine-specific phospholipase A 1 (PS-PLA 1), are candidates for novel biomarkers in melanoma, glaucoma and diabetic nephropathy. However, it is not clear whether serum levels of ATX/ PS-PLA 1 would be associated with pathological and clinical findings of lupus nephritis (LN). Methods: In this retrospective cohort study, serum samples were collected from 39 patients with LN and 37 patients with other glomerular diseases. The serum levels of ATX and PS-PLA 1 were evaluated for an association with renal pathology and clinical phenotypes of LN. Results: The serum levels of ATX and PS-PLA 1 were higher in the patients with LN as compared to those with other glomerular diseases. Among the classes of LN, the patients with class IV showed the trend of lower serum levels of ATX. Moreover, the patients with lower levels of ATX exhibited higher scores of activity index (AI) and chronicity index (CI). The level of ATX tended to be negatively correlated with AI and CI. These results might be explained by the effect of treatment, because the serum levels of ATX and PS-PLA 1 were inversely correlated with the daily amount of oral prednisolone. Moreover, they did not reflect the level of proteinuria or kidney survival in LN patients. Conclusion: Although the serum levels of ATX and PS-PLA 1 were affected by the treatment, these levels were higher in the patients with LN. The potential clinical benefits of these markers need to be clarified in further studies.

Daptomycin (DAP) is widely used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. The emergence of DAP non-susceptible MRSA strains during therapy is a major concern in clinical settings. Recent studies revealed that MRSA spontaneously reverts to a subsequent methicillin-susceptible S. aureus (MSSA) strain. However, it is not clear whether DAP non-susceptible MRSA has the ability to revert to a susceptible strain. We obtained an MRSA strain pair, DAP non-susceptible strain and subsequent DAP susceptible strain, from a patient. To understand the underlying mechanism by which DAP non-susceptible MRSA reverts to a susceptible strain, we performed genetic and phenotypic analysis in the strain pair. Although whole-genome analysis revealed four missense mutations, including L826F in mprF, in both strains, the net cell-surface charge was similar between the DAP non-susceptible and susceptible strains. However, the thickness of the cell wall was higher in the DAP non-susceptible strain, which was decreased to the same level as the control after reversion to the DAP susceptible strain. Moreover, the non-susceptible strain showed higher mRNA expression of the two-component system (TCS), such as VraSR, yycG and GraS, with the up-regulated transcription levels of cell-wall biosynthesis-related genes. The expression levels of those genes were decreased after reversion to the susceptible strain. These results indicated that DAP non-susceptibility due to up-regulation of the TCS and cell-wall biosynthesis-related genes may be reversible by the discontinuation of DAP, leading to reversion to the DAP susceptible phenotype.

Background. Recent studies revealed the connection between amino acid chirality and diseases. We previously reported that the gut microbiota produced various D-amino acids in a murine acute kidney injury (AKI) model. Here, we further explore the pathophysiological role of D-Alanine (Ala) in AKI. Methods. We analyzed the transcripts of the N-methyl-D-aspartate (NMDA) receptor, a receptor for D-Ala, in tubular epithelial cells (TECs). Then, the therapeutic effect of D-Ala was assessed in vivo and in vitro. Lastly, the plasma level of D-Ala was evaluated in AKI patients. Results. The Grin genes encoding NMDA receptor subtypes were expressed in TECs. Hypoxia condition changes the gene expressions of Grin1, Grin2A and Grin2B. D-Ala protected TECs from hypoxia-related cell injury and induced proliferation after hypoxia. These protective effects are associated with the chirality of D-Ala. D-Ala inhibits ROS production and improves mitochondrial membrane potential, through NMDA receptor signaling. The ratio of D-Ala/L-Ala was increased in feces, plasma, and urine after the induction of I/R. Moreover, enterobacteriaceae, such as Escherichia coli, Klebsiella oxytoca produced D-Ala. The oral administration of D-Ala ameliorated kidney injury after I/R induction in mice. The deficiency of NMDA subunit NR1 on tubular cell worsened kidney damage in AKI. In addition, the plasma level of D-Ala was increased and reflected the level of renal function in AKI patients. Conclusions. D-Ala has protective effects on I/R-induced kidney injury. Moreover, the plasma level of D-Ala reflects the eGFR in AKI patients. D-Ala could be a promising therapeutic target and potential biomarker for AKI.

Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Recent studies have revealed a new biological function of trehalose as an autophagy inducer. Thus far, there are few reports regarding the therapeutic effects of trehalose on fibrotic diseases. Therefore, we examined whether trehalose has anti-fibrotic effects on PF. PF was induced by intraperitoneal injection of chlorhexidine gluconate (CG). CG challenges induced the increase of peritoneal thickness, ColIα 1 mRNA expression and hydroxyproline content, all of which were significantly attenuated by trehalose. In addition, CG challenges induced a marked peritoneal accumulation of α-SMA + myofibroblasts that was reduced by trehalose. The number of Wt1 + α-SMA + cells in the peritoneum increased following CG challenges, suggesting that a part of α-SMA + myofibroblasts were derived from peritoneal mesothelial cells (PMCs). The number of Wt1 + α-SMA + cells was also suppressed by trehalose. Additionally, trehalose attenuated the increase of α-SMA and ColIα 1 mRNA expression induced by TGF-β 1 through Snail protein degradation, which was dependent on autophagy in PMCs. These results suggest that trehalose might be a novel therapeutic agent for PF through the induction of autophagy and the suppression of mesothelial-to-mesenchymal transition in PMCs. Organ fibrosis is a common pathway that finally results in organ failure. Disease-related injuries are responsible for triggering fibrogenic responses. Fibrosis is a short-term adaptive response for wound healing, but prolonged injuries progress and lead to the overproduction of extracellular matrix (ECM). The dynamic deposition of ECM promotes progression to organ fibrosis and ultimately to organ failure 1. Peritoneal fibrosis (PF) is a serious complication for patients undergoing peritoneal dialysis (PD) 2 , which is a life-sustaining therapy for patients with end-stage renal disease worldwide, which accounts for 11% of the overall dialysis population 3. Dialysis solution is hyperosmotic and hyperglycemic, and can induce consecutive peritoneal injuries, thus inducing the progression of peritoneal fibrosis 4. The development of PF causes encapsulating peritoneal sclerosis, which is a lethal complication of PD and an important problem that makes long-term PD difficult 2,5,6. However, the precise molecular mechanisms for the development of PF need to be clarified to establish therapeutic strategies.