Attenuating Renal Interstitial Fibrosis by Shenqi Pill via Reducing Inflammation Response Regulated by NF-κB Pathway In Vitro and In Vivo.

INTRODUCTION: One of the most significant clinical features of chronic  kidney disease is renal interstitial fibrosis (RIF). This study aimed  to investigate the role and mechanism of Shenqi Pill (SQP) on RIF. METHODS: RIF model was established by conducting unilateral  ureteral obstruction (UUO) surgery on rat or stimulating human  kidney-2 (HK-2) cell with transforming growth factor ß1 (TGFß1).  After modeling, the rats in the SQP low dose group (SQP-L), SQP  middle dose group (SQP-M) and SQP high dose group (SQP-H)  were treated with SQP at 1.5, 3 or 6 g/kg/d, and the cells in the  TGFß1+SQP-L/M/H were treated with 2.5%, 5%, 10% SQP-containing  serum. In in vivo assays, serum creatinine (SCr) and blood urea  nitrogen (BUN) content were measured, kidney histopathology  was evaluated., and α-smooth muscle actin (α-SMA) expression  was detected by immunohistochemistry. Interleukin-1ß (IL-1ß),  interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) content,  inhibitor of kappa B alpha (IKBα) and P65 phosphorylation were  assessed. Meanwhile, cell viability, inflammatory cytokines content,  α-SMA expression, IKBα and P65 phosphorylation were detected  in vitro experiment.  Results. SQP exhibited reno-protective effect by decreasing SCr  and BUN content, improving renal interstitial damage, blunting  fibronectin (FN) and α-SMA expression in RIF rats. Similarly, after  the treatment with SQP-containing serum, viability and α-SMA  expression were remarkably decreased in TGFß1-stimulated HK-2  cell. Furthermore, SQP markedly down-regulated IL-1ß, IL-6, and  TNF-α content, IKBα and RelA (P65) phosphorylation both in vivo and in vitro.  Conclusion. SQP has a reno-protective effect against RIF in vivo and in vitro, and the effect is partly linked to nuclear factor-kappa  B (NF-κB) pathway related inflammatory response, which indicates  that SQP may be a candidate drug for RIF. DOI: 10.52547/ijkd.7546.

Shen Qi Wan-Containing Serum Alleviates Renal Interstitial Fibrosis via Restraining Notch1-Mediated Epithelial-Mesenchymal Transition.

Objective: Shen Qi Wan (SQW) is the most classic prescription for the clinical therapy of chronic kidney disease in China. Nevertheless, the function of SQW in renal interstitial fibrosis (RIF) has not been clearly clarified. Our purpose was to explore the protective function of SQW on RIF. Methods: After intervention with SQW-containing serum alone at increasing concentrations (2.5, 5, and 10%) or in combination with siNotch1, the transforming growth factor-beta (TGF-ß)-induced HK-2 cell viability, extracellular matrix (ECM)-, epithelial-mesenchymal transition (EMT), and Notch1 pathway-associated protein expressions were assessed by cell counting kit-8, qRT-PCR, western blot, and immunofluorescence assays. Results: SQW-containing serum intensified the viability of TGF-ß-mediated HK-2 cells. Besides, it augmented the collagen II and E-cadherin levels, and weakened the fibronectin, α-SMA, vimentin, N-cadherin, and collagen I levels in HK-2 cells triggered by TGF-ß. Moreover, it is found that TGF-ß led to the upregulation of Notch1, Jag1, HEY1, HES1, and TGF-ß in HK-2 cells, which was partially offset by SQW-containing serum. Furthermore, cotreatment of SQW-containing serum and Notch1 knockdown further apparently alleviated the Notch1, vimentin, N-cadherin, collagen I, and fibronectin levels in HK-2 cells induced by TGF-ß. Conclusion: Collectively, these findings elucidated that SQW-containing serum attenuated RIF via restraining EMT through the repression of the Notch1 pathway.

Superior Creep Resistance and Remnant Strength of Novel Tempered Ferritic-Martensitic Steels Designed by Element Addition.

The in situ combustion (ISC) technique is promisingly applied in heavy oil recovery, whereas the operation inevitably causes high temperature and high pressure for a long duration in the thermal recovery well. As a critical component, oil casing, traditionally made of plain carbon steel in China, generally suffers from poor creep resistance and degraded remnant strength under such a harsh environment, which leads to frequent casing damage and inferior recovery efficiency. In this study, a strategy was adopted to tackle the issue by adding chromium (Cr) element into the plain carbon steel. We designed two types of novel steel with the respective addition of 1 wt.% and 13 wt.% Cr element into plain carbon steel for oil casing. Surprisingly, the trace addition of Cr element with 1 wt.% effectively lowered the creep rate in a creep test at 600 °C and 400 MPa and maintained high remnant tensile strength after creep. More significantly, prior creep history dramatically enhanced remnant strength when Cr element was added up to 13 wt.%. After a long-term creep time of 96 h, the samples were conferred by a stress increment of ~92.5 MPa (~11.0%) relative to the creep-free counterparts, whereas the value was reduced by ~158.4 MPa (~17.8%) for plain carbon steel under the same deformation conditions. Such superior mechanical performances in the Cr-doped steels are mainly ascribed to precipitation retardation of carbides and sluggish precipitate coarsening, which continuously favors a precipitation-strengthening effect in steel. These findings provide a fundamental understanding of precipitation response and creep behaviors and, more importantly, enable the development of high-performance steels used in the field of unconventional petroleum and gas resources.

Angiotensin II degrades myeloid cell leukemia 1 in human umbilical vein endothelial cells.

Angiotensin II (Ang II) plays a central role in cardiovascular diseases by causing endothelial apoptosis and dysfunction. Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of apoptosis-regulating proteins. It has been reported that Mcl-1 plays a pivotal role in protecting cells against apoptosis. Presently, the effects of Ang II on the expression of Mcl-1 remain unknown. In this study, we report, for the first time, that the antiapoptotic protein Mcl-1 is degraded by the proteasome during Ang II-induced apoptosis in HUVECs. Notably, our results demonstrate that prior phosphorylation by GSK-3ß is required for proteasomal degradation of Mcl-1. Notably, the reduced level of Mcl-1 was abolished by a specific GSK-3ß inhibitor, suggesting that the phosphorylation of Mcl-1 by GSK-3ß is required for proteasomal degradation of Mcl-1. Overexpression of Mcl-1 rescued apoptosis induced by Ang II, however, knockdown of Mcl-1 exacerbated Ang II-induced apoptosis, thereby indicating that the protein level of Mcl-1 determines the response of endothelial cells to this drug. © 2017 IUBMB Life, 69(5):321-327, 2017.

Brain pharmacokinetics of tetramethylpyrazine after intranasal and intravenous administration in awake rats.

Brain pharmacokinetic behaviors of tetramethylpyrazine (TMP) following intranasal (i.n.) and intravenous (i.v.) administration, have been investigated using brain microdialysis technique in free-moving rats. A cross-over design was employed in the present experiment. The same set of rats (n=5) received i.v. injection at a dose of 10 mg/kg TMP via tail vein. Equal dose was administered intranasally. After application, the dialysates sampled from the left striatum were measured by HPLC-UV detection. The results indicated that the mean corrected TMP concentration of 1.49 microg/ml was obtained at 5 min following i.n. dosing while no TMP in the dialysate sampled 5 min after i.v. injection was detected, in the range of our measurement limit. No compartment model was most suitable for analysis of the concentration vs. time results after i.n. dosing. Thus, a non-compartment model was used in the analysis of all experimental data. No significant differences in brain pharmacokinetic parameters, except Cmax, were found between both i.n. and i.v. administration routes. AUCi.n./AUCi.v. ratio was 92.42%. Finally, compared with i.v. application, intranasal administration of TMP could obtain significantly fast absorption from nasal to ipsilateral striatum and equal bioavailability. Therapeutically relevant nasal formulation is a potential alternative for intravenous administration approach for TMP.