PMID: 

Int Immunopharmacol. 2019 Jul 31 ;75:105782. Epub 2019 Jul 31. PMID: 31376623

Abstract Title: 

Naringin mitigates myocardial strain and the inflammatory response in sepsis-induced myocardial dysfunction through regulation of PI3K/AKT/NF-κB pathway.

Abstract: 

Sepsis-induced myocardial dysfunction (SIMD) is a manifestation of severe sepsis and is the main cause of increased mortality in sepsis patients. Naringin (Nar) has been reported to possess various biological activities and pharmacological properties. Therefore, the present study was undertaken to evaluate whether Nar can protect rats from the effects of LPS-induced SIMD. SD Rats were pre-treated with Nar (50 and 100 mg/kg) for 7 days before administration of a single dose of LPS (10 mg/kg, i.p.) on the seventh day. We found that Nar treatment markedly improved the global strain and strain rate of longitudinal, circumference, and radial direction (GLS/GLSr, GCS/GCSr, GRS/GRSr) compared to the LPS group. The layer-specific strain decreased gradually from the endocardial layer to epicardial layer, and the most serious damage occurred in the endocardial layer. Moreover, Nar significantly decreased the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and myocardial enzymes (CK, LDH, and AST) induced by LPS and attenuated the inflammation response. Finally, Nar also inhibited NF-κB nuclear translocation and the activity of iNOS in H9c2 cardiomyocytes by activating PI3K/AKT signaling pathway. These results suggest that naringin may possess novel therapeutic potential for protection against LPS-induced myocardial dysfunction.

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PMID: 

Phytother Res. 2019 Jul 24. Epub 2019 Jul 24. PMID: 31342620

Abstract Title: 

Genistein inhibits nasopharyngeal cancer stem cells through sonic hedgehog signaling.

Abstract: 

Genistein, a soy derived isoflavanoid compound, exerts anticancer effects in various cancers. Nasopharyngeal cancer stem cells (NCSCs) are a small subpopulation of cancer cells which are responsible for initiation, progression, metastasis, and recurrence of nasopharyngeal cancer. The present study aimed to investigate the suppressive effects of genistein on NCSCs and its underlying mechanism. NCSCs were enriched from human nasopharyngeal cancer cell lines CNE2 and HONE1 through tumorsphere-forming assay. It was shown that genistein inhibited the tumorsphere formation capacity, decreased the number of EpCAMcells, downregulated the expression of NCSCs markers, suppressed cell proliferation, and induced apoptosis of NCSCs. Genistein suppressed the activity of Sonic hedgehog (SHH) signaling, which was important for the maintenance of NCSCs, while activation of SHH signaling by purmorphamine diminished the inhibitory effects of genistein on NCSCs. Our data suggested that genistein inhibited NCSCs through the suppression of SHH signaling. These findings support the use of genistein for targeting NCSCs.

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PMID: 

Arch Med Sci. 2019 Jul ;15(4):1001-1009. Epub 2018 Oct 3. PMID: 31360194

Abstract Title: 

Genistein-triggered anticancer activity against liver cancer cell line HepG2 involves ROS generation, mitochondrial apoptosis, G2/M cell cycle arrest and inhibition of cell migration.

Abstract: 

Introduction: Liver cancer is one of the most common malignancies across the globe and one of the major causes of cancer-related mortality. With limited available treatment options, there is an urgent need to look for new available options. Genistein is an important plant flavonoid and has been shown to possess tremendous pharmacological potential. The objective of the present study was therefore to evaluate the anticancer effect of the genistein.Material and methods: The antiproliferative activity and ICof genistein were determined by MTT assay. Reactive oxygen species (ROS) and cycle distribution were investigated by flow cytometry. Apoptosis was detected by DAPI and annexin V/IP staining. Cell migration was investigated by wound healing assay. Protein expression was estimated by western blotting.Results: MTT assay revealed that genistein reduced the cell viability of HepG2 cancer cells in a dose-dependent manner. Genistein also reduced the colony forming potential of the HepG2 cell concentration dependently. The ICof genistein was found to be 25μM. Genistein caused G2/M cell cycle arrest and G2/M cells increased from 4.2% in the control to 56.4% at 100 μM concentration. Genistein prompted generation of significant (

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PMID: 

Support Care Cancer. 2018 Dec ;26(12):4001-4009. Epub 2018 Jul 19. PMID: 30022350

Abstract Title: 

Meta-analysis of randomized controlled trials of the efficacy of propolis mouthwash in cancer therapy-induced oral mucositis.

Abstract: 

PURPOSE: This meta-analysis aimed to evaluate the efficacy and safety of propolis mouthwash in cancer patients with therapy-induced oral mucositis.METHODS: This was a systematic review of randomized control trails (RCTs). We searched ten electronic databases for studies published prior to April 06, 2017. The included RCTs were published in English and Chinese. The Jadad score was used to evaluate the quality of the articles identified. Two reviewers independently evaluated each of the studies. The data were entered into Review Manager (RevMan) 5.3 software and checked for accuracy. Outcome incidence analysis was performed using odds ratios (ORs).RESULTS: Of the 352 articles identified, five potentially relevant articles met our inclusion criteria. These 5 RCTs included a total of 209 participants. The Jadad score for methodological quality was 3.60 ± 0.55. No obvious publication bias was noted. The incidence of severe oral mucositis was significantly lower in the propolis group than in the control group (OR = 0.35, p = 0. 003). The corresponding 95% confidence interval (CI) was 0.18 to 0.70. Between-study heterogeneity was low (I = 0.000, p = 0.45). No side effects were reported.CONCLUSIONS: Propolis mouthwash is effective and safe in the treatment of severe oral mucositis. To maintain propolis safety, propolis usage should occur under the supervision of medical staff and health professionals. Future multi-center studies and a clinical protocol are needed to confirm the current findings regarding the efficacy and safety of propolis mouthwash.

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PMID: 

Cell Mol Biol (Noisy-le-grand). 2018 Jun 25 ;64(8):1-10. Epub 2018 Jun 25. PMID: 29981677

Abstract Title: 

Flavonoids, bioactive components of propolis, exhibit cytotoxic activity and induce cell cycle arrest and apoptosis in human breast cancer cells MDA-MB-231 and MCF-7 – a comparative study.

Abstract: 

Breast cancer is one of the most common causes of mortality in women. Flavonoids, among other compounds, are bioactive constituents of propolis. In this comparative study, we investigated the effects of flavonoids apigenin (API), genistein (GEN), hesperidin (HES), naringin (NAR) and quercetin (QUE) on the proliferation, apoptosis, and cell cycle of two different human cancer cells – MDA-MB-231, estrogen-negative, and MCF-7, estrogen-positive receptor breast carcinoma cells. Many cytotoxic reports of flavonoids were performed by MTT assay. However, it's reported that MTT is reduced in metabolically active cells and yields an insoluble purple formazan, which indicates that obtained cytotoxic results of flavonoids could be inconsistent. Cell viability was measured by NR, neutral red assay, while the percentage of apoptotic cells and cell cycle arrest were determined by flow cytometry and Muse cell cycle assay, respectively. The results showed a high dose-dependent effect in cell viability tests. IC50 values were as follows (MCF-7/MDA-MB-231, for 48 h, inµM): 9.39/50.83 for HES, 25.19/88.17 for API, 40.26/333.51 for NAR, 49.49/47.50 for GEN and 95.12/130.10 for QUE. Flavonoid-induced apoptosis was dose- and time-dependent, for both cancer cell lines, though flavonoids were more active on MCF-7 cells. The flavonoids also induced cell cycle arrest incancer cells.

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PMID: 

Anticancer Agents Med Chem. 2018 ;18(9):1330-1337. PMID: 30088453

Abstract Title: 

Reversing Multidrug Resistance in Chemo-resistant Human Lung Adenocarcinoma (A549/DOX) Cells by Algerian Propolis Through Direct Inhibiting the P-gp Efflux-pump, G0/G1 Cell Cycle Arrest and Apoptosis Induction.

Abstract: 

BACKGROUND: Lung cancer is one of the most common malignancies with the highest incidence and mortality rate worldwide. Multidrug Resistance (MDR) continues to pose a major challenge for the clinicians and pharmacologists to effectively treat this disease. A new approach using natural substances with moderate or low cytotoxic properties become a promising hope for reversing multidrug resistance due to pgp- overexpression.OBJECTIVE: This study aims to explore the efficacy of Algerian propolis in reversing multidrug resistance and sensitizing chemo-resistant lung cancer cells (A549/DOX) to chemotherapy with DOX.METHODS: Resistant lung adenocarcinoma A549/DOX cell line was developed and used as in vitro model for MDR. Cell viability, Annexin V-PI apoptosis assay and cell cycle progression were tested to evaluate the reversal effect of propolis alone or in combination with DOX. Caspases 3, 8 and 9 assays were conducted to determine the type of apoptotic pathway. To investigate the mechanisms of MDR reversal agents, intracellular accumulation of DOX and P-gp-pump activity were investigated.RESULTS: Our results showed that the obtained chemo-resistant cells were 13-fold more resistant to DOX than the parental A549 cells. Propolis showed dramatically cell growth inhibition on A549/DOX cells (The IC50 was 50.44± 0.07µg/ml). The killing effect of propolis was due to G0/G1 cell cycle arrest and apoptosis induction. After 24hours treatment, propolis at 100 µg/ml caused cells accumulation in G0/G1 phase and increased with 50, 65-fold the percentage of apoptotic population sub-G. Annexin V-PI assay showed that propolis induces apoptosis with 53.57-fold at 100 µg/ml. It induced intrinsic apoptotic pathway by increasing caspase-3 (22.15-fold) and caspase-9 (16.73-fold) activities. The direct approach to investigate the mechanisms of reversal agents is to detect the accumulation of P-gp substrates in resistant cells. Our results indicated that resistant cells poorly accumulated Doxorubicin and rhodamine 123 (7-fold lower) when compared to parental A549 cells, suggesting that chemo-resistant cells overexpress P-gp which pump DOX out of cells. Propolis inhibited in a concentration-dependent manner,the pgp efflux-pump, enhancing thereby the intracellular level of DOX with 5.48- fold against 3.33 fold obtained with verapamil, the conventional P-gp inhibitor.CONCLUSION: Taken together, Algerian propolis reverses multidrug resistance in resistant human lung adenocarcinoma cells through direct inhibiting the transport function of pgp-pump resulting in enhancing intracellular DOX-accumulation, G0/G1 cell cycle arrest and apoptosis induction. Thus, propolis could be developed as a chemotherapeutic agent for reversing multidrug resistance.

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PMID: 

Nutrients. 2018 Aug 26 ;10(9). Epub 2018 Aug 26. PMID: 30149677

Abstract Title: 

Chinese Propolis Exerts Anti-Proliferation Effects in Human Melanoma Cells by Targeting NLRP1 Inflammatory Pathway, Inducing Apoptosis, Cell Cycle Arrest, and Autophagy.

Abstract: 

Melanoma is a malignant tumor that begins in the melanocyte and has the highest mortality rate among all cutaneous tumors. Chinese propolis (CP) has been shown to have a potent antitumor effect against various cancers. In this study, we uncovered the combined effects of antiproliferation and anti-inflammation of CP on suppressing the progression of human melanoma cell line A375. We evaluated the alterations of protein expression after CP treatment by Western blot. After CP treatment, A375 cells underwent intrinsic apoptosis and cell cycle arrest. Furthermore, we found that CP suppressed inflammation in A375 cells. NLRP1 (NLR family pyrin domain containing 1), confirmed as a proinflammatory protein in melanoma progression, was downregulated significantly by CP, as were the NLRP1-related caspase activation and recruitment domains (CARD) proteins, including caspase-1 and caspase-4. Additionally, decreasing mRNA levels of,, andfurther proved the negative regulation of CP on the melanoma inflammatory environment. We also discovered that CP induced autophagy in A375 cells. Interestingly, inhibiting autophagy in CP-treated cells diminished its antitumor effect, suggesting that the autophagy was attributed to CP-induced apoptosis. Collectively, CP is a promising candidate for drug development for melanoma therapy.

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PMID: 

Molecules. 2018 Sep 27 ;23(10). Epub 2018 Sep 27. PMID: 30262742

Abstract Title: 

Anti-Inflammatory, Anti-Diabetic, and Anti-Alzheimer's Effects of Prenylated Flavonoids from Okinawa Propolis: An Investigation by Experimental and Computational Studies.

Abstract: 

Okinawa propolis (OP) and its major ingredients were reported to have anti-cancer effects and lifespan-extending effects onthrough inactivation of the oncogenic kinase, p21-activated kinase 1 (PAK1). Herein, five prenylated flavonoids from OP, nymphaeol-A (NA), nymphaeol-B (NB), nymphaeol-C (NC), isonymphaeol-B (INB), and 3'-geranyl-naringenin (GN), were evaluated for their anti-inflammatory, anti-diabetic, and anti-Alzheimer's effects using in vitro techniques. They showed significant anti-inflammatory effects through inhibition of albumin denaturation (half maximal inhibitory concentration (IC) values of 0.26⁻1.02 µM), nitrite accumulation (ICvalues of 2.4⁻7.0 µM), and cyclooxygenase-2 (COX-2) activity (ICvalues of 11.74⁻24.03 µM). They also strongly suppressed in vitro α-glucosidase enzyme activity with ICvalues of 3.77⁻5.66 µM. However, only INB and NA inhibited acetylcholinesterase significantly compared to the standard drug donepezil, with ICvalues of 7.23 and 7.77µM, respectively. Molecular docking results indicated that OP compounds have good binding affinity to the α-glucosidase and acetylcholinesterase proteins, making non-bonded interactions with their active residues and surrounding allosteric residues. In addition, none of the compounds violated Lipinski's rule of five and showed notable toxicity parameters. Density functional theory (DFT)-based global reactivity descriptors demonstrated their high reactive nature along with the kinetic stability. In conclusion, this combined study suggests that OP components might be beneficial in the treatment of inflammation, type 2 diabetes mellitus, and Alzheimer's disease.

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PMID: 

Phytother Res. 2019 Mar ;33(3):591-601. Epub 2018 Nov 28. PMID: 30488503

Abstract Title: 

The chemical composition and events related to the cytotoxic effects of propolis on osteosarcoma cells: A comparative assessment of Colombian samples.

Abstract: 

Osteosarcoma (OSA) is a type of bone cancer showing an aggressive biological behavior with metastatic progression. Because propolis potential for the development of new antitumoral drugs has been indicated, we evaluated the chemical composition of Colombian propolis samples and the mechanisms involved in their cytotoxic effects on OSA cells. The chemical composition was analyzed by GC-MS and the DPPH free radical scavenging activity was measured. Cluster and principal components analysis were used to establish an association with their inhibitory concentration 50% (IC). Cell viability was analyzed by MTT assay; apoptosis was determined by flow cytometry; mitochondrial membrane permeability and reactive oxygen species were evaluated by rhodamine 123 and DCFH-DA. Transwell assay was used to evaluate the invasiveness of propolis-treated cells. Samples were grouped: Cluster 1 contained diterpenes and benzophenones and showed the highest antiradical activity; Cluster 2 was characterized by triterpenes, fatty acid, and diterpenes. Usm contained diterpenes and triterpenes different of the other samples and Sil contained triterpenes and flavonoids. Apoptosis, mitochondrial membrane alteration, and suppression of cell invasion were the main mechanisms involved in the inhibition of OSA cells in vitro, suggesting the potential of Colombian propolis to discover new antitumor drugs.

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PMID: 

Biotech Histochem. 2019 Apr ;94(3):204-213. Epub 2018 Dec 4. PMID: 30512970

Abstract Title: 

Biochemical and morphological evaluation of the effects of propolis on cisplatin induced kidney damage in rats.

Abstract: 

Cisplatin (CP) is a chemotherapeutic agent used to treat various types of cancer; nephrotoxicity is the most common adverse effect of the drug. We investigated the protective effects of propolis against CP induced kidney injury. Thirty-six male rats were divided into six equal groups: untreated control group, 50 mg/kg/day propolis group, 100 mg/kg/day propolis group, single-dose 7 mg/kg CP group, 7 mg/kg CP + 50 mg/kg/day propolis and 7 mg/kg CP + 100 mg/kg propolis. Rats were sacrificed after 14 days and kidneys were removed for histopathological and biochemical analyses. We used hematoxylin&eosin and periodic acid-Schiff staining to evaluate kidney histopathology and we used the TUNEL technique to assess apoptosis. We also measured total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), ischemia-modified albumin (IMA) and malondialdehyde (MDA) levels in tissue and blood specimens. Normal morphology was observed in the control, 50 mg/kg/day propolis and 100 mg/kg/day propolis groups by light microscopy. Degeneration of tubule cells, edema and tubule dilation were increased in the CP group compared to the control group. Degeneration of tubule cells and dilation of Bowman's spaces were decreased in the CP + 50 mg/kg/day propolis and CP + 100 mg/kg/day propolis groups compared to the CP group. Tubule dilation decreased significantly in the CP + 100 mg/kg propolis group compared to the CP group. Also, the 7 mg/kg CP group exhibited altered proximal tubule epithelial cells, loss of brush border and thickening of the parietal layer of Bowman's capsule in glomeruli and basal laminae of tubules. A normal brush border was observed in the CP + 50 mg/kg/day propolis and CP + 100 mg/kg/day groups. Serum OSI and MDA levels were increased in the CP group compared to the control group. Serum MDA levelsdecreased significantly in the CP + 50 mg/kg/day propolis and 100 mg/kg CP + propolis groups compared to the CP group. CP caused significant damage to kidney tissue; propolis exhibited dose-dependent prevention of tissue damage.

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