Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of polycystic kidney disease (PKD) and is a typical adult-onset multisystem disorder. It is a progressive disease characterized by the disruption of renal tubular integrity, involving the modulation of cellular proliferation and apoptosis. Most ADPKD results from a mutation in either the PKD1 or PKD2 gene encoding polycystin-1 and polycystin-2, respectively. With the inconsistent disease course of ADPKD, biomarkers that can predict the treatment efficacy and rapid progression of the disease are needed. Studies have identified neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for predicting the progression of ADPKD patients. The NGAL protein is expressed at a low level in the kidneys, which helps to regulate iron transport and participates in epithelial differentiation, inflammation, and cell proliferation. NGAL level also increases in serum and urine during renal detrimental conditions such as ischemia and acute and chronic kidney diseases. On the other hand, some studies have also demonstrated that NGAL may act as a tubulogenic factor controlling cell growth and that the upregulation of the Ngal gene hinders tubular cell proliferation, resulting in significantly reduced cyst growth in cellular and murine models of ADPKD. This review attempts to correlate ADPKD and NGAL based on available research findings to evaluate the therapeutic potential of NGAL in ADPKD.

Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer’s disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamine’s screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (TauRD) with pro-aggregant mutation ΔK280. In the kinase assay for these 7 compounds, residual GSK-3β activities ranged from 36.1% to 90.0% were detected at the IC50 of SB-216763. In the cell assay, only compounds VB-030 and VB-037 reduced Tau aggregation in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. In SH-SY5Y cells expressing ΔK280 TauRD, neither VB-030 nor VB-037 increased expression of GSK-3α Ser21 or GSK-3β Ser9. Among extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT), mitogen-activated protein kinase 14 (P38) and mitogenactivated protein kinase 8 (JNK) which modulate Tau phosphorylation, VB-037 attenuated active phosphorylation of P38 Thr180/ Tyr182, whereas VB-030 had no effect on the phosphorylation status of ERK, AKT, P38 or JNK. However, both VB-030 and VB-037 reduced endogenous Tau phosphorylation at Ser202, Thr231, Ser396 and Ser404 in neuronally differentiated SH-SY5Y expressing ΔK280 TauRD. In addition, VB-030 and VB-037 further improved neuronal survival and/or neurite length and branch in mouse hippocampal primary culture under Tau cytotoxicity. Overall, through inhibiting GSK-3β kinase activity and/or p-P38 (Thr180/Tyr182), both compounds may serve as promising candidates to reduce Tau aggregation/cytotoxicity for AD treatment.

Alzheimer’s disease (AD) is a neurodegenerative disease with progressive memory loss and the cognitive decline. AD is mainly caused by abnormal accumulation of misfolded amyloid β (Aβ), which leads to neurodegeneration via a number of possible mechanisms such as down-regulation of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TRKB) signaling pathway. 7 ,8-Dihydroxyflavone (7,8-DHF), a TRKB agonist, has demonstrated potential to enhance BDNF-TRKB pathway in various neurodegenerative diseases. T o expand the capacity of flavones as TRKB agonists, two natural flavones quercetin and apigenin, were evaluated. With tryptophan fluorescence quenching assay, we illustrated the direct interaction between quercetin/ apigenin and TRKB extracellular domain. Employing Aβ folding reporter SH-SY5Y cells, we showed that quercetin and apigenin reduced Aβ-aggregation, oxidative stress, caspase-1 and acetylcholinesterase activities, as well as improved the neurite outgrowth. Treatments with quercetin and apigenin increased TRKB Tyr516 and Tyr817 and downstream cAMP-response-element binding protein (CREB) Ser133 to activate transcription of BDNF and BCL2 apoptosis regulator (BCL2), as well as reduced the expression of pro-apoptotic BCL2 associated X protein (BAX). Knockdown of TRKB counteracted the improvement of neurite outgrowth by quercetin and apigenin. Our results demonstrate that quercetin and apigenin are to work likely as a direct agonist on TRKB for their neuroprotective action, strengthening the therapeutic potential of quercetin and apigenin in treating AD.