PMID: 

Pharmacol Res. 2020 Feb 11:104690. Epub 2020 Feb 11. PMID: 32057894

Abstract Title: 

Berberine-mediated up-regulation of surfactant protein D facilitates cartilage repair by modulating immune responses via the inhibition of TLR4/NF-ĸB signaling.

Abstract: 

The innate immune system drives inflammatory joint damage in osteoarthritis (OA) and regulates cartilage repair. Berberine chloride (BBR) is an isoquinoline alkaloid that shows immunomodulatory activity in a variety of cell lines. However, the immunomodulatory mechanisms of BBR in chondrocytes during OA are largely unknown. Herein, we assessed the ability of BBR to mediate chondroprotection through its effects on innate immunity. We found that BBR up-regulated the expression of surfactant protein D (SP-D) in OA cartilage, a key regulator of inflammation and innate immunity both in the airways and extrapulmonary tissues, including joint cartilage. To further explore these findings, we used recombinant adeno-associated virus (rAAV)-mediated knockdown of SP-D. Silencing was assessed in rat model of surgically-induced OA in the presence or absence of BBR treatment, 10 weeks post-surgery. We observed a clear improvement in histological scores of BBR-treated animals compared to those treated with BBR and the rAAV-SP-D vector. In addition, animals co-treated with BBR + recombinant human SP-D (rhSP-D) exhibited significantly lower histological scores than those treated with BBR alone. BBR treatment led to significantly reduced immune cell infiltration mediated through TLR4, F4/80, CD68 and CD34, whilst SP-D silencing reversed this improvement. In contrast, rhSP-D treatment enhanced the protective phenotype. We further explored how BBR influences SP-D and other OA-associated genes in vitro. We observed an up-regulation of SP-D and a marked decline in TRAF6, TLR4, MD-2 and MyD88 expression, as well as NF-κB p65 and IκBα phosphorylation in chondrocytestreated with sodium nitroprusside. siRNAs specific for SP-D were able to partially reverse this phenotype, whilst both rhSP-D and the TLR4 inhibitor TAK-242 enhanced the effects. Together, these results are consistent with a model wherein SP-D has therapeutic potential for OA treatment. Concomitantly, BBR modulates immune responses and decreases cartilage degradation. These findings suggest that BBR achieves this function through releasing SP-D from MD2/SP-D complexes and through the inhibition of TLR4/NF-κB signaling.

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PMID: 

Asian Pac J Cancer Prev. 2016 ;17(7):3077-84. PMID: 27509932

Abstract Title: 

AntiTumor and Immunoregulatory Effects of Fermented Papaya Preparation (FPP: SAIDOPS501).

Abstract: 

Various beneficial effects have been described for fermented papaya preparation (FPP: SAIDOPS501) based on its antioxidative and antiinflammatory functions. The present study was designed to determine the effects of FPP on carcinogenesis in vivo, and immunomodulatory function in vitro. Mice were injected with RL male 1 cells subcutaneously or 3methylcholantherene (MCA) intravenously to induce cancer and orally or intraperitoneally treated with FPP solution. Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers and patients with atopic dermatitis, treated with FPP, and subjected to measurement of cytokine production and changes in Foxp3expressing regulatory T cell (Treg) stimulated with phytohemagglutinin (PHA). Administration of FPP suppressed tumor size and the incidence of malignancy. In vitro, treatment of PBMC with FPP induced IL1?, TNFα and IFNγ production. Moreover, FPP suppressed proliferation of PHAstimulated Foxp3expressing Treg. These results suggest that FPP has chemotherapeutic properties.

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PMID: 

Nutr Neurosci. 2018 Apr ;21(3):176-184. Epub 2016 Nov 14. PMID: 27841081

Abstract Title: 

Neuroprotective effect of fermented papaya preparation by activation of Nrf2 pathway in astrocytes.

Abstract: 

OBJECTIVES: Nuclear factor erythroid 2-related factor (Nrf2) in astrocyte plays important roles in brain homeostasis. Fermented papaya preparation (FPP) has anti-oxidative, anti-inflammatory, immunoregulatory properties. The present study investigated the effects of FPP on activation of Nrf2 and release of Nrf2-regulated neuroprotective antioxidants and detoxifying molecules.METHODS: Primary cultured astrocytes from rat embryos were treated with FPP for 6 or 24 hours. The expression levels of nuclear Nrf2 and cytoplasmic Nrf2-regulated molecules were determined by western blot analysis and immunohistochemistry. Glutathione levels were measured in cells and medium. Dopaminergic neurons were exposed 6-hydroxydopamine (6-OHDA) with/without pre-treatment with FPP astrocytes. Mice were treated orally with FPP for 2 weeks.RESULTS: FPP increased nuclear translocation of Nrf2 in striatal astrocytes, induced up-regulation of NAD(P)H quinine oxidoreductase-1, glutathione-S transferase and hemeoxygenase-1, and increased glutathione level and the percentage of metallothionein-expressing astrocytes. Moreover, FPP suppressed 6-OHDA-induced dopaminergic neuronal loss in not only neuron-astrocyte mixed culture, but also neuron-rich cultures pre-treated with glial conditioned medium. Two-week oral treatment of mice with FPP resulted in Nrf2 activation and increase in glutathione level in striatum.DISCUSSION: The results indicated that FPP enhances the anti-oxidative capacity through activation of Nrf2 in astrocytes, suggesting it may provide neuroprotection in oxidative stress-related neurodegenerative diseases.

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PMID: 

Cancers (Basel). 2019 Jan 20 ;11(1). Epub 2019 Jan 20. PMID: 30669508

Abstract Title: 

Oral Administration of Fermented Papaya (FPP) Controls the Growth of a Murine Melanoma through the In Vivo Induction of a Natural Antioxidant Response.

Abstract: 

Prolonged oxidative stress may play a key role in tumor development. Antioxidant molecules are contained in many foods and seem to have a potential role in future anti-tumor strategies. Among the natural antioxidants the beneficial effect of Fermented Papaya (FPP) is well known. The aim of this study was to investigate the effects of orally administered FPPin either the prevention or treatment of a murine model of melanoma. The tumor growth was analyzed together with the blood levels of both oxidants (ROS) and anti-oxidants (SOD-1 and GSH). The results showed that FPPcontrolled tumor growth, reducing the tumor mass of about three to seven times vs. untreated mice. The most significant effect was obtained with sublingual administration of FPPclose to the inoculation of melanoma. At the time of the sacrifice none of mice treated with FPPhad metastases and the subcutaneous tumors were significantly smaller and amelanotic, compared to untreated mice. Moreover, the FPPanti-tumor effect was consistent with the decrease of total ROS levels and the increase in the blood levels of GSH and SOD-1. This study shows that a potent anti-oxidant treatment through FPPmay contribute to both preventing and inhibiting tumors growth.

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PMID: 

Antioxidants (Basel). 2020 Feb 7 ;9(2). Epub 2020 Feb 7. PMID: 32046112

Abstract Title: 

Beneficial Effects of Fermented Papaya Preparation (FPP) Supplementation on Redox Balance and Aging in a Mouse Model.

Abstract: 

In recent decades much attention has been paid to how dietary antioxidants may positively affect the human health, including the beneficial effects of fermented foods and beverages. Fermented Papaya Preparation (FPP) has been shown to represent a valuable approach to obtain systemic antioxidants effect. In this study, we wanted to verify whether FPPhad a clear and scientifically supported in vivo anti-aging effect together with the induction of a systemic antioxidant reaction. To this purpose we daily treated a mouse model suitable for aging studies (C57BL/6J) with FPP-supplemented water from either the 6th weeks (early treatment) or the 51th weeks (late treatment) of age as compared to mice receiving only tap water. After 10 months of FPPtreatment, we evaluated the telomerase activity, antioxidants and Reactive Oxygen Species ROS plasmatic levels and the telomeres length in the bone marrow and ovaries in both mice groups. The results showed that the daily FPPassumption induced increase in telomeres length in bone marrow and ovary, together with an increase in the plasmatic levels of telomerase activity, and antioxidant levels, with a decrease of ROS. Early treatment resulted to be more effective, suggesting a potential key role of FPPin preventing the age-related molecular damages.

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PMID: 

Int J Public Health. 2020 Jan ;65(1):45-53. Epub 2020 Jan 25. PMID: 31982934

Abstract Title: 

The association between sugar-sweetened beverages intake, body mass index, and inflammation in US adults.

Abstract: 

OBJECTIVES: This study aims to (1) assess the associations between sugar-sweetened beverages (SSB) consumption and C-reactive protein (CRP) levels, and (2) evaluate the modifying effect of body mass index (BMI) on the association between SSB consumption and CRP levels.METHODS: A total of 6856 eligible adults were selected from the 2007-2010 National Health and Nutrition Examination Survey (NHANES). Average quantity of SSB consumption was calculated from 2-day 24-h dietary recalls. All data analyses were performed with appropriate sampling weights.RESULTS: Compared with non-SSB drinkers, a 0.26 mg/l higher CRP was observed in heavy SSB drinkers after adjusting for demographic characteristics, lifestyle patterns, and BMI. An effect modification of BMI on SSB intake and CRP levels was detected (P 

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PMID: 

J Obes Metab Syndr. 2020 Feb 7. Epub 2020 Feb 7. PMID: 32045514

Abstract Title: 

Three-Month Daily Consumption of Sugar-Sweetened Beverages Affects the Liver, Adipose Tissue, and Glucose Metabolism.

Abstract: 

Background: Growing evidence suggests links between sugar-sweetened beverages (SSBs) and metabolic disorders. We investigated the effects of SSBs commonly consumed by adolescents and their relationships to glucose metabolism and fatty liver.Methods: We treated 7-week old male C57BL/6 mice with water (control) or one of three different SSBs, carbonated soda (Coca-Cola), milk-sweetened milk coffee (Maxwell), or chocolate-added cocoa (Choco-Latte), for 13 weeks (n=10 in each group). Half of the animals were fed a regular chow diet and the other half a high-fat diet (40% fat). Body composition and biochemical variables were investigated at the end of treatment. Histology of the liver and adipose tissue, as well as molecular signaling related to glucose and lipid metabolism, were also evaluated.Results: During the 13-week treatment, mice treated with chocolate-added cocoa or milk-sweetened coffee showed significantly greater increases in body weight compared with controls, especially when fed a high-fat diet. Fasting glucose level was higher in the three SSB-treated groups compared with the control group. Lipid droplets in the liver, fat cell size, and number of CD68-positive cells in adipose tissue were greater in the SSB-treated groups than in the control group. SSB treatments increased the expression of genes related to inflammatory processes in the liver and adipose tissue. Phosphorylation of AKT and glycogen synthase kinase in muscle was significantly reduced in SSB-treated groups.Conclusion: Daily consumption of SSBs over 3 months lead to metabolic impairment and weight gain and may contribute to development of metabolic diseases.

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PMID: 

Mol Nutr Food Res. 2019 06 ;63(11):e1900082. Epub 2019 Apr 3. PMID: 30893514

Abstract Title: 

GC-(4→8)-GCG, A Proanthocyanidin Dimer from Camellia ptilophylla, Modulates Obesity and Adipose Tissue Inflammation in High-Fat Diet Induced Obese Mice.

Abstract: 

SCOPE: Excessive fat accumulation in adipose tissue leads to obesity and related chronic inflammation. This study aims to examine the effects of gallocatechin -(4→8)-gallocatechin-3-O-gallate (GC-(4→8)-GCG), a main proanthocyanidin dimer from Camellia ptilophylla (Cocoa tea), on adipocyte- and adipose-related inflammation in vivo and in vitro.METHODS AND RESULTS: C57BL/6 mice are fed a high-fat diet (HFD) and GC-(4→8)-GCG (40 or 80 mg kgd) for 8 weeks. The metabolic profiles, adipose tissue hypertrophy, macrophage infiltration, and inflammatory cytokine production are investigated. Additionally, 3T3-L1 preadipocytes are utilized to investigate the effect of GC-(4→8)-GCG on preadipocyte differentiation and the tumor necrosis factor (TNF)-α-stimulated inflammatory response in vitro. GC-(4→8)-GCG supplementation decreases HFD-induced epididymal white adipose tissue (eWAT) hypertrophy, suppresses proinflammatory cytokine production and macrophage infiltration in eWAT, and improves insulin sensitivity in HFD-induced obese mice. In vitro, GC-(4→8)-GCG shows a strong anti-adipogenic potential in 3T3-L1 preadipocyte by inhibiting the expression of key adipogenic transcription factors and decreasing the production of proinflammatory cytokines by inhibiting the activation of the nuclear factor (NF)-κB, Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT3) and mitogen-activated protein kinase (MAPK) signaling pathways.CONCLUSION: GC-(4→8)-GCG can modulate obesity and improve obesity-related insulin resistance by inhibiting preadipocyte differentiation and the related proinflammatory responses.

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PMID: 

Food Res Int. 2020 Mar ;129:108854. Epub 2019 Dec 2. PMID: 32036895

Abstract Title: 

Cocoa tea (Camellia ptilophylla) induces mitochondria-dependent apoptosis in HCT116 cells via ROS generation and PI3K/Akt signaling pathway.

Abstract: 

Cocoa tea (Camellia ptilophylla), a natural gallocatechin gallate (GCG)-rich and low caffeine-containing tea species, has been recently reported to possess various bioactivities. However, the anti-colon cancer effects of Cocoa tea and its underlying mechanisms remain virtually unknown. This study aimed to assess the anti-proliferative and pro-apoptotic effects of water extract of Cocoa tea (CWE) on human colon cancer HCT116 cells compared with Yunnan Daye tea (YWE). Primarily, CWE showed stronger anti-proliferation and apoptosis induction than YWE. Moreover, reduction of mitochondrial membrane potential (MMP), up-regulation of Bax/Bcl-2 ratio, release of cytochrome c, activation of caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP) were observed, suggesting that mitochondrial apoptotic pathway was activated by CWE. Furthermore, CWE-induced apoptosis in HCT116 cells was dependent on the generation of intracellular reactive oxygen species (ROS) and down-regulation of phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Pretreatment with ROS scavenger N-acetyl cysteine (NAC) attenuated the impact of CWE on mitochondria-related apoptosis proteins, and partially recovered the inhibition of Akt phosphorylation. These results indicated that ROS generation mediated mitochondrial dysfunction and inactivation of PI3K/Akt pathway in CWE-induced HCT116 cell apoptosis. Additionally, CWE significantly inhibited tumor growth in HCT116 tumor-bearing mice, suggesting that Cocoa tea could act as a potential functional beverage to prevent or treat colorectal cancer.

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PMID: 

Anticancer Res. 2020 Feb ;40(2):689-694. PMID: 32014909

Abstract Title: 

Delivery of Apoptosis-inducing Piperine to Triple-negative Breast Cancer CellsCo-polymeric Nanoparticles.

Abstract: 

BACKGROUND/AIM: Piperine, a major alkaloid of the fruit of black pepper plants, selectively inhibits the growth of triple-negative breast cancer cells but its lipophilicity restricts possible clinical application. This study therefore determined the feasibility of encapsulating piperine in nanoparticles (NPs) to increase its solubility in an aqueous environment.MATERIALS AND METHODS: Piperine-loaded biodegradable methoxy poly(ethylene glycol)-poly(lactic-co-glycolic) acid copolymer-based NPs were produced by single emulsion solvent extraction and thin-film hydration. Growth and viability of triple-negative breast cancer (TNBC) cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin-V-FLUOS/propidium iodide staining, respectively.RESULTS: Thin-film hydration was superior to single emulsion solvent extraction, yielding piperine-loaded NPs with an average size of 50 nm. Piperine-loaded NPs inhibited TNBC cell growth and induced apoptosis while sparing normal fibroblasts.CONCLUSION: It is feasible to deliver a cytotoxic concentration of piperine to TNBC cells via NPs with the potential for improved bioavailability and solubility in biological fluids.

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