Comparative Study on the Role of Berberine and Berberis lycium Royle Roots Extract against the Biochemical Markers and Cyclin D1 Expression in HCC Animal Model

Diethylamine nitrosamine (DEN), as an initiator of liver tumor, and carbon tetrachloride (CCl4), as a tumor promoter, have been used to study the molecular events of liver cancer in animal models. Recently, our in vitro study reported BLE (Berberis lycium Royle ethanol extract) as the most effective agent against liver cancer, thus we continued our study in vivo to assess the hepatoprotective effect of BLE and its most active alkaloid, berberine, in albino mice (70 male). Moreover, we investigated the biochemical/immunohistochemical effects of a single alkaloid versus the effect of Berberis extract in mice liver. Hepatic cancer was induced in mice by a single intraperitoneal injection with DEN (100 mg/kg b.wt), followed by biweekly injections of CCl4 (0.5 mL/kg) for 30 days. The development of liver cancer was assessed after 60 days of DEN injection by measuring the elevated level of the serum tumor marker alpha-fetoprotein (AFP) and liver function test (ALT, AST, ALP, and BUN) markers. After the confirmation of liver cancer development, the BLE extract and berberine were fed to mice for 90 days and the serum biomarkers for liver injury (LFTs and AFP) were measured again. Overall, berberine (120 mg/kg b.wt) proved to be a stronger agent in reducing the symptoms of HCC in mice, as compared with BLE. Histopathological analysis agreed well with the biochemical observations. Immunohistochemistry analysis suggested significant suppression of the quantitative expression of the key oncogene cyclin D1 at low (60 mg/kg) and high (120 mg/kg) doses of berberine. These findings implicate the amelioration of hepatocarcinoma by berberine more prominently in mice, by suppression of cyclin-dependent kinase activator (CD1) expression, reducing LFTs, as well as AFP, in the serum. Thus, our findings are novel, as berberine may help in controlling the perturbation in CD1 associated with aggressive forms of HCC. However, future studies should be directed at finding out whether berberine has any effect on inhibitors (p27 and CDKI) of cyclin-dependent kinase too.

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Opposite Effects of Single-Dose and Multidose Administration of the Ethanol Extract of Danshen on CYP3A in Healthy Volunteers

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/730734 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Furong Qiu ◽

Jian Jiang ◽

Yueming Ma ◽

Guangji Wang ◽

Chenglu Gao ◽

...

Keyword(s):

Single Dose ◽

Healthy Volunteers ◽

Plasma Concentrations ◽

In Vitro Study ◽

Ethanol Extract ◽

Tanshinone Iia ◽

Open Label ◽

The Mean

The aim of this study was to investigate the effect of single- and multidose administration of the ethanol extract of danshen on in vivo CYP3A activity in healthy volunteers. A sequential, open-label, and three-period pharmacokinetic interaction study design was used based on 12 healthy male individuals. The plasma concentrations of midazolam and its metabolite 1-hydroxymidazolam were measured. Treatment with single dose of the extract caused the meanCmaxof midazolam to increase by 87% compared with control. After 10 days of the danshen extract intake, the mean AUC0–12,Cmax, andt1/2of midazolam were decreased by 79.9%, 66.6%, and 43.8%, respectively. The mean clearance of midazolam was increased by 501.6% compared with control. The in vitro study showed that dihydrotanshinone I in the extract could inhibit CYP3A, while tanshinone IIA and cryptotanshinone could induce CYP3A. In conclusion, a single-dose administration of the danshen extract can inhibit intestinal CYP3A, but multidose administration can induce intestinal and hepatic CYP3A.

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A dominant-negative cyclin D1 mutant prevents nuclear import of cyclin-dependent kinase 4 (CDK4) and its phosphorylation by CDK-activating kinase.

Molecular and Cellular Biology ◽

10.1128/mcb.17.12.7362 ◽

1997 ◽

Vol 17 (12) ◽

pp. 7362-7374 ◽

Cited By ~ 117

Author(s):

J A Diehl ◽

C J Sherr

Keyword(s):

Cyclin D1 ◽

Nuclear Localization ◽

Mammalian Cells ◽

Phosphorylation Site ◽

Dominant Negative ◽

Cyclin Dependent Kinase ◽

Linker Peptide ◽

Cdk Activating Kinase

Cyclins contain two characteristic cyclin folds, each consisting of five alpha-helical bundles, which are connected to one another by a short linker peptide. The first repeat makes direct contact with cyclin-dependent kinase (CDK) subunits in assembled holoenzyme complexes, whereas the second does not contribute directly to the CDK interface. Although threonine 156 in mouse cyclin D1 is predicted to lie at the carboxyl terminus of the linker peptide that separates the two cyclin folds and is buried within the cyclin subunit, mutation of this residue to alanine has profound effects on the behavior of the derived cyclin D1-CDK4 complexes. CDK4 in complexes with mutant cyclin D1 (T156A or T156E but not T156S) is not phosphorylated by recombinant CDK-activating kinase (CAK) in vitro, fails to undergo activating T-loop phosphorylation in vivo, and remains catalytically inactive and unable to phosphorylate the retinoblastoma protein. Moreover, when it is ectopically overexpressed in mammalian cells, cyclin D1 (T156A) assembles with CDK4 in the cytoplasm but is not imported into the cell nucleus. CAK phosphorylation is not required for nuclear transport of cyclin D1-CDK4 complexes, because complexes containing wild-type cyclin D1 and a CDK4 (T172A) mutant lacking the CAK phosphorylation site are efficiently imported. In contrast, enforced overexpression of the CDK inhibitor p21Cip1 together with mutant cyclin D1 (T156A)-CDK4 complexes enhanced their nuclear localization. These results suggest that cyclin D1 (T156A or T156E) forms abortive complexes with CDK4 that prevent recognition by CAK and by other cellular factors that are required for their nuclear localization. These properties enable ectopically overexpressed cyclin D1 (T156A), or a more stable T156A/T286A double mutant that is resistant to ubiquitination, to compete with endogenous cyclin D1 in mammalian cells, thereby mobilizing CDK4 into cytoplasmic, catalytically inactive complexes and dominantly inhibiting the ability of transfected NIH 3T3 fibroblasts to enter S phase.

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Chrysanthemum indicum Attenuates Cisplatin-induced Nephrotoxicity both in vivo and in vitro

Natural Product Communications ◽

10.1177/1934578x1501000306 ◽

2015 ◽

Vol 10 (3) ◽

pp. 1934578X1501000 ◽

Cited By ~ 3

Author(s):

Tae-Won Kim ◽

Young-Jung Kim ◽

So-Ra Park ◽

Chang-Seob Seo ◽

Hyekyung Ha ◽

...

Keyword(s):

Protective Effect ◽

Inflammatory Diseases ◽

In Vitro Study ◽

Ethanol Extract ◽

Sprague Dawley ◽

Pk15 Cell ◽

P53 Expression ◽

Chrysanthemum Indicum

Chrysanthemum indicum Linné has been used in traditional medicine to treat various inflammatory diseases in East Asia. The aim of the present study was to investigate the protective effect of C. indicum ethanol extract (CILE) against cisplatin-induced nephrotoxicity. An HPLC-photodiode array method was used for fingerprint analysis of the CILE and ten major constituents were quantitatively analyzed. The protective effect of CILE on cisplatin-induced nephrotoxicity was assessed using both in vitro (porcine kidney cell; PK15 cell) and in vivo (Sprague Dawley rat) experiments. In the in vitro study, CILE enhanced PK15 cell viability after cisplatin treatment with recovered antioxidant status. Moreover, the increased p53 expression after cisplatin treatment was decreased in the CILE pretreated cells. In the in vivo study, SD rats were treated for 28 consecutive days with CILE (0, 100, 300 and 500 mg/kg). On day 23, a single dose of cisplatin (5 mg/kg) was injected to induce nephrotoxicity. The CILE pretreated group showed recovered serum renal function index with ameliorated oxidative stress. Histopathological alterations and apoptosis in the kidney were also decreased in CILE pretreated rats. Taken together, CILE could attenuate cisplatin-induced nephrotoxicity and might be a beneficial agent for acute renal failure management.

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Arsenic trioxide-loaded CalliSpheres: In vitro study of drug release and antitumor activity, and in vivo study of pharmacokinetics, treatment efficacy and safety in liver cancer

Oncology Reports ◽

10.3892/or.2021.8075 ◽

2021 ◽

Vol 46 (1) ◽

Author(s):

Xuhua Duan ◽

Guorui Zhao ◽

Xinwei Han ◽

Jianzhuang Ren ◽

Hao Li ◽

...

Keyword(s):

Liver Cancer ◽

Antitumor Activity ◽

Drug Release ◽

Arsenic Trioxide ◽

Treatment Efficacy ◽

In Vitro Study ◽

In Vivo Study ◽

Efficacy And Safety

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Melatonin Differentially Modulates NF-кB Expression in Breast and Liver Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180131112304 ◽

2019 ◽

Vol 18 (12) ◽

pp. 1688-1694 ◽

Cited By ~ 7

Author(s):

Jucimara Colombo ◽

Bruna V. Jardim-Perassi ◽

João P.S. Ferreira ◽

Cristine Z. Braga ◽

Nathália M. Sonehara ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Transcription Factor ◽

Liver Cancer ◽

Cancer Cells ◽

Hepg2 Cells ◽

In Vitro Study ◽

Inhibitory Effect

Background: NF-kB (nuclear factor kappa B) is a transcription factor composed of two subunits, p50 and p65, which plays a key role in the inflammatory process. Melatonin has oncostatic, antiangiogenic and antimetastatic properties, and some recent studies have indicated an inhibitory effect of melatonin on NF-kB in some types of cancer. This work aims to investigate the effects of melatonin treatment on the expression of NFkB in breast and liver cancer models. Method: The breast cancer xenographic model was performed using female Balb/c nude athymic mice injected with MDA-MB-231 cells. The animals were treated with 40 mg/Kg of melatonin for 21 days. Volume of the tumors was measured with a digital caliper. Hepatocarcinoma model was developed by using the HepG2 cells in vitro, treated with 1 mM melatonin for 24 h. The expression of NF-kB protein was verified by immunohistochemistry and immunocytochemistry and quantified by optical densitometry, in vivo study and in vitro study, respectively. NF-kB gene expression was performed by quantitative RT-PCR. Results: The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size (P=0.0022). There was a decrease in NF-kB protein staining (P=0.0027) and gene expression (P=0.0185) in mice treated with melatonin. The opposite results were observed for the hepatocarcinoma model. HepG2 cells treated with melatonin showed an increase in the NF-kB immunostaining when compared to control cells (P=0.0042). Conclusion: Our results indicated that the treatment with melatonin was able to decrease both gene and protein expressions of NF-kB in breast cancer cells and, conversely, increase the transcription factor protein expression in hepatocarcinoma cells. These data highlighted a double role in the expression of NF-kB, depending on the cell type. Further studies are needed to better elucidate the action of melatonin in NF-kB, since this transcription factor acts on different signaling pathways that are fundamental for carcinogenesis.

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Tumor-derived exosomal circPSMA1 facilitates the tumorigenesis, metastasis, and migration in triple-negative breast cancer (TNBC) through miR-637/Akt1/β-catenin (cyclin D1) axis

Cell Death and Disease ◽

10.1038/s41419-021-03680-1 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Su-jin Yang ◽

Dan-dan Wang ◽

Shan-liang Zhong ◽

Wen-quan Chen ◽

Feng-liang Wang ◽

...

Keyword(s):

Cyclin D1 ◽

Immune Cells ◽

Tumor Development ◽

Treatment Strategies ◽

Tumor Promoter ◽

Circular Rnas ◽

Proliferation Capacity ◽

Tnbc Cell

AbstractCircular RNAs (circRNAs) are increasingly gaining importance and attention due to their diverse potential functions and their value as diagnostic biomarkers (disease specific). This study aims to explore the novel mechanisms by which exosome-contained circRNAs promote tumor development and metastasis in TNBC. We identified increased circRNA circPSMA1 in TNBC cells, their exosomes, and serum exosomes samples from TNBC patients. The overexpression of circPSMA1 promoted TNBC cell proliferation, migration, and metastasis both in vitro and in vivo. Moreover, we investigated the tumor-infiltrating immune cells (TICs) or stromal components in immune microenvironment (IME), and identified the significant differences in the immune cells between TNBC and non-TNBC samples. Mechanistically, circPSMA1 acted as a “miRNAs sponge” to absorb miR-637; miR-637 inhibited TNBC cell migration and metastasis by directly targeted Akt1, which recognized as a key immune-related gene and affected downstream genes β-catenin and cyclin D1. Subsequent co-culture experiments also demonstrated that exosomes from TNBC carrying large amounts of circPSMA1 could transmit migration and proliferation capacity to recipient cells. Kaplan–Meier plots showed that high expression of Akt1 and low expression of mir-637 are highly correlated with poor prognosis in patients with lymph node metastasis of TNBC. Collectively, all these results reveal that circPSMA1 functions as a tumor promoter through the circPSMA1/miR-637/Akt1-β-catenin (cyclin D1) regulatory axis, which can facilitate the tumorigenesis, metastasis, and immunosuppression of TNBC. Our research proposes a fresh perspective on novel potential biomarkers and immune treatment strategies for TNBC.

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