Pharmacokinetic profiling of ZCL-278, a cdc42 inhibitor, and its effectiveness against chronic kidney disease.

ZCL-278 is a selective small molecule specifically inhibiting the Cdc42-intersectin interaction, yet its in-vivo pharmacokinetic and pharmacodynamic properties against renal diseases had not been determined. Thus, our study explored the absorption, distribution and excretion of ZCL-278 as well as its pharmacological efficacy against chronic kidney disease (CKD). With the optimized detection method, absolute oral bioavailability of ZCL-278 was determined as 10.99 % in male and 17.34 % in female rats. ZCL-278 was rapidly and abundantly distributed in various tissues, especially the kidney and heart, while few excreted through urine and feces. In the adenine-induced CKD mice, the increased plasma creatinine and urea, the decreased body weight as well as the renal pathological alterations, including vacuolization of renal tubular epithelial cells, granular degeneration, cell flattening, luminal dilation, and cylindruria, were significantly ameliorated after ZCL-278 administration. Moreover, ZCL-278 could also reverse the increased intensities of renal inflammation and fibrosis in the CKD mice. These results clarified the pharmacokinetics of ZCL-278 in rats and preliminarily indicated that ZCL-278 has favorable pharmacodynamic properties for CKD primed for lead development and optimization, warranting further drug development.

Differentiated metabolomic profiling reveals plasma amino acid signatures for primary glomerular disease.

Primary glomerular disease (PGD) is an idiopathic cause of renal glomerular lesions that is characterized by proteinuria or hematuria and is the leading cause of chronic kidney disease (CKD). The identification of circulating biomarkers for the diagnosis of PGD requires a thorough understanding of the metabolic defects involved. In this study, ultra-high performance liquid chromatography-tandem mass spectrometry was performed to characterize the amino acid (AA) profiles of patients with pathologically diagnosed PGD, including minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), membranous nephropathy, and immunoglobulin A nephropathy. The plasma concentrations of asparagine and ornithine were low, and that of aspartic acid was high, in patients with all the pathologic types of PGD, compared to healthy controls. Two distinct diagnostic models were generated using the differential plasma AA profiles using logistic regression and receiver operating characteristic analyses, with areas under the curves of 1.000 and accuracies up to 100.0% in patients with MCD and FSGS. In conclusion, the progression of PGD is associated with alterations in AA profiles, The present findings provide a theoretical basis for the use of AAs as a non-invasive, real-time, rapid, and simple biomarker for the diagnosis of various pathologic types of PGD.

Metabolomic Profiling of Amino Acids in Human Plasma Distinguishes Diabetic Kidney Disease From Type 2 Diabetes Mellitus.

Background: Diabetic kidney disease (DKD) is a highly prevalent complication in patients with type 2 diabetes mellitus (T2DM). Patients with DKD exhibit changes in plasma levels of amino acids (AAs) due to insulin resistance, reduced protein intake, and impaired renal transport of AAs. The role of AAs in distinguishing DKD from T2DM and healthy controls has yet to be elucidated. This study aimed to investigate the metabolomic profiling of AAs in the plasma of patients with DKD. Methods: We established an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to detect the plasma levels of the 20 AAs in healthy controls (n = 112), patients with T2DM (n = 101), and patients with DKD (n = 101). The key AAs associated with DKD were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) models with loading plots, shared and unique structures (SUS) plots, and variable importance in projection (VIP) values. The discrimination accuracies of these key AAs were then determined by analyses of receiver-operating characteristic (ROC) curves. Results: Metabolomic profiling of plasma revealed significant alterations in levels of the 20 AAs in patients with DKD when compared to those in either patients with T2DM or healthy controls. Metabolomic profiling of the 20 AAs showed a visual separation of patients with DKD from patients with T2DM and healthy controls in OPLS-DA models. Based on loading plots, SUS plots, and VIP values in the OPLS-DA models, we identified valine and cysteine as potential contributors to the progression of DKD from patients with T2DM. Histidine was identified as a key mediator that could distinguish patients with DKD from healthy controls. Plasma levels of histidine and valine were decreased significantly in patients with DKD with a decline in kidney function, and had excellent performance in distinguishing patients with DKD from patients with T2DM and healthy controls according to ROC curves. Conclusion: Plasma levels of histidine and valine were identified as the main AAs that can distinguish patients with DKD. Our findings provide new options for the prevention, treatment, and management of DKD.

Wavelet coherence analysis of spontaneous oscillations in cerebral tissue oxyhemoglobin concentrations and arterial blood pressure in elderly subjects.

This study aims to assess the relationship between spontaneous oscillations in changes in cerebral tissue oxyhemoglobin concentrations (Delta [HbO2]) and arterial blood pressure (ABP) signals in healthy elderly subjects during the resting state using wavelet coherence analysis. Continuous recordings of near-infrared spectroscopy (NIRS) and ABP signals were obtained from simultaneous measurements in 33 healthy elderly subjects (age: 70.7±7.9 years) and 27 young subjects (age: 25.2±3.7 years) during the resting state. The coherence between Delta [HbO2] and ABP oscillations in six frequency intervals (I, 0.4-2 Hz; II, 0.15-0.4 Hz; III, 0.05-0.15 Hz; IV, 0.02-0.05 Hz, V, 0.005-0.0095 Hz and VI, 0.005-0.0095 Hz) was analyzed using wavelet coherence analysis. In elderly subjects, the Delta [HbO2] and ABP oscillations were significantly wavelet coherent in interval I, and wavelet phase coherent in intervals I, II and IV. The wavelet coherence in interval I was significantly higher (p=0.040), in elderly subjects than in young subjects whereas that in interval V significantly lower (p=0.015). In addition, the wavelet phase coherence in interval IV was significantly higher in elderly subjects than in young subjects (p=0.028). The difference in the wavelet coherence of the elderly subjects and the young subjects indicates an altered cerebral autoregulation caused by aging. This study provides new insight into the dynamics of Delta [HbO2] and ABP oscillations and may be useful in identifying the risk for dynamic cerebral autoregulation processes.

Assessment of cerebral oxygenation oscillations in subjects with hypertension.

PURPOSE: The objective of this study was to assess the spontaneous oscillations in subjects with hypertension based on the wavelet transform of cerebral oxygenation signal measured with near-infrared spectroscopy (NIRS). METHODS: Continuous recordings of NIRS and arterial blood pressure (ABP) signals were obtained from simultaneous measurements in 20 healthy subjects (age: 70.8±5.2 years) and 22 subjects with hypertension (age: 72.5±6.8 years). RESULTS: Using spectral analysis based on wavelet transform, five frequency intervals were identified (I, 0.4-2 Hz; II, 0.15-0.4 Hz; III, 0.06-0.15 Hz; IV, 0.02-0.06 Hz and V, 0.005-0.02 Hz). The amplitudes of Δ[Hb] and Δ[HbO2] in intervals I, II and III were significantly higher in hypertensive patients, who have increased mean flow velocity in middle cerebral artery (MCA), compared to that in the healthy subjects (p<0.01). The amplitudes of the ABP in frequency intervals III and V were significantly higher in hypertensive patients than in the healthy subjects (p<0.01). CONCLUSIONS: The present findings revealed that hypertension and increased mean flow velocity in MCA have significant effect on the cerebral oscillations. The higher cerebral oscillations might be related to the intracerebral atherosclerosis in response to systemic hypertension. In addition, the higher spontaneous oscillations in intervals III and V in ABP indicate a metabolic regulation and myogenic response to hypertension.

Age-related changes in spontaneous oscillations assessed by wavelet transform of cerebral oxygenation and arterial blood pressure signals.

The study aims to assess the spontaneous oscillations in elderly subjects based on the wavelet transform of cerebral oxygenation (CO) and arterial blood pressure (ABP) signals. Continuous recordings of near-infrared spectroscopy (NIRS) and ABP signals were obtained from simultaneous measurements in 20 young subjects (age: 27.3 ± 7.1 years) and 15 elderly subjects (age: 70.8 ± 5.1 years) at rest. Using spectral analysis based on wavelet transform, five frequency intervals were identified (I, 0.005 to 0.02 Hz; II, 0.02 to 0.06 Hz; III, 0.06 to 0.15 Hz; IV, 0.15 to 0.40 Hz; and V, 0.40 to 2.0 Hz). The average amplitudes of the Δ[HbO2] and tissue oxygenation index in intervals I to V and the relative amplitudes in intervals IV and V were significantly lower in elderly subjects than in young subjects (P<0.05). In addition, the relative amplitudes of the ABP in interval I were significantly lower in elderly subjects than in young subjects (P=0.016). The present findings suggest the presence of a cerebrovascular degenerative process caused by aging. Spontaneous oscillations in the CO could be used as an indicator of cerebrovascular changes and could be used to identify the risk for cerebrovascular degenerative processes.