Silibinin Inhibits Neutrophilic Inflammation and Mucus Secretion Induced by Cigarette Smoke via Suppression of ERK‐SP1 Pathway

Silibinin, the main ingredient of silymarin, has been used as a traditional drug for over 2000 years to treat a range of liver diseases. Recent studies have also demonstrated that silibinin possesses antiinflammatory and anticancer properties. In the study, we researched the efficacy of silibinin on the development of COPD using a cigarette smoke (CS)‐induced and lipopolysaccharide (LPS)‐induced COPD model mice and stimulation of NCI‐H292 cells with CS condensate. Silibinin was administered to mice by oral gavage 1 h before CS exposure for 10 days. In in vitro experiment, we evaluated the effect of silibinin on the expression of MUC5AC in H292 cells stimulated with CS condensate. Furthermore, silibinin suppressed the CS and LPS treatment‐induced extracellular signal‐regulated kinase (ERK) phosphorylation and SP‐1 expression. Silibinin also decreased airway inflammation and reduced the expression of MUC5AC and myeloperoxidase. Furthermore, co‐treatment with silibinin and ERK inhibitors considerably decreased the levels of pro‐inflammatory mediators, ERK phosphorylation, and SP‐1 expression. Taken together, the results indicate that silibinin effectively suppressed the neutrophilic airway inflammation provoked by treatment with LPS and CS, which was closely associated with downregulation of ERK phosphorylation. Therefore, our searching offers that silibinin has a remedical probable for COPD disease. Copyright © 2016 John Wiley & Sons, Ltd.     

Cisplatin nephrotoxicity and protection by silibinin

BACKGROUND: The anticancer drug cisplatin is known to have toxic side-effectson different segments of the nephron. The flavonoid silibininhas previously been shown to be protective in models of hepatotoxicity.The aim of the present study was to evaluate, whether silibinincan also ameliorate alterations in renal glomerular and tubularfunction and tubular morphology induced by cisplatin. METHODS: In a rat model renal damage was induced by a single injectionof cisplatin (5 mg/kg body weight). The protective effects ofsilibinin were studied in rats that received the flavonoid (200mg/kg body weight, i.v.) 1 h prior to the administration ofcisplatin. Kidney function was monitored by analysing urinarymarkers of glomerular and tubular function over a period of11 days. Animals of a second group, with identical treatment,were sacrificed 4 days after drug application for an evaluationof tubular morphology at the light-microscopical level. RESULTS: Administration of cisplatin caused a decline in kidney functionwithin a day following treatment. Symptoms observed were forexample decreases in creatinine clearance and increases in proteinuria,in the urinary activity of the proximal tubular enzymes alanineaminopeptidase and N-acetyl-ß-D-glucosaminidase andin renal magnesium wasting. The effects of cisplatin on creatinineclearance and proteinuria were totally prevented by a pretreatmentof the animals with silibinin. Impairment of proximal tubularfunction was ameliorated, that is enzymuria and magnesium wastingwas less pronounced. Silibinin alone had no effect on kidneyfunction. Treatment with silibinin distinctly diminished morphologicalalterations observed in the S₃-segment of the proximal tubule4 days after cisplatin administration. CONCLUSIONS: The effects of cisplatin on glomerular and proximal tubularfunction as well as proximal tubular morphology could totallyor partly be ameliorated by silibinin. It is concluded thatsilibinin can act as a nephroprotectant and it is suggestedthat it could have beneficial effects on the kidney in clinicalsettings.     

水飞蓟宾固体分散体的制备及体外溶出研究

目的：制备了水飞蓟宾的固体分散体,并检测其体外溶解度及溶出速度。方法：选择尿素、聚乙烯吡咯烷酮（ＰＶＰ）、泊洛沙姆１８８等３种载体,用熔融法和共沉淀法制备水飞蓟宾固体分散体,并进行差热分析,Ｘ－射线粉末衍射分析以鉴别药物在载体中的存在状态,最后进行了体外溶出研究。结果：水飞蓟宾在ＰＶＰ中以无定型存在,在泊洛沙姆１８８中以微细结晶存在,在尿素中大部分仍以晶体形式存在,少量以分子状态存在。溶出研究结果表明泊洛沙姆１８８载体的水飞蓟宾固体分散体的溶解度最大,溶出速度最快。结论：泊洛沙姆是提高水飞蓟宾溶解度及溶出速度的理想载体。     

Synergistic Growth Inhibitory Effects of Chrysin and Metformin Combination on Breast Cancer Cells through hTERT and Cyclin D1 Suppression

Objective: To explore the possibility of a novel chemopreventive strategy for improving breast cancer treatment,the anticancer effects of a combination two natural compounds, Chrysin and Metformin, against T47D breast cancercells were investigated. Materials and Methods: After treatment of T47D cells with Metformin, Chrysin and the twodrugs in combination, toxicity to cancer cells was evaluated by MTT assay. Real time PCR was then used to determinethe expression levels of hTERT and cyclin D1 genes. Results: The MTT test findings showed that the combination ofmetformin and chrysin had high synergistic effects in killing cancer cells. In addition PCR demonstrated a significantdecrease in cyclin D1 and hTERT gene expression in the T47D breast cancer cell line. Conclusion: The conmbinationof metformin and chrysin suppressing hTERT and cyclin D1 gene expression might offer an appropriate approach forbreast cancer therapy.     

Silibinin protects rat pancreatic β‐cell through up‐regulation of estrogen receptors' signaling against amylin‐ or Aβ1–42‐induced reactive oxygen species/reactive nitrogen species generation

Amylin and amyloid‐β (Aβ) were found to induce reactive oxygen species (ROS) and reactive nitrogen species (RNS) in rat pancreatic β‐cell line, INS‐1 cells, leading to cell death. In this study, we report on reciprocal relationship between the expression of estrogen receptors (ERs) α and β (ERα and ERβ) and generation of ROS/RNS in amylin/Aβ_1–42‐treated INS‐1 cells. That is, pharmacological activation of ERs in INS‐1 cells significantly decreases ROS/RNS generation, but blockage of ERs increases ROS/RNS generation. Silibinin is a natural polyphenolic flavonoid isolated from milk thistle with phytoestrogen activities, also known as silybin. Treatment with silibinin down‐regulated ROS/RNS production induced by treatment with amylin/Aβ_1–42 in the cells. Silencing ERs expression with siRNAs targeting ERs showed that the protective effect of silibinin was markedly weakened, indicating that silibinin protection is largely attributed to activation of ERs' signaling. The binding of silibinin to ERs implies that the protective effect of silibinin on amylin/Aβ_1–42‐treated INS‐1 cells owes to down‐regulation of ROS/RNS through the activation of ERs phosphorylation. Amylin and Aβ_1–42 cotreatment enhanced furthermore ROS/RNS generation and cytotoxicity through further down‐regulation of ERs phosphorylation, and this was reversed by silibinin. Silibinin also protects INS‐1 cells from amylin and Aβ_1–42 cotreatment. These results indicate that protective effect of silibinin is mediated by enhancement of ERs phosphorylation that depresses ROS/RNS generation in amylin/Aβ_1–42‐treated INS‐1 cells.     

水飞蓟宾联合顺铂诱导人肺腺癌细胞A549凋亡及机制

目的探讨水飞蓟宾联合顺铂对人肺癌细胞A549的杀伤效应及机制。方法将人肺癌细胞A549分别用水飞蓟宾、顺铂及两者联合干预后,采用MTT法检测不同干预方案对A549细胞的抑制作用,流式细胞术检测细胞凋亡情况,Western blot法检测细胞Bcl-2与Bax的表达;利用小RNA抑制Bax的表达后,观察水飞蓟宾联合顺铂对A549细胞凋亡的诱导作用。结果水飞蓟宾联合顺铂对A549细胞增殖的抑制率(69.9±6.8)%,凋亡率(53.5±4.2)%;水飞蓟宾对A549细胞增殖的抑制率(6.9±0.7)%,凋亡率(7.9±1.5)%;顺铂分别为(13.3±2.9)%和(16.8±2.2)%。水飞蓟宾联合顺铂治疗A549细胞的增殖抑制率和凋亡率均优于单用水飞蓟宾和顺铂治疗组(P0.05)。水飞蓟宾联合顺铂诱导A549细胞凋亡依赖于细胞内Bcl-2/Bax的比值,当转染Bax si RNA后,水飞蓟宾联合顺铂对A549的凋亡诱导率为(27.6±3.0)%,未转染Bax si RNA则两者联合治疗A549凋亡诱导率为(50.6±4.7)%,差异有统计学意义(P0.05)。结论水飞蓟宾联合顺铂通过降低Bcl-2/Bax比例诱导人肺癌细胞发生凋亡。     

水飞蓟宾通过降低MEK/ERK途径依赖的MMP9蛋白表达抑制人乳腺癌细胞的侵袭转移

目的：探讨水飞蓟宾对人乳腺癌细胞生长和侵袭转移的影响及机制。方法：用不同浓度水飞蓟宾处理人乳腺癌细胞系MCF-7 24h,用MTT法和台盼蓝染色法检测水飞蓟宾对MCF-7细胞的抑制作用;用transwell技术检测水飞蓟宾对MCF-7细胞侵袭转移的影响;Western blot检测水飞蓟宾对MCF-7细胞MEK及ERK蛋白磷酸化水平及MMP9表达水平的影响。结果：水飞蓟宾可显著抑制MCF-7细胞的增殖并造成肿瘤细胞死亡;水飞蓟宾通过抑制MEK和ERK的磷酸化降低MMP9的表达并抑制MCF-7细胞侵袭转移的能力。结论：水飞蓟宾抑制人乳腺癌细胞的生长和侵袭转移。     

Synthesis and Antiproliferative Activity of Silybin Conjugates with Salinomycin and Monensin

Aiming at development of multitarget drugs for the anticancer treatment, new silybin ( SIL ) conjugates with salinomycin ( SAL ) and monensin ( MON ) were synthesized, in mild esterification conditions, and their antiproliferative activity was studied. The conjugates obtained exhibit anticancer activity against HepG2, LoVo and LoVo/DX cancer cell lines. Moreover, MON ‐ SIL conjugate exhibits higher anticancer potential and better selectivity than the corresponding SAL ‐ SIL conjugate.     

Silibinin prevents amyloid β peptide-induced memory impairment and oxidative stress in mice

Background and purpose:

Accumulated evidence suggests that oxidative stress is involved in amyloid β (Aβ)-induced cognitive dysfunction. Silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybum marianum), has been shown to have antioxidative properties; however, it remains unclear whether silibinin improves Aβ-induced neurotoxicity. In the present study, we examined the effect of silibinin on the memory impairment and accumulation of oxidative stress induced by Aβ_25–35 in mice.

Experimental approach:

Aggregated Aβ_25–35 (3 nmol) was intracerebroventricularly administered to mice. Treatment with silibinin (2, 20 and 200 mg·kg⁻¹, once a day, p.o.) was started immediately after the injection of Aβ_25–35. Locomotor activity was evaluated 6 days after the Aβ_25–35 treatment, and cognitive function was evaluated in a Y-maze and novel object recognition tests 6–11 days after the Aβ_25–35 treatment. The levels of lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the hippocampus were measured 7 days after the Aβ_25–35 injection.

Key results:

Silibinin prevented the memory impairment induced by Aβ_25–35 in the Y-maze and novel object recognition tests. Repeated treatment with silibinin attenuated the Aβ_25–35-induced accumulation of malondialdehyde and depletion of glutathione in the hippocampus.

Conclusions and implications:

Silibinin prevents memory impairment and oxidative damage induced by Aβ_25–35 and may be a potential therapeutic agent for Alzheimer''s disease.