Pharmacokinetics and disposition of monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) after intravenous dosing of antiseptic XueBiJing injection in human subjects and rats.

AIM: Monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides. METHODS: Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro. RESULTS: A total of 18 monoterpene glycosides were detected in XueBiJing injection (content levels, 0.001-2.47 mmol/L), and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorin increased proportionally as the dose was increased. Rat lung, heart, and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability. CONCLUSION: Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.

Based on functional and histopathological correlations: is diffusion kurtosis imaging valuable for noninvasive assessment of renal damage in early-stage of chronic kidney disease?

PURPOSE: To evaluate the potential of 3 T magnetic resonance diffusion kurtosis imaging (DKI) in assessing the renal damage in early-stage of chronic kidney disease (CKD) patients with normal or slightly changed functional index, using histopathology as reference standard. METHODS: 49 CKD patients and 18 healthy volunteers were recruited in this study. CKD patients were divided into two groups based on estimated glomerular filtration rate (eGFR): Study group I (eGFR ≥ 90 ml/min/1.73 m2 [n = 20]) and Study group II (eGFR < 90 ml/min/1.73 m2 [n = 29]). DKI was performed in all participants. The DKI parameters (mean kurtosis [MK], mean diffusivity [MD], fractional anisotropy [FA]) of renal cortex and medulla were measured. The differences of parenchymal MD, MK and FA values among the different groups were compared. The correlations between DKI parameters and clinicopathological characteristics were assessed. Diagnostic performance of DKI to assess renal damage in early-stage of CKD was analyzed. RESULTS: The cortex MD and MK showed significant difference among three groups (P < 0.05): trend of cortex MD: Study group II < Study group I < control group; trend of cortex MK: control group < Study group I < Study group II. The cortex MD and MK and medulla FA were correlated with eGFR and Interstitial fibrosis/Tubular atrophy score (0.3 < r < 0.5). Cortex MD and MK yielded an AUC of 0.752 for differentiating healthy volunteers from CKD patients with eGFR ≥ 90 ml/min/1.73 m2. CONCLUSION: DKI shows potential in non-invasive and multi-parameter quantitative assessment of renal damage in early-stage of CKD patients and provide additional information for changes in renal function and histopathology.

Evaluating the renal mild tubulointerstitial damage and renal function in IgAN patients: a comparative study based on diffusion kurtosis imaging and diffusion tensor imaging.

OBJECTIVE: To compare the performance of 3.0 T magnetic resonance diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in evaluation of the degree of tubulointerstitial damage and renal function in Immunoglobulin A Nephropathy (IgAN) patients. METHODS: Both DKI and DTI were performed in 40 IgAN patients and 17 healthy volunteers. IgAN patients were divided into two groups according to tubulointerstitial lesion score: Mild injury group, n = 24; Moderate-severe injury group, n = 16. DKI characteristic parameters [mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr)] and DTI parameters [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), radial diffusivity (Dr)] of renal cortex and medulla were measured and compared among different groups. Correlations between DKI, DTI parameters and clinicopathological characteristics were assessed. Diagnostic performance of DKI and DTI to evaluate tubulointerstitial damage of IgAN was compared. RESULTS: Cortical MK, Kr, Da and parenchymal Ka significantly differed among three groups (P < 0.05). Cortical MK, Kr, Ka were negatively correlated with estimated glomerular filtration rate (eGFR) (MK: r = - 0.613; Kr: r = - 0.539; Ka: r = - 0.664) and positively correlated with tubulointerstitial lesion score (MK: r = 0.655; Kr: r = 0.577; Ka: r = 0.661) (all P < 0.001). Lower correlation coefficient was found among cortical FA, MD, Dr and eGFR, tubulointerstitial lesion score (all|r|< 0.350). The AUCs of DKI and DTI parameters for differentiating Mild injury group from control group were (cortical MK 0.822, cortical Ka 0.816; cortical FA 0.515, cortical MD 0.714) and for differentiating Mild injury group from Moderate-severe injury group were (cortical MK 0.813, cortical Ka 0.831; medulla FA 0.784, medulla MD 0.586). CONCLUSION: Compared with DTI, DKI was more sensitive and accurate to probe the renal function and the tubulointerstitial damage of IgAN, especially the mild tubulointerstitial damage.

Efficacy and safety of percutaneous renal biopsy performed using 18G needle versus 16G needle: a single-center retrospective study.

BACKGROUND: At present, both 16G and 18G needles are used for percutaneous renal biopsy in China. This study aimed to compare the efficacy and safety of biopsy performed with the 18G needle vs. the 16G needle. METHODS: The data of patients who underwent percutaneous renal biopsy at our hospital between January 2015 and December 2019 were retrospectively analyzed. The number of glomeruli obtained by puncture and postoperative complications were compared between patients undergoing biopsy with the 16G and 18G needles. Continuous variables were compared by the t test or the Mann-Whitney U test, and categorical variables by the chi-square test. Correlation analysis was used to examine the relationship of different variables with hematoma size. RESULTS: Of the total 3138 kidney biopsies, 2526 were performed with the18G needle and 612 with the 16G needle. The number of glomeruli obtained was not significantly different between the two groups (P = 0.078). Large hematomas were significantly more common the 16G group than in the 18G group (9.31% vs. 5.98%, P = 0.003). Arteriovenous fistula was also more common in the 16G group (1.14% vs. 0.23%, P = 0.005). Other complications were rare, with similar incidence in the two groups. CONCLUSION: The 18G needle is as effective as the 16G needle for percutaneous renal biopsy. The risk of large hematoma and arteriovenous fistula appear to be lower with the 18G needle.

Tetrandrine may treat membranous glomerulopathy via P13K/Akt signaling pathway regulation: therapeutic mechanism validation using Heymann nephritis rat model.

Membranous glomerulopathy (MGN) is an autoimmune kidney disease that is the primary cause of nephrotic syndrome (NS) in adults. Tetrandrine, a bisbenzylisoquinoline alkaloid, is known to have numerous pharmacological effects. In this study, network pharmacology analysis and experimental validation were conducted to analyze the mechanisms by which tetrandrine functions as a therapeutic intervention for MGN. A systematic network pharmacology method was applied to identify potential targets and determine the therapeutic mechanism of tetrandrine in MGN treatment. A Heymann nephritis (HN) rat model was developed to assess the therapeutic effects of tetrandrine on NS and validate the predicted molecular mechanisms. We obtained 86 potential targets of tetrandrine for the treatment of NS. In vivo experiments showed that tetrandrine could reduce the 24-h urine protein content, decrease glomerular basement membrane proliferation, and significantly decrease thylakoid stroma and cell proliferation in the HN rat kidney tissue. Moreover, tetrandrine suppressed kidney cell apoptosis and upregulated the expression of nephrin and podocin in HN model rats. qRT-PCR results revealed that tetrandrine inhibited IL-1ß, TNFα, and MCP-1 levels in HN model rats. Western blot results indicated that tetrandrine can protect against MGN via the PI3K/Akt signaling pathway. Thus, by using a combination of network and experimental pharmacology methods, we demonstrate that tetrandrine can treat MGN via the PI3K/Akt signaling pathway and provide novel insights into the mechanisms underlying tetrandrine-mediated management of MGN.

Ginsenoside Rg1 protection against ß-amyloid peptide-induced neuronal apoptosis via estrogen receptor α and glucocorticoid receptor-dependent anti-protein nitration pathway.

Ginsenoside Rg1 (Rg1) acts as a neuroprotective agent against various insults, however, the underlying mechanism has not been fully elucidated yet. Here, we report that Rg1 protects primary rat cerebrocortical neurons against ß-amyloid peptide25₋35 (Aß25₋35) injury via estrogen receptor α (ERα) and glucocorticoid receptor (GR)-dependent anti-protein nitration pathway. In primary rat cerebrocortical neuron cultures under basal conditions, Rg1 leads to nuclear translocation of ERα and GR, induces related responsive gene PR, pS2 and MKP-1, SGK transcription. Meantime, Rg1 also increases the basal level of ERK1/2 phosphorylation. In the presence of toxic level of Aß25₋35, Rg1 maintains ERK1/2 phosphorylation, attenuates iNOS expression, NO production, and inhibits NF-κB nuclear translocation, protein nitration and cell death. The antiapoptotic effects of Rg1 via both ERα and GR were abolished by small interfering RNAs (siRNA). ERK1/2 phosphorylation inhibitor U0126 can block downstream iNOS expression and NO generation. Interestingly, the anti-protein nitration effect of Rg1 is well matched with ERα and GR activation, although its anti-ROS production effect is in an ERα- and GR-independent manner. These results suggest that Rg1 ameliorates Aß25₋35-induced neuronal apoptosis at least in part by two complementary ERα- and GR-dependent downstream pathways: (1) upregulation of ERK1/2 phosphorylation followed by inhibiting iNOS expression, NO generation and protein tyrosine nitration. (2) reduction NF-κB nuclear translocation. These data provide new understanding into the mechanisms of Rg1 anti-apoptotic functions after Aß25₋35 exposure, suggesting that ERα and GR-dependent anti-protein tyrosine nitration pathway might take an important role in the neuroprotective effect of Rg1.