(-)-Stepholidine (SPD), a natural product isolated from the Chinese herb Stephania, possesses dopamine (DA) D1 partial agonistic and D2 antagonistic properties in the nigrostriatal and mesocorticolimbic DAergic pathways. These unique dual effects have suggested that SPD can effectively restore previously imbalanced functional linkage between D1 and D2 receptors under schizophrenic conditions, in which, SPD improves both the negative and positive symptoms of schizophrenia. SPD also relieves the motor symptoms of Parkinson’s disease (PD) when co-administered with Levodopa. Furthermore, SPD exhibits neuroprotective effects through an antioxidative mechanism and slows down the progression of neuronal degeneration in the substantia nigra (SN) of PD patients and/or animal models. Therefore, SPD is a novel, natural compound with potentially therapeutic roles in the treatment of schizophrenia and/or PD.

Background: Acute kidney injury (AKI) is associated with damage to the nephrons and tubular epithelial cells (TECs), which can lead to chronic kidney disease and end-stage renal disease. Identifying new biomarkers before kidney dysfunction will offer crucial insight into preventive and therapeutic options for the treatment of AKI. Early growth response 1 (EGR1) has been found to be a pioneer transcription factor that can sequentially turn on/off key downstream genes to regulate whole-body regeneration processes in the leopard worm. Whether EGR1 modulates renal regeneration processes in AKI remains to be elucidated. Methods: AKI models of ischemia-reperfusion injury (IRI) and folic acid (FA) were developed to investigate the roles of EGR1 in kidney injury and regeneration. To further determine the function of EGR1, Egr1 -/-mice were applied. Furthermore, RNA sequencing of renal TECs, Chromatin Immunoprecipitation (ChIP) assay, and Dual-luciferase reporter assay were carried out to investigate whether EGR1 affects the expression of SOX9. Results: EGR1 is highly expressed in the kidney after AKI both in humans and mice through analysis of the Gene Expression Omnibus (GEO) database. Furthermore, we verified that EGR1 rapidly up-regulates in the very early stage of IRI and nephrotoxic models of AKI, and validation studies confirmed the essential roles of EGR1 in renal tubular cell regeneration. Further experiments affirmed that genetic inhibition of Egr1 aggravates the severity of AKI in mouse models. Furthermore, our results revealed that EGR1 could increase SOX9 expression in renal TECs by directly binding to the promoter of the Sox9 gene, thus promoting SOX9 + cell proliferation by activating the Wnt/β-catenin pathway. Conclusions: Together, our results demonstrated that rapid and transient induction of EGR1 plays a renoprotective role in AKI, which highlights the prospects of using EGR1 as a potential therapeutic target for the treatment of AKI.

While elevated plasma prorenin levels are commonly found in diabetic patients and correlate with diabetic nephropathy, the pathological role of prorenin, if any, remains unclear. Prorenin binding to the (pro)renin receptor [(p)RR] unmasks prorenin catalytic activity. We asked whether elevated prorenin could be activated at the site of renal mesangial cells (MCs) through receptor binding without being proteolytically converted to renin. Recombinant inactive rat prorenin and a mutant prorenin that is noncleavable, i.e., cannot be activated proteolytically, are produced in 293 cells. After MCs were incubated with 10(-7) M native or mutant prorenin for 6 h, cultured supernatant acquired the ability to generate angiotensin I (ANG I) from angiotensinogen, indicating both prorenins were activated. Small interfering RNA (siRNA) against the (p)RR blocked their activation. Furthermore, either native or mutant rat prorenin at 10(-7) M alone similarly and significantly induced transforming growth factor-β(1), plasminogen activator inhibitor-1 (PAI-1), and fibronectin mRNA expression, and these effects were blocked by (p)RR siRNA, but not by the ANG II receptor antagonist, saralasin. When angiotensinogen was also added to cultured MCs with inactive native or mutant prorenin, PAI-1 and fibronectin were further increased significantly compared with prorenin or mutant prorenin alone. This effect was blocked partially by treatment with (p)RR siRNA or saralasin. We conclude that prorenin binds the (p)RR on renal MCs and is activated nonproteolytically. This activation leads to increased expression of PAI-1 and transforming growth factor-β(1) via ANG II-independent and ANG II-dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may play a role in the development of diabetic nephropathy.

Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 ± 18 to 138 ± 17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor β (TGFβ) 1 (TGFβ1), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-myosin heavy chain (β-MHC), TGFβ1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-β-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, β-catenin, and Akt-mediated signals.

Background Febuxostat is a novel non‐purine selective inhibitor of xanthine oxidase (NP‐SIXO) being developed for the management of hyperuricemia in patients with gout. Aim The effects of age and gender on the pharmacokinetics (PK), pharmacodynamics (PD), and safety of febuxostat were evaluated. Methods In a phase‐1, parallel group, open‐label, multiple dose study, male (M) and female (F) subjects between 19–40 years old[young (Y), 12M/12F] and 65–76 years old[elderly (E), 12M/12F] received once daily 80 mg oral doses of febuxostat for 7 days. Blood samples were collected to assess the PK of febuxostat and its active metabolites (67M‐1, 67M‐2, 67M‐4) as well as its effect on uric acid (PD marker). Protein binding and safety of febuxostat were also assessed. Results The results are shown in the table below. The overall incidence of study drug related adverse events (AEs) was lower in M than in F (13% vs 54%) and in Y than in E (25% vs 42%). The most common AEs were headache and constipation. The majority of AEs were mild in severity. Conclusion Neither age nor gender had any clinically significant effect on the PK, PD, and safety of febuxostat. Therefore, febuxostat does not require any dose adjustment based on age or gender. Clinical Pharmacology & Therapeutics (2005) 77, P50–P50; doi: Mean± SD Plasma Pharmacokinetic and Serum Uric Acid (sUA) Parameters on Day 7 Age Gender Analyte Parameter Y E M F FebuxostatCmax,u (ng/mL)28±1227±924±1031±101,2AUC24,u (ng·h/mL)56±1961±2054±2363±151,2fu (%)0.7±0.10.7±0.20.7±0.10.7±0.167M‐1AUC24 (ng·h/mL)225±63265±84224±68265±8067M‐2AUC24 (ng·h/mL)229±76243±69240±81232±6367M‐4AUC24 (ng·h/mL)235±77270±125223±70281±125sUACmean,24 (%change)−55±8−56±9−52±7−59±81 Cmax,u or AUC24,u: Unbound Cmax or AUC24; fu: Unbound fraction; Cmean,24: sUA 24‐hour mean concentration;1 Statistically significantly different from M (p≤ 0.05)2 Not statistically significantly different from M (p>0.05) with weight as a covariate