QiShenYiQi Attenuates Renal Interstitial Fibrosis by Blocking the Activation of β-Catenin

<div><p>Chronic kidney disease (CKD) is becoming a worldwide problem. However, current treatment options are limited. In the current study we showed that QiShenYiQi (QSYQ), a water-ethanol extract from several Chinese medicines, is a potent inhibitor of renal interstitial fibrosis. QSYQ inhibited transforming growth factor-β1 (TGF-β1)-responsive α-smooth muscle actin (α-SMA), collagen I, and fibronectin up-regulation in obstructive nephropathy and cultured cells. Administration of QSYQ also inhibited the established renal interstitial fibrosis in obstructive nephropathy. Interestingly, QSYQ selectively inhibited TGF-β1-induced β-catenin up-regulation and downstream gene transcription. Taken together, our study suggests that QSYQ selectively inhibits TGF-β1-induced β-catenin up-regulation and might have significant therapeutic potential for the treatment of renal fibrosis.</p></div

QSYQ time-dependently inhibited the fibrotic activity mediated by TGF-β1 in NRK 52E cells.

<p>NRK 52E cells were pre-incubated with TGF-β1 (10 ng/ml) and treated with QSYQ (20 μg/ml) 0, 12, and 24h after TGF-β1 incubation, respectively. Cells were harvested 36 h after TGF-β1 stimulation for real-time PCR and 48 h after TGF-β1 stimulation for Western blot analysis, respectively. (A) Real-time PCR analyses of α-SMA, collagen I, and fibronectin. (B) Western blot analyses of α-SMA, collagen I, and fibronectin. *<i>p<</i>10⁻⁸ vs TGF-β1 and QSYQ untreated cells. ANOVA, <i>p<</i>10⁻⁸ for QSYQ-treated cells in A and B. Data are expressed as the mean ± SD of three independent experiments.</p

QSYQ blocked TGF-β1-induced β-catenin up-regulation and downstream gene transcription.

<p>NRK52E cells were pre-incubated with or without QSYQ (5, 10, and 20 μg/ml) before treatment with TGF-β1 (10 ng/ml). (A) Cells were collected 24 h after treatment with TGF-β1 for total protein extraction, followed by immunobloting using antibodies against β-catenin. * p = 0.001 vs TGF-β1 and QSYQ untreated cells. ANOVA, p<i><</i>10⁻⁸ for QSYQ-treated cells; (B) Cells were collected for nuclear protein extraction, followed by immunobloting using antibodies against β-catenin; * p = 0.002 vs TGF-β1 and QSYQ untreated cells. ANOVA, p = 0.001 for QSYQ-treated cells. (C) Immunofluorescence staining revealed that QSYQ treatment inhibited TGFβ1-induced nuclei translocation of β-catenin (800×). (D) Real-time PCR analyses of PAI 1 and Snail. *p<i><</i>10⁻⁸ vs TGF-β1 and QSYQ untreated cells. ANOVA, p<i><</i>10⁻⁸ for QSYQ-treated cells. (E) Cell lysates were collected for total protein extraction, followed by immunobloting using anti-PAI 1 and anti-Snail antibodies. *p = 0.002 vs TGF-β1 and QSYQ untreated cells (PAI 1), p = 0.001 (Snail). ANOVA, p<i><</i>10⁻⁸ for QSYQ-treated cells. Data are expressed as the mean ± SD of three independent experiments.</p

QSYQ blocked β-catenin up-regulation and downstream gene transcription in UUO kidney.

<p>Rats received vehicle or QSYQ at an oral dose of 250 or 500mg/kg/d following UUO, and were sacrificed at day 14. (A) Immunohistochemical staining of β-catenin. (B) Representative bands (two cases) of Western blot analyses for the expression of TGF-β and β-catenin in the obstructed kidneys. * p<i><</i>10⁻⁸ vs sham operation groups. ANOVA, <i>p<</i>10⁻⁸ in QSYQ-treated rats. (C) Real-time PCR analyses of PAI1 and snail. (D) Western blot analyses of PAI 1 and snail. * p<i><</i>10⁻⁸ vs sham operation groups. # p<i><</i>10⁻⁸ vs. UUO groups (PAI 1) and p = 0.001 (Snail); n = 6 for each group.</p

QSYQ attenuated renal interstitial fibrosis in UUO.

<p>Rats received vehicle or QSYQ at an oral dose of 250 or 500 mg/kg/d following UUO, and were sacrificed at day 14. (A) Schematic presentation of the experimental design. (B) HE and Masson trichrome staining in the obstructed kidney. (C) Real-time PCR of α-SMA, collagen I, and fibronectin. (D) Immunohistochemical staining of α-SMA, collagen I, and fibronectin. (E) Representative bands (two cases) of Western blot analyses for the expression of α-SMA, collagen I, and fibronectin in the obstructed kidneys. *<i>p<</i>10⁻⁸ vs sham operation group. ANOVA, <i>p<</i>10⁻⁸ in QSYQ-treated rats in B, C, and E; n = 6 for each group.</p

QSYQ dose-dependently inhibited the fibrotic activity mediated by TGF-β1 in NRK 52E cells.

<p>NRK 52E cells were pre-incubated with QSYQ (5, 10, and 20 μg/ml) for 1h before TGF-β1 (10 ng/ml) treatment. Cells were harvested 36h after TGF-β1 stimulation for real-time PCR and 48h after TGF-β1 stimulation for Western blot analyses, respectively. (A) Real-time PCR analyses of α-SMA, collagen I, and fibronectin. *p = 0.002 vs. TGF-β1 and QSYQ untreated cells (α-SMA), p = 0.001 (collagen I) and p = <i><</i>10⁻⁸ (fibronectin). ANOVA, p = 0.002 for QSYQ-treated cells (α-SMA), p = 0.001 (collagen I) and p = 0.002 (fibronectin). (B) Western blot analyses of α-SMA, collagen I, and fibronectin. *p = 0.002 vs. TGF-β1 and QSYQ untreated cells (α-SMA), p = 0.001 (collagen I) and p = 0.001 (fibronectin). ANOVA, p<i><</i>10⁻⁸ for QSYQ-treated cells. Data are expressed as the mean ± SD of three independent experiments.</p

Table2_Adverse events of bevacizumab for triple negative breast cancer and HER-2 negative metastatic breast cancer: A meta-analysis.doc

Background: Triple-negative breast cancer (TNBC) and HER-2 negative metastatic breast cancer (HER-2 negative MBC) are intractable to various treatment schemes. Bevacizumab as a novel anti-VEGF drug, its safety for these two high-risk breast cancers remains controversial. Therefore, we conducted this meta-analysis to assess the safety of Bevacizumab for TNBC and HER-2 negative MBC.Methods: We searched Medline, Embase, Web of science and Cochrane databases updated to 1 Oct 2022 for relevant randomized controlled trials (RCTs). In all, 18 RCTs articles with 12,664 female patients were included. We used any grade Adverse Events (AEs) and grade ≥3 AEs to assess the AEs of Bevacizumab.Results: Our study demonstrated that the application of Bevacizumab was associated with increased incidence of grade ≥3 AEs (RR = 1.37, 95% CI 1.30–1.45, Rate: 52.59% vs. 41.32%). Any grade AEs (RR = 1.06, 95% CI 1.04–1.08, Rate: 64.55% vs. 70.59%) did not show a significant statistical difference in both overall results and among the subgroups. In subgroup analysis, HER-2 negative MBC (RR = 1.57, 95% CI 1.41–1.75, Rate: 39.49% vs. 25.6%), dosage over 15 mg/3w (RR = 1.44, 95% CI 1.07–1.92, Rate: 28.67% vs. 19.93%) and endocrine therapy (ET) (RR = 2.32, 95% CI 1.73–3.12, Rate: 31.17% vs. 13.42%) were associated with higher risk of grade ≥3 AEs. Of all graded ≥3 AEs, proteinuria (RR = 9.22, 95%CI 4.49–18.93, Rate: 4.22% vs. 0.38%), mucosal inflammation (RR = 8.12, 95%CI 2.46–26.77, Rate: 3.49% vs. 0.43%), palmar-plantar erythrodysesthesia syndrome (RR = 6.95, 95%CI 2.47–19.57, Rate: 6.01% vs. 0.87%), increased Alanine aminotransferase (ALT) (RR = 6.95, 95%CI 1.59–30.38, Rate: 3.13% vs. 0.24%) and hypertension (RR = 4.94, 95%CI 3.84–6.35, Rate: 9.44% vs. 2.02%) had the top five risk ratios.Conclusion: The addition of Bevacizumab for TNBC and HER-2 negative MBC patients showed an increased incidence of AEs especially for grade ≥3 AEs. The risk of developing different AEs varies mostly dependent on the type of breast cancer and combined therapy.Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/#recordDetails], identifier [CRD42022354743].</p

(±)-Aspongamide A, an <i>N</i>‑Acetyldopamine Trimer Isolated from the Insect <i>Aspongopus chinensis,</i> Is an Inhibitor of p‑Smad3

(±)-Aspongamide A (<b>1</b>), an unusual trimer of <i>N</i>-acetyldopamine (NADA) bearing a novel tetrahydrobenzo­[<i>a</i>]­dibenzo­[<i>b</i>,<i>e</i>]­[1,4]­dioxine structure, and a pair of NADA dimeric enantiomers (<b>2</b>) were isolated from <i>Aspongopus chinensis</i>. The structures of compounds <b>1</b> and <b>2</b> were assigned using spectroscopic methods. Compound <b>1</b> was found to be an inhibitor of Smad3 phosphorylation in transforming growth factor-β1 (TGF-β1) induced rat renal proximal tubular cells and suppressed extracellular matrix expression in mesangial cells under diabetic conditions

Table3_Adverse events of bevacizumab for triple negative breast cancer and HER-2 negative metastatic breast cancer: A meta-analysis.doc

Background: Triple-negative breast cancer (TNBC) and HER-2 negative metastatic breast cancer (HER-2 negative MBC) are intractable to various treatment schemes. Bevacizumab as a novel anti-VEGF drug, its safety for these two high-risk breast cancers remains controversial. Therefore, we conducted this meta-analysis to assess the safety of Bevacizumab for TNBC and HER-2 negative MBC.Methods: We searched Medline, Embase, Web of science and Cochrane databases updated to 1 Oct 2022 for relevant randomized controlled trials (RCTs). In all, 18 RCTs articles with 12,664 female patients were included. We used any grade Adverse Events (AEs) and grade ≥3 AEs to assess the AEs of Bevacizumab.Results: Our study demonstrated that the application of Bevacizumab was associated with increased incidence of grade ≥3 AEs (RR = 1.37, 95% CI 1.30–1.45, Rate: 52.59% vs. 41.32%). Any grade AEs (RR = 1.06, 95% CI 1.04–1.08, Rate: 64.55% vs. 70.59%) did not show a significant statistical difference in both overall results and among the subgroups. In subgroup analysis, HER-2 negative MBC (RR = 1.57, 95% CI 1.41–1.75, Rate: 39.49% vs. 25.6%), dosage over 15 mg/3w (RR = 1.44, 95% CI 1.07–1.92, Rate: 28.67% vs. 19.93%) and endocrine therapy (ET) (RR = 2.32, 95% CI 1.73–3.12, Rate: 31.17% vs. 13.42%) were associated with higher risk of grade ≥3 AEs. Of all graded ≥3 AEs, proteinuria (RR = 9.22, 95%CI 4.49–18.93, Rate: 4.22% vs. 0.38%), mucosal inflammation (RR = 8.12, 95%CI 2.46–26.77, Rate: 3.49% vs. 0.43%), palmar-plantar erythrodysesthesia syndrome (RR = 6.95, 95%CI 2.47–19.57, Rate: 6.01% vs. 0.87%), increased Alanine aminotransferase (ALT) (RR = 6.95, 95%CI 1.59–30.38, Rate: 3.13% vs. 0.24%) and hypertension (RR = 4.94, 95%CI 3.84–6.35, Rate: 9.44% vs. 2.02%) had the top five risk ratios.Conclusion: The addition of Bevacizumab for TNBC and HER-2 negative MBC patients showed an increased incidence of AEs especially for grade ≥3 AEs. The risk of developing different AEs varies mostly dependent on the type of breast cancer and combined therapy.Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/#recordDetails], identifier [CRD42022354743].</p

Table1_Adverse events of bevacizumab for triple negative breast cancer and HER-2 negative metastatic breast cancer: A meta-analysis.doc

Background: Triple-negative breast cancer (TNBC) and HER-2 negative metastatic breast cancer (HER-2 negative MBC) are intractable to various treatment schemes. Bevacizumab as a novel anti-VEGF drug, its safety for these two high-risk breast cancers remains controversial. Therefore, we conducted this meta-analysis to assess the safety of Bevacizumab for TNBC and HER-2 negative MBC.Methods: We searched Medline, Embase, Web of science and Cochrane databases updated to 1 Oct 2022 for relevant randomized controlled trials (RCTs). In all, 18 RCTs articles with 12,664 female patients were included. We used any grade Adverse Events (AEs) and grade ≥3 AEs to assess the AEs of Bevacizumab.Results: Our study demonstrated that the application of Bevacizumab was associated with increased incidence of grade ≥3 AEs (RR = 1.37, 95% CI 1.30–1.45, Rate: 52.59% vs. 41.32%). Any grade AEs (RR = 1.06, 95% CI 1.04–1.08, Rate: 64.55% vs. 70.59%) did not show a significant statistical difference in both overall results and among the subgroups. In subgroup analysis, HER-2 negative MBC (RR = 1.57, 95% CI 1.41–1.75, Rate: 39.49% vs. 25.6%), dosage over 15 mg/3w (RR = 1.44, 95% CI 1.07–1.92, Rate: 28.67% vs. 19.93%) and endocrine therapy (ET) (RR = 2.32, 95% CI 1.73–3.12, Rate: 31.17% vs. 13.42%) were associated with higher risk of grade ≥3 AEs. Of all graded ≥3 AEs, proteinuria (RR = 9.22, 95%CI 4.49–18.93, Rate: 4.22% vs. 0.38%), mucosal inflammation (RR = 8.12, 95%CI 2.46–26.77, Rate: 3.49% vs. 0.43%), palmar-plantar erythrodysesthesia syndrome (RR = 6.95, 95%CI 2.47–19.57, Rate: 6.01% vs. 0.87%), increased Alanine aminotransferase (ALT) (RR = 6.95, 95%CI 1.59–30.38, Rate: 3.13% vs. 0.24%) and hypertension (RR = 4.94, 95%CI 3.84–6.35, Rate: 9.44% vs. 2.02%) had the top five risk ratios.Conclusion: The addition of Bevacizumab for TNBC and HER-2 negative MBC patients showed an increased incidence of AEs especially for grade ≥3 AEs. The risk of developing different AEs varies mostly dependent on the type of breast cancer and combined therapy.Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/#recordDetails], identifier [CRD42022354743].</p