PMID: 

Mol Med Rep. 2020 Feb ;21(2):641-648. Epub 2019 Dec 17. PMID: 31974615

Abstract Title: 

Crocetin alleviates myocardial ischemia/reperfusion injury by regulating inflammation and the unfolded protein response.

Abstract: 

Crocetin, a natural compound, has been demonstrated to exhibit beneficial effects in cardiovascular diseases. Previous studies demonstrated that crocetin reduced ischemia/reperfusion (I/R) injury by attenuating cytotoxicity and cellular apoptosis. However, the previous mechanistic studies did not fully elucidate its pharmacological effects on cardiac damage, especially I/R injury. The present study verified its cardioprotective effects in a Langendorff perfusion system, an ex vivo model of I/R. It was demonstrated that crocetin significantly attenuated the activities of pro‑inflammatory cytokines and nuclear factor erythroid‑2 related factor 2 (Nrf2)/heme oxygenase‑1 signaling. The present study provided novel insight that crocetin regulated the unfolded proteinresponse (UPR) and decreased associated protein levels to protect the heart. Furthermore, it was identified that Nrf2 played a key role in the cardioprotective effect of crocetin by attenuating inflammation and the UPR.

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PMID: 

Neural Regen Res. 2020 Aug ;15(8):1408-1416. PMID: 31997799

Abstract Title: 

Beneficial effects of saffron (L.) in ocular pathologies, particularly neurodegenerative retinal diseases.

Abstract: 

Saffron (Crocus sativus L.) has been traditionally used in food preparation and as a medicinal plant. It currently has numerous therapeutic properties attributed to it, such as protection against ischemia, as well as anticonvulsant, antidepressant, anxiolytic, hypolipidemic, anti-atherogenic, anti-hypertensive, antidiabetic, and anti-cancer properties. In addition, saffron has remarkable beneficial properties, such as anti-apoptotic, anti-inflammatory and antioxidant activities, due to its main metabolites, among which crocin and crocetin stand out. Furthermore, increasing evidence underwrites the possible neuroprotective role of the main bioactive saffron constituents in neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, both in experimental models and in clinical studies in patients. Currently, saffron supplementation is being tested for ocular neurodegenerative pathologies, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration and glaucoma, among others, and shows beneficial effects. The present article provides a comprehensive and up to date report of the investigations on the beneficial effects of saffron extracts on the main neurodegenerative ocular pathologies and other ocular diseases. This review showed that saffron extracts could be considered promising therapeutic agents to help in the treatment of ocular neurodegenerative diseases.

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PMID: 

Environ Sci Pollut Res Int. 2020 Jan 22. Epub 2020 Jan 22. PMID: 31965510

Abstract Title: 

Carnosic acid alleviates chlorpyrifos-induced oxidative stress and inflammation in mice cerebral and ocular tissues.

Abstract: 

Chlorpyrifos is an organophosphate pesticide whose exposure leads to inhibition of acetylcholinesterase (AChE) enzyme and induces oxidative stress, inflammation, and neurotoxicity. The current study was designed to evaluate the efficacy of carnosic acid (CA) in ameliorating CPF-induced cytotoxicity in mice brain and eye tissues. We allocated 40 male Swiss albino mice to receive DMSO 1% solution, oral CA 60 mg/kg/day bw, CPF 12 mg/kg/day bw via gastric gavage, or CPF plus CA at 30 and 60 mg/kg/day bw. Carnosic acid was administered once/day for 14 days, while CPF was administered in the last 7 days of the experiment. Biochemical analysis showed that CPF administration was associated with significant increases in the serum concentrations of interleukin-1β, IL-6, and tumor necrosis factor-α, while it was associated with significant reductions in serum AChE levels in mice. Moreover, CPF-intoxicated mice exhibited significantly higher levels of malondialdehyde and nitric oxide in the brain and eye tissues. However, they had significantly lower levels of reduced glutathione, glutathione peroxidase, superoxide dismutase, and catalase in comparison with normal controls. Pretreatment with CA at 30 and 60 mg/kg/day bw for 14 days significantly alleviated all the aforementioned CPF-inducedalterations in a dose-dependent manner; more frequent restorations of the normal control ranges were observed in the higher dose group. In conclusion, CA offers a neuroprotective effect against CPF-induced oxidative stress and inflammation and should be further studied in upcoming experimental and clinical research.

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PMID: 

Cancers (Basel). 2020 Jan 22 ;12(2). Epub 2020 Jan 22. PMID: 31979093

Abstract Title: 

Phenethyl Isothiocyanate Suppresses Stemness in the Chemo- and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin.

Abstract: 

Resistance to chemotherapy and radiation therapy is considered a major therapeutic barrier in breast cancer. Cancer stem cells (CSCs) play a prominent role in chemo and radiotherapy resistance. The established chemo and radio-resistant triple-negative breast cancer (TNBC) cell line MDA-MB-231/IR displays greater CSC characteristics than the parental MDA-MB-231 cells. Escalating evidence demonstrates that metadherin (MTDH) is associated with a number of cancer signaling pathways as well as breast cancer therapy resistance, making it an attractive therapeutic target. Kaplan-Meier plot analysis revealed a correlation between higher levels of MTDH and shorter lifetimes in breast cancer and TNBC patients. Moreover, there was a positive correlation between the MTDH and CD44 expression levels in The Cancer Genome Atlas breast cancer database. We demonstrate that MTDH plays a pivotal role in the regulation of stemness in MDA-MB-231/IR cells. Knockdown of MTDH in MDA-MB-231/IR cells resulted in a reduction in the CSC population, aldehyde dehydrogenase activity, and major CSC markers, includingβ-catenin, CD44, and Slug. In addition, MTDH knockdown increased reactive oxygen species (ROS) levels in MDA-MB-231/IR cells. We found that phenethyl isothiocyanate (PEITC), a well-known pro-oxidant phytochemical, suppressed stemness in MDA-MB-231/IR cells through ROS modulation via the downregulation of MTDH. Co-treatment of PEITC and N-Acetylcysteine (a ROS scavenger) caused alterations in PEITC induced cell death and CSC markers. Moreover, PEITC regulated MTDH expression at the post-transcriptional level, which was confirmed using cycloheximide, a protein synthesis inhibitor.

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PMID: 

Eur J Med Chem. 2020 Feb 1 ;187:111951. Epub 2019 Dec 4. PMID: 31821990

Abstract Title: 

Potential cytotoxic and anti-metastatic effects of berberine on gynaecological cancers with drug-associated resistance.

Abstract: 

Gynaecological disorders, such as cervical, ovarian, and endometrial cancers are the second most prevalent cancer types in women worldwide. Therapeutic approaches for gynaecological cancers involve chemotherapy, radiation, and surgery. However, lifespan is not improved, and novel medications are required. Among various phytochemicals, berberine, a well-known natural product, has been shown to be a promising cancer chemopreventive agent. Pharmacokinetics, safety, and efficacy of berberine have been investigated in the several experiments against numerous diseases. Here, we aimed to provide a literature review from available published investigations showing the anticancer effects of berberine and its various synthetic analogues against gynaecological disorders, including cervical, ovarian, and endometrial cancers. In conclusion, berberine has been found to efficiently inhibit viability, proliferation, and migration of cancer cells, mainly, via induction of apoptosis by both mitochondrial dependent and -independent pathways. Additionally, structural modification of berberine showed that berberine analogues can improve its antitumor effects against gynaecological cancers.

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PMID: 

J BUON. 2019 Sep-Oct;24(5):1870-1875. PMID: 31786849

Abstract Title: 

Berbamine exerts anticancer effects on human colon cancer cells via induction of autophagy and apoptosis, inhibition of cell migration and MEK/ERK signalling pathway.

Abstract: 

PURPOSE: Berbamine is a plant-derived alkaloid with amazing and wide diversity of pharmacological properties which range from antimicrobial and anticancer. Nonetheless, the anticancer properties of Berbamine have not been thoroughly evaluated against colon cancer cells. This study was undertaken to evaluate the anticancer effects of Berbamine against human colon cancer cells (HT-29 colon cancer cells).Μethods: CCK-8 assay was used to determine the cell viability. DAPI and propidium iodide (PI) staining assays were used for the detection of apoptosis. Electron microscopy was used for the determination of autophagy. Wound healing assay was used to monitor cell migration. Protein expression was determined by western blotting.RESULTS: The results showed that Berbamine caused a remarkable decrease in the HT-29 cell viability with an IC50 of 14µM, while the high IC50 of Berbamine against the normal CDD-18Co cells indicated low toxicity of this molecule against the normal cells. DAPI and PI staining assays showed nuclear fragmentation, indicative of apoptosis in HT-29 cells. Berbamine also caused activation of caspase-3 and 9 and increased the Bax/Bcl-2 ratio. Electron microscopic analysis showed that Berbamine triggered the development of autophagic vesicles in the HT-29 cells which was concomitant with the increase in protein levels of LC3B-I, ATG-5, ATG-12 and Beclin-1. Wound healing assay showed that Berbamine decreased the migration potential of the HT-29 and also blocked the MEK/ERK signalling pathway in colon cancer cells.CONCLUSION: Berbamine may prove an efficient lead molecule for the development of more potent anticancer agents through semi-synthetic approaches.

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PMID: 

Onco Targets Ther. 2019 ;12:11437-11451. Epub 2019 Dec 24. PMID: 31920333

Abstract Title: 

Berbamine Enhances the Efficacy of Gefitinib by Suppressing STAT3 Signaling in Pancreatic Cancer Cells.

Abstract: 

Background: Small molecular inhibitors such as gefitinib (Gefi), which target EGF receptor (EGFR), are considered to be a viable pathway for the selective inhibition of pancreatic cancer (PC) development. However, the large difference in Gefi response between PC patient individuals and PC cell lines severely limits the clinical efficacy of Gefi. Berbamine (BBM) is a well-known natural-derived antitumor agent. However, no study yet exists on whether BBM can enhance the sensitivity of PC cells to Gefi or its underlying mechanisms.Methods: MTS assay and clonogenic assay were used to determine whether BBM could enhance the anti-PC activity of Gefi by. Flow cytometric analysis was performed to study the cell cycle progression and rate of apoptosis after combined treatment with BBM and Gefi. Surface plasmon resonance (SPR) and Western blot experiments were carried out to detect the STAT3 binding affinity and the STAT3 inhibitory effect of BBM. Molecular docking and Molecular dynamic simulation were used to predicting the dominant interaction between BBM and STAT3.Results: This study found that BBM synergizes with Gefi to inhibit cell growth and induce cell cycle arrest and PC cell apoptosis. Mechanistically, our results showed that BBM and Gefi have synergistic inhibitory effects on STAT3 phosphorylation, but have little effect on other EGFR downstream pathways, suggesting that BBM may exert sensitization through the inhibition of STAT3. Besides, BBM has a high affinity for STAT3 and a good inhibitory effect on STAT3 activation, further indicating that BBM was a potent direct STAT3 inhibitor. Molecular modeling between STAT3 and BBM suggested that BBM formed several key hydrophilic interactions with STAT3.Conclusion: Our findings suggest that the combination of BBM and Gefi could be further developed as a potential PC therapy.

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PMID: 

Environ Sci Pollut Res Int. 2019 Dec 16. Epub 2019 Dec 16. PMID: 31845254

Abstract Title: 

Hepatoprotective role of berberine against paraquat-induced liver toxicity in rat.

Abstract: 

Paraquat (PQ) is a herbicide agent commonly used in agricultural applications. Hepatotoxicity is among clinical complications associated with PQ intoxication. Oxidative stress and its subsequent events are major mechanisms identified in PQ-induced liver toxicity. Berberine (BBR) is a natural antioxidant widely investigated for its hepatoprotective effects. The present study designed to evaluate the potential cytoprotective properties of BBR against PQ-induced cytotoxicity in primary cultured rat hepatocytes and in vivo test of liver function enzymes. Cellular and biochemical parameters including lactate dehydrogenase (LDH), cell viability, ROS formation, glutathione (GSH) content, and mitochondrial membrane potential in the PQ-treated hepatocytes were measured, and the mentioned markers were evaluated in the presence of BBR. BBR treatment caused significant decrease in PQ-induced cell death, ROS formation, and LDH release. On the other hand, it was found that BBR inhibits cellular glutathione depletion in PQ-treated hepatocytes. Also, BBR treatment significantly diminished PQ-induced the liver function enzyme elevation. These data mention the potential hepatoprotective effect of BBR with therapeutic capability against PQ-induced liver damage.

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PMID: 

Appl Microbiol Biotechnol. 2020 Feb ;104(4):1737-1749. Epub 2019 Dec 23. PMID: 31867696

Abstract Title: 

Berberine ameliorates colonic damage accompanied with the modulation of dysfunctional bacteria and functions in ulcerative colitis rats.

Abstract: 

Intestinal flora imbalance is one of the potential pathogenesis of inflammatory bowel diseases, and the study aims to discover the effect of berberine on the composition and function of gut microbiota in ulcerative colitis (UC) rats. UC rats were induced by dextran sulfate sodium (DSS) and administrated with berberine. Colonic morphological changes and claudin-1 protein of colon tissues were primarily examined to validate the protective effects brought by berberine treatment. Then the composition and function of gut microbiota were analyzed, accompanied with quantitative analysis of serum amino acids. The results showed that berberine could not only ameliorate the colonic damages in DSS-induced UC rats but also regulate the gut microbiota by increasing lactic acid-producing bacteria and carbohydrate hydrolysis bacteria as well as decreasing conditional pathogenic bacteria. Accordingly, the relevant functions of above bacteria were improved, including the metabolism and biosynthesis of amino acids, capability of DNA replication and repair, carbohydrate digestion and absorption and glycolysis/gluconeogenesis. Furthermore, the serum amino acids were regulated and showed high correlation with the gut microbiota after berberine treatment. In conclusion, the study confirms the effect of berberine on ameliorating the colonic damage and highlights some specific bacteria and relevant functions linked with berberine treatment, exploring the potential of gut microbiota as a diagnostic biomarker or a therapeutic target in UC treatment.

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PMID: 

Biochem Pharmacol. 2019 Dec 23 ;174:113776. Epub 2019 Dec 23. PMID: 31874145

Abstract Title: 

Berberine suppresses colon cancer cell proliferation by inhibiting the SCAP/SREBP-1 signaling pathway-mediated lipogenesis.

Abstract: 

Lipid metabolism is a significant section of energy homeostasis, and it affects the development of various cancers. Previous studies have revealed that berberine has strong anticancer and blood lipid-lowering effects. Here, we further investigated the effects of berberine on cell proliferation and lipogenesis in colon cancer cells and the relationship between the two effects. We found that berberine inhibited cell proliferation by inducing G0/G1 phase cell cycle arrest in colon cancer cells. Moreover, the expressions of key lipogenic enzymes were down-regulated by berberine and led to the suppressed lipid synthesis, which was linked to cell proliferation via Wnt/β-catenin pathway. Importantly, berberine inhibited sterol regulatory element-binding protein-1 (SREBP-1) activation and SREBP cleavage-activating protein (SCAP) expression, resulting in the downregulation of these lipogenic enzymes. Knockdown of SCAP by shRNA could abolish the effect of berberineon SREBP-1 activation. Besides the inhibitory effects in vitro, berberine suppressed the growth and lipogenesis of colon cancer xenograft in a SCAP-dependent manner as well. Together, our results suggest that berberine may serve as a candidate against tumor growth of colon cancer partially through targeting SCAP/SREBP-1 pathway driving lipogenesis.

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