PMID: 

Front Pharmacol. 2019 ;10:542. Epub 2019 May 21. PMID: 31164821

Abstract Title: 

Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines.

Abstract: 

Parthenolide (PT) is a sesquiterpene lactone isolated from. In this study, PT showed varying cytotoxic effects against different solid tumor cell lines. HCT116 (p53) colon carcinoma cells and their parental HCT116 knockout p53 (p53) cell lines showed a resistance degree of 2.36. On the other hand, wild-type U87.MG cells or cells transfected with a deletion-activatedcDNA (U87.MGΔEGFR) exhibited slight sensitivity toward PT. Multidrug-resistant MDA-MB-231-BCRP cells were even more sensitive toward PT than sensitive MDA-MB-231-pcDNA cells with a resistance degree of 0.07 (collateral sensitivity). To the best of our knowledge, hypersensitivity (collateral sensitivity) in MDA-MB-231-BCRP cell line is reported in this study for the first time. We attempted to identify the mechanism of collateral sensitivity. Firstly, we found that PT bound to IKK preventing IκBα degradation and eventually inhibition of the nuclear factor kappa B (NF-κB) pathway. Down-regulation of hypoxia inducing factor 1-alpha (HIF-1α) in MDA-MB-231-BCRP resistant cells may be a second mechanism, since it is a target gene of NF-κB. Moreover, PT also showed epigenetic effect by inhibition of HDAC activity as shown using both molecular docking and HDAC activity assay. Based on COMPARE and hierarchical cluster analyses, we found gene expression profiles that predicted sensitivity or resistance of 47 tumor cell lines toward PT. Interestingly, pathway analyses of gene expression profiles revealed NF-κB and HIF signaling as top networks of these genes, cellular functions and canonical pathways influencing the activity of PT against tumor cells. In conclusion, PT exerted profound cytotoxic activity against various cancer cell lines mainly against BCRP-overexpressing tumor cells, suggesting PT as novel candidate for cancer treatment.

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PMID: 

Med Sci Monit. 2019 Jul 8 ;25:5054-5061. Epub 2019 Jul 8. PMID: 31322140

Abstract Title: 

Parthenolide Inhibits the Proliferation of MDA-T32 Papillary Thyroid Carcinoma Cells in Vitro and in Mouse Tumor Xenografts and Activates Autophagy and Apoptosis by Downregulation of the Mammalian Target of Rapamycin (mTOR)/PI3K/AKT Signaling Pathway.

Abstract: 

BACKGROUNDThis study aimed to examine the effects of the sesquiterpene lactone, parthenolide, on migration, autophagy, and apoptosis of MDA-T32 human papillary thyroid carcinoma cellsin vitroand in mouse tumor xenografts.MATERIAL AND METHODSCell proliferation and viability of MDA-T32 human papillary thyroid carcinoma cells were determined by MTT assay, and cell migration was studied using a transwell assay. Fluorescence microscopy using acridine orange (AO) and ethidium bromide (EB) staining evaluated apoptosis. Transmission electron microscopy was used to study the effects of parthenolide on autophagy, and Western blot examined the levels of autophagy-associated proteins, including Bax, Bcl-2, and LC3-ll. Mice (n=10) were injected with 5×10⁶ MDA-T32 cells subcutaneously into the left flank, and xenograft tumors were grown for six weeks. Control untreated mice (n=5) were compared with treated mice (n=5) given parthenolide three times per week.RESULTSParthenolide resulted in a dose-dependent reduction in viability and cell migration of MDA-T32 cells, with a half-maximal inhibitory concentration (IC₅₀) of 12 µM. AO and EB staining showed that parthenolide induced cell apoptosis and electron microscopy identified autophagosomes in MDA-T32 cells. Parthenolide induced increased expression of the autophagocytic proteins, LC3-II and beclin-1, had a dose-dependent inhibitory effect on the mTOR/PI3K/AKT cascade in MDA-T32 cells and inhibited the growth of the mouse xenograft tumorsin vivo.CONCLUSIONSParthenolide inhibited the growth and migration of MDA-T32 human papillary thyroid carcinoma cellsin vitroand mouse tumor xenografts and activated autophagy and apoptosis by downregulation of the mTOR/PI3K/AKT signaling pathway.

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PMID: 

Curr Med Chem. 2019 Aug 16. Epub 2019 Aug 16. PMID: 31419929

Abstract Title: 

Parthenolide and Its Analogues: A New Potential Strategy for the Treatment of Triple-Negative Breast Tumors.

Abstract: 

Triple negative breast cancers (TNBC) are heterogeneous and aggressive pathologies, with distinct morphological and clinical characteristics associated with their genetic diversity, epigenetics, transcriptional changes and aberrant molecular patterns. Treatment with anti-neoplastic drugs exerts systemic effects with low specificity, and incipient improvement in overall survival due to chemoresistance and recurrence. New alternatives for TNBC treatment are urgent and parthenolide or its analogues have been explored. Parthenolide is a sesquiterpene lactone with promising antitumor effects against TNBC cell lines. This review highlights the importance of parthenolide and its analogue drugs in TNBC treatment.

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PMID: 

Intest Res. 2019 Aug 23. Epub 2019 Aug 23. PMID: 31426622

Abstract Title: 

Parthenolide inhibits transforming growth factorβ1-induced epithelial-mesenchymal transition in colorectal cancer cells.

Abstract: 

Background/Aims: Transforming growth factor-β1 (TGF-β1) induction of epithelial-mesenchymal transition (EMT) is one of the mechanisms by which colorectal cancer (CRC) cells acquire migratory and invasive capacities, and subsequently metastasize. Parthenolide (PT) expresses multiple anti-cancer and anti-inflammatory activities that inhibit nuclear factor κB by targeting the IκB kinase complex. In the present study, we aimed to investigate whether PT can inhibit TGF-β1-induced EMT in CRC cell lines.Methods: HT-29 and SW480 cell lines were used in the experiment. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and sub-G1 analysis was measured by flow cytometry. The induction of EMT by TGF-β1 and inhibition of the process by PT was analyzed by phase contrast microscopy, wounding healing, cellular migration and invasion assays, and Western blotting.Results: TGF-β1 inhibits HT-29 cell proliferation, but has no effect on SW480 cell proliferation; different concentrations of TGF-β1 did not induce apoptosis in HT-29 and SW480 cells. PT attenuates TGF-β1-induced elongated, fibroblast-like shape changing in cells. PT inhibits TGF-β1-induced cell migration and cell invasion. In addition, other EMT markers such as β-catenin, Vimentin, Snail, and Slug were suppressed by PT, while E-cadherin was increased by PT.Conclusions: Our findings show that PT inhibits TGF-β1-induced EMT by suppressing the expression of the mesenchymal protein and increasing expression of the epithelial protein. These findings suggest a novel approach for CRC treatment by suppression of TGF-β1-induced EMT.

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PMID: 

Phytother Res. 2019 Sep 9. Epub 2019 Sep 9. PMID: 31497910

Abstract Title: 

Parthenolide ameliorates intracerebral hemorrhage-induced brain injury in rats.

Abstract: 

Neuroinflammation and oxidative stress are key contributors to intracranial hemorrhage (ICH)-induced brain injury. Parthenolide (PN) is a sesquiterpene lactone that has been observed to have antioxidative, anti-inflammatory, and neuroprotective potentials. However, the role of PN in ICH remains unclear. Therefore, we investigated the neuroprotective effects and underlying mechanisms of PN on an experimental model of ICH in rats. Our results showed that PN treatment improved neurological deficit and brain edema in ICH rats. The ipsilateral hemispheres of the brain were separated and homogenized. The concentrations of TNF-α, interleukin (IL)-6, and IL-17 in the homogenates were detected by enzyme-linked immunosorbent assay. We found that PN inhibited the production of proinflammatory cytokines in an ICH rat model. The ROS and glutathione (GSH) levels, as well as the activity of superoxide dismutase (SOD) in the homogenates were measured. ICH caused an increase in ROS level, and the decreases in GSH level and SOD activity were mitigated by PN treatment. Furthermore, PN significantly suppressed the expressions of active caspase-3 and Bax in ipsilateral hemispheres of the brain at Day 3 after ICH, as well as increased the surviving neurons. Finally, the ICH-induced activation of TLR4/NF-κB pathway was suppressed by PN treatment. These findings suggested that PN could be beneficial in the therapeutic strategy for ICH treatment.

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PMID: 

Int J Pharm. 2019 Aug 26 ;570:118644. Epub 2019 Aug 26. PMID: 31465837

Abstract Title: 

Colon-specific microspheres loaded with puerarin reduce tumorigenesis and metastasis in colitis-associated colorectal cancer.

Abstract: 

Colitis-associated colorectal cancer (CAC) is a common malignancy that develops in chronically inflamed mucosa and is usually accompanied by metastases at other sites. Puerarin, a natural isoflavone isolated from the root of the Pueraria lobata (Willd.) Ohwi, has potential anti-colon cancer activity. However, the poor solubility and low bioavailability of puerarin has restricted its application in the pharmaceutical industry. In the present study, pH-responsive alginate microspheres loaded with puerarin were prepared by emulsification/internal gelation for targeted treatment of colitis-associated colorectal cancer. Herein, puerarin, as an active drug, could participate in the construction of alginate microspheres with hydrogen bonding. The microspheres exhibited pH-responsive release behavior with little release of puerarin in simulated gastric fluid and high amounts (approximately 55%) of release in simulated colonic fluid. A fluorescence tracer indicated microspheres had high retention time of more than 20 h in the colon. Meanwhile, puerarin-loaded alginate microspheres not only significantly decreased the inflammatory response by downregulating the levels of pro-tumorigenic cytokines, but they reduced tumorigenesis and metastasis by inhibiting epithelial-mesenchymal transitions in AOM/DSS-inducedcolitis-associated colorectal cancer in mice. The overall results suggested that puerarin-loaded alginate microspheres could effectively inhibit development of colonic tumors, which could be developed as a promising therapeutic strategy for colitis-associated colorectal cancer.

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PMID: 

Molecules. 2019 May 4 ;24(9). Epub 2019 May 4. PMID: 31060218

Abstract Title: 

Extracts from Cell Suspension Cultures of Strawberry (Duch): Cytotoxic Effects on Human Cancer Cells.

Abstract: 

Natural compounds are emerging as agents for the treatment of malignant diseases. We previously showed that extracts from in vitro cell suspension cultures of strawberry reduced murine melanoma cell proliferation, as shown for fruit extracts. In this work, chromatographic, mass spectrometric, and spectrophotometric analyses were carried out to identify the bioactive compound exerting the detected cytotoxic activity. Moreover, aiming to confirm the anti-proliferative activity of the extracts against both paediatric and adult human tumors, cytotoxic experiments were performed on neuroblastoma, colon, and cervix carcinoma cell lines. Extracts from in vitro cell suspension cultures of strawberry induced a statistically significant reduction of cell growth in all the tumor cell lines tested. Interestingly, human fibroblasts from healthy donors were not subjected to this cytotoxic effect, highlighting the importance of further preclinical investigations. The accurate mass measurement, fragmentation patterns, and characteristic mass spectra and mass losses, together with the differences in chromatographic retention times and absorbance spectra, led us to hypothesize that the compound acting as an anti-proliferative agent could be a novel acetal dihydrofurofuran derivative (CHO, molecular mass 154.0630 amu).

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Don’t California my [Insert State Here]: The egregious injustice of SB276 and its trailer bill, which solidified sweeping vaccine legislation into law, was enacted under the false pretenses of fraudulent exemptions, targets medically fragile children, and will usher in an age of medical tyranny

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PMID: 

iScience. 2019 Aug 16 ;19:676-690. Epub 2019 Aug 16. PMID: 31472342

Abstract Title: 

Blueberry Extract Improves Obesity through Regulation of the Gut Microbiota and Bile Acids via Pathways Involving FXR and TGR5.

Abstract: 

The metabolic improvement effect of blueberries has long been recognized, although its precise mechanism(s) remains obscure. Here, we show that phenolic blueberry extract (BE) treatment improved diet- and genetically induced metabolic syndromes, which were linked to increased energy expenditure in brown adipose tissue (BAT) and improved lipid metabolism in the liver via pathways involving the bile acid (BA) receptors TGR5 and FXR. These observations were strongly correlated with the regulation of BAs (e.g., a decrease in the FXR inhibitors TαMCA and TβMCA) and the gut microbiota (GM) (e.g., an expansion of Bifidobacteria and Lactobacillus), because antibiotic treatment completely blunted the regulation of the GM and BAs and the metabolic effects of BE. We also observed similar results in db/db mice. Furthermore, treating mouse primary cells derived from the liver and BAT with the combinations of BAs mimicking the in vivo alterations upon BE treatment mirrored the in vivo observations in mice.

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PMID: 

Curr Alzheimer Res. 2018 02 22 ;15(4):363-380. PMID: 28847284

Abstract Title: 

Modulation of Inflammation as a Way of Delaying Alzheimer's Disease Progression: The Diet's Role.

Abstract: 

BACKGROUND: Most of the recent reports suggest that inflammatory mediators play a central role in the etiopathogenesis of Alzheimer's disease (AD) and that the conditions leading to a chronic low-grade inflammation, such as stress, depression, obesity and metabolic syndrome, increase the odds of developing Mild Cognitive Impairment (MCI) and AD. Microglia cells are the main actors in the AD process: stimuli from the microenvironment may induce microglia cells to switch to a classically activated inflammatory phenotype M1, or, on the contrary to an alternatively activated M2 phenotype characterized by the secretion of different types of cytokines. Many attempts are currently being made in order to delay the progression of AD by reducing inflammatory mechanisms underlying the disease. Several studies support a relationship among neuroinflammation and nutrients, foods or dietary patterns, taking into account the synergistic or antagonistic biochemical interactions among nutrients as well as the different food sources of the same nutrient. Natural antioxidant and anti-inflammatory compounds found in plant foods, such as fruits, particularly berries (such as strawberry, blueberry, blackcurrant, blackberry, blueberry and mulberry) have been shown to exert neuroprotective activity. It is still unclear whether the dietary bioactive compounds enter the Blood Brain Barrier (BBB) playing a direct antiinflammatory or pro-inflammatory effect on microglia and/or other Central Nervous System (CNS) cells. Another hypothesis is that they may trigger a peripheral reaction that induce indirectly a CNS' response. The subsequent synthesis of cytokines may drive microglia polarization by different ways. So, via an indirect route microglia detects and responds to immune-to-brain signaling.CONCLUSION: This review summarizes current evidence about the potential mechanisms of the interaction among diet, neuroinflammation and AD.

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