An inhibitor with GSK3ß and DYRK1A dual inhibitory properties reduces Tau hyperphosphorylation and ameliorates disease in models of Alzheimer's disease.

Since Alzheimer's disease (AD) is a complex and multifactorial neuropathology, the discovery of multi-targeted inhibitors has gradually demonstrated greater therapeutic potential. Neurofibrillary tangles (NFTs), the main neuropathologic hallmarks of AD, are mainly associated with hyperphosphorylation of the microtubule-associated protein Tau. The overexpression of GSK3ß and DYRK1A has been recognized as an important contributor to hyperphosphorylation of Tau, leading to the strategy of using dual-targets inhibitors for the treatment of this disorder. ZDWX-12 and ZDWX-25, as harmine derivatives, were found good inhibition on dual targets in our previous study. Here, we firstly evaluated the inhibition effect of Tau hyperphosphorylation using two compounds by HEK293-Tau P301L cell-based model and okadaic acid (OKA)-induced mouse model. We found that ZDWX-25 was more effective than ZDWX-12. Then, based on comprehensively investigations on ZDWX-25 in vitro and in vivo, 1) the capability of ZDWX-25 to show a reduction in phosphorylation of multiple Tau epitopes in OKA-induced neurodegeneration cell models, and 2) the effect of reduction on NFTs by 3xTg-AD mouse model under administration of ZDWX-25, an orally bioavailable, brain-penetrant dual-targets inhibitor with low toxicity. Our data highlight that ZDWX-25 is a promising drug for treating AD.

Serum-Urine Matched Metabolomics for Predicting Progression of Henoch-Schonlein Purpura Nephritis.

Henoch-Schonlein purpura nephritis (HSPN) is a common glomerulonephritis secondary to Henoch-Schonlein purpura (HSP) that affects systemic metabolism. Currently, there is a rarity of biomarkers to predict the progression of HSPN. This work sought to screen metabolic markers to predict the progression of HSPN via serum-urine matched metabolomics. A total of 90 HSPN patients were enrolled, including 46 HSPN (+) patients with severe kidney damage (persistent proteinuria >0.3 g/day) and 44 HSPN (-) patients without obvious symptoms (proteinuria < 0.3 g/day). Untargeted metabolomics was determined by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q/TOF-MS). A total of 38 and 50 differential metabolites were, respectively, identified in serum and urine from the comparison between HSPN (+) and HSPN (-) patients. Altered metabolic pathways in HSPN (+) mainly included glycerophospholipid metabolism, pyruvate metabolism, and citrate cycle. A panel of choline and cis-vaccenic acid gave areas under the curve of 92.69% in serum and 72.43% in urine for differential diagnosis between HSPN (+) and HSPN (-). In addition, the two metabolites showed a significant association with clinical indices of HSPN. These results suggest that serum-urine matched metabolomics comprehensively characterized the metabolic differences between HSPN (+) and HSPN (-), and choline and cis-vaccenic acid could serve as biomarkers to predict HSPN progression.

New Insights into the Pathogenesis of IgA Nephropathy.

BACKGROUND: IgA nephropathy, a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (autoantigen) and anti-glycan autoantibodies deposit in glomeruli and induce renal injury. Multiple genetic loci associated with disease risk have been identified. The prevalence of risk alleles varies geographically, highest in eastern Asia and northern Europe, fewer in other parts of Europe and North America, and the least in Africa. IgA nephropathy is diagnosed from pathological assessment of a renal biopsy specimen. Currently, therapy is not disease-targeted but rather is focused on maintaining control of blood pressure and proteinuria, ideally with suppression of angiotensin II. Possible additional approaches differ between countries. Disease-specific therapy as well as new tools for diagnosis, prognosis, and assessment of responses to therapy are needed. SUMMARY: Glycosylation pathways associated with aberrant O-glycosylation of IgA1 and, thus, production of autoantigen, have been identified. Furthermore, unique characteristics of the autoantibodies in IgA nephropathy have been uncovered. Many of these biochemical features are shared by patients with IgA nephropathy and Henoch-Schönlein purpura nephritis, suggesting that the two diseases may represent opposite ends of a spectrum of a disease process. Understanding the molecular mechanisms involved in formation of pathogenic IgA1-containing immune complexes will enable development of disease-specific therapies as well as diagnostic and prognostic biomarkers. KEY MESSAGES: IgA nephropathy is an autoimmune disease caused by glomerular deposition of nephritogenic circulating immune complexes consisting of galactose-deficient IgA1 (autoantigen) bound by anti-glycan autoantibodies. A better understanding of the multi-step process of pathogenesis of IgA nephropathy and the genetic and environmental contributing factors will lead to development of biomarkers to identify patients with progressive disease who would benefit from a future disease-specific therapy.

[Production of aldosterone by rat mesangial cell and the accumulation of extracellular matrix induced by aldosterone].

OBJECTIVE: To investigate whether aldosterone (Aldo) may be synthesized by glomerular mesangial cells and whether Aldo promotes the synthesis of fibronectin (FN) and type IV collagen in mesangial cells. METHODS: Rat mesangial cells (RMC) were cultured and then divided into 4 groups: control group, AngII group (AngII of the concentrations of 10(-10), 10(-9), 10(-8), 10(-7), and 10(-6) mol/L was added), losartan group (AngII 1 type inhibitor losartan and AngII were added), and KCL group (KCL of the concentrations of 7 and 9 mmol/L was added). 48 hours after the RNAs of the cells in different groups were collected to detect the Aldo synthesized by the RMCs themselves. Another RMCs were cultured and divided into 4 groups: control group, Aldo group (Aldo of the concentration of 10(-7) mol/L was added), spironolactone + Aldo group (spironolactone 10(-9) mol/L and Aldo 10(-7) mol/L were added), and spironolactone group (spironolactone 10(-9) mol/L was added). RT-PCR was used to detect the expression of the Aldo synthase CYP11B2, mineralocorticoid receptor (MR), and 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2 (an enzyme required for MR ligand specificity) mRNAs and proteins. The level of Aldo in the incubation medium was detected by radioimmunoassay. After being exposed to 10(-7) mol/L Aldo for 24 h, the level of FN and type IV collagen in the incubation medium were examined by ELISA and Western blotting respectively. RESULTS: CYP11B2, MR, and 11 beta-HSD2 mRNA expressions were detectable in RMCs by RT-PCR and confirmed by sequencing. The concentration of Aldo in the incubation medium was 1.605 pg/10(6) cells. The mRNA expression of CYP11B2 was significantly up-regulated by both AngII and potassium. Immunocytochemistry showed that MR and 11 beta-HSD2 were distributed in both the cytoplasm and the nucleolus. After treatment of 10(-7) mol/L Aldo for 24 hours, the concentration of FN was 74 +/- 16 ng/ml, significantly higher than the baseline value (12.4 +/- 1.9 ng/ml, P < 0.05) and those of spironolactone group and spironolactone + Aldo groups (17.8 +/- 3.6 ng/ml and 25.9 +/- 5.3 ng/ml respectively); and the level of type IV collagen was 136% +/- 14%, significantly higher than the baseline level (100%, P < 0.05), and those of spironolactone group and spironolactone + Aldo groups (112% +/- 33% and 102% +/- 10% respectively). CONCLUSION: RMCs synthesize Aldo. Aldosterone also acts on RMCs, leading to extracellular matrix accumulation AngII and potassium are involved in the regulation of local production of aldosterone.