PMID: 

Gut Microbes. 2020 May 6:1-14. Epub 2020 May 6. PMID: 32372706

Abstract Title: 

Berberine and its structural analogs have differing effects on functional profiles of individual gut microbiomes.

Abstract: 

The understanding of the effects of compounds on the gut microbiome is limited. In particular, it is unclear whether structurally similar compounds would have similar or distinct effects on the gut microbiome. Here, we selected berberine (BBR), an isoquinoline quaternary alkaloid, and 16 structural analogs and evaluated their effects on seven individual gut microbiomes cultured. The responses of the individual microbiomes were evaluated by metaproteomic profiles and by assessing butyrate production. We show that both interindividual differences and compound treatments significantly contributed to the variance of metaproteomic profiles. BBR and eight analogs led to changes in proteins involved in microbial defense and stress responses and enrichment of proteins from Verrucomicrobia, Proteobacteria, and Bacteroidetes phyla. It also led to a decrease in proteins from the Firmicutes phylum and its Clostridiales order which correlated to decrease proteins involved in the butyrate production pathway and butyrate concentration. Three of the compounds, sanguinarine, chelerythrine, and ethoxysanguinarine, activated bacterial protective mechanisms, enriched Proteobacteria, increased opacity proteins, and markedly reduced butyrate production. Dihydroberberine had a similar function to BBR in enriching thegenus. In addition, it showed less overall adverse impacts on the functionality of the gut microbiome, including a better maintenance of the butyrate level. Our study shows thatmicrobiome assay can assess differential regulating effects of compounds with subtle differences and reveals that compound analogs can have distinct effects on the microbiome.

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PMID: 

Complement Ther Clin Pract. 2020 May ;39:101113. Epub 2020 Feb 1. PMID: 32379652

Abstract Title: 

The effect of berberine supplementation on obesity indices: A dose- response meta-analysis and systematic review of randomized controlled trials.

Abstract: 

BACKGROUND: and purpose: Clinical studies investigating the effects of berberine supplementation on anthropometric indices in humans have generated inconsistent results. Thus, the objective of this systematic review and meta-analysis was to clarify the effects of berberine supplementation on obesity indices in human subjects.METHODS: Several online medical databases were systematically searched up to February 2019. All clinical trials exploring the effects of berberine supplementation on indices of obesity were included. The combined weighted mean difference (WMD) of eligible studies was assessed using a random-effects model. We evaluated publication bias by using the Egger's test.RESULTS: Overall, 10 studies were included. The combined outcomes suggested a significant influence of berberine administration on body mass index (BMI) (WMD: -0.29 kg/m, 95% CI: -0.51 to -0.08, p = 0.006) and waist circumference (WC) (WMD: -2.75 cm, 95% CI: -4.88 to -0.62, p = 0.01). However, berberine supplementation yielded no significant decline in body weight (BW) (WMD: -0.11 kg, 95% CI: -0.99 to 0.76, p = 0.79). Following the dose-response evaluation, berberine intake was foundto significantly reduce BMI (r = -0.02) and WC (r = -0.72) based on treatment duration.CONCLUSION: The results of the current study support the use of berberine supplementation for the improvement of obesity indices.

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PMID: 

Oxid Med Cell Longev. 2020 ;2020:2963020. Epub 2020 Mar 9. PMID: 32215171

Abstract Title: 

Red Beetroot Extract Abrogates Chlorpyrifos-Induced Cortical Damage in Rats.

Abstract: 

Organophosphorus insecticides including chlorpyrifos (CPF) are mainly used for agriculture, household, and military purposes; their application is associated with various adverse reactions in animals and humans. This study was conducted to evaluate the potential neuroprotective effect of red beetroot methanolic extract (RBR) against CPF-induced cortical damage. Twenty-eight adult male Wistar albino rats were divided into 4 groups (= 7 in each group): the control group was administered physiological saline (0.9% NaCl), the CPF group was administered CPF (10 mg/kg), the RBR group was administered RBR (300 mg/kg), and the RBR+CPF group was treated with RBR (300 mg/kg) 1 hr before CPF (10 mg/kg) supplementation. All groups were treated for 28 days. Rats exposed to CPF exhibited a significant decrease in cortical acetylcholinesterase activity and brain-derived neurotrophic factor and a decrease in glial fibrillary acidic protein. CPF intoxication increased lipid peroxidation, inducible nitric oxide synthase expression, and nitric oxide production. This was accompanied by a decrease in glutathione content and in the activities of glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase in the cortical tissue. Additionally, CPF enhanced inflammatory response, indicated by increased levels and expression of interleukin-1and tumor necrosis factor-. CPF triggered neuronal apoptosis by upregulating Bax and caspase-3 and downregulating Bcl-2. However, RBR reversed the induced neuronal alterations following CPF intoxication. Our findings suggest that RBR can minimize and prevent CPF neurotoxicity through its antioxidant, anti-inflammatory, and antiapoptotic activities.

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PMID: 

J Physiol. 2020 May 5. Epub 2020 May 5. PMID: 32368787

Abstract Title: 

Beetroot juice lowers blood pressure and improves endothelial function in pregnant eNOSmice: importance of nitrate-independent effects.

Abstract: 

KEY POINTS: Maternal hypertension is associated with increased rates of pregnancy pathologies, including fetal growth restriction, due at least in part to reductions in nitric oxide (NO) bioavailability and associated vascular dysfunction. Dietary nitrate supplementation, from beetroot juice (BRJ), has been shown to increase NO bioavailability and improve cardiovascular function in both preclinical and clinical studies. This study is the first to investigate effects of dietary nitrate supplementation in a pregnant animal model. Importantly, effects of nitrate-containing BRJ were compared with both 'placebo' (nitrate-depleted) BRJ as well as water to control for potential nitrate-independent effects. Our data show novel, nitrate-independent effects of BRJ to lower blood pressure and improve vascular function in endothelial nitric oxide synthase knockout (eNOS) mice. These findings suggest potential beneficial effects of BRJ supplementation in pregnancy, and emphasise the importance of accounting for nitrate-independent effects of BRJ in study design and interpretation.ABSTRACT: Maternal hypertension associates with adverse pregnancy outcomes, including fetal growth restriction (FGR), due in part to reductions in nitric oxide (NO) bioavailability. We hypothesized that maternal dietary nitrate administration would increase NO bioavailability to reduce systolic blood pressure (SBP), improve vascular function and increase fetal growth in pregnant endothelial NO synthase knockout (eNOS) mice, which exhibit hypertension, endothelial dysfunction and FGR. Pregnant wildtype (WT) and eNOSmice were supplemented with nitrate-containing beetroot juice (BRJ+) from gestational day (GD) 12.5. Control mice received an equivalent dose of nitrate-depleted BRJ (BRJ-) or normal drinking water. At GD17.5, maternal SBP was measured; at GD18.5, maternal nitrate/nitrite concentrations, uterine artery (UtA) blood flow and endothelial function were assessed, and pregnancy outcomes determined. Plasma nitrate concentrations were increased in both WT and eNOSmice supplemented with BRJ+ (P

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PMID: 

Biofactors. 2017 Jul 8 ;43(4):567-576. Epub 2017 May 16. PMID: 28509396

Abstract Title: 

Anti-inflammatory, antioxidant, and immunomodulatory effects of curcumin in ovalbumin-sensitized rat.

Abstract: 

BACKGROUND: Anti-inflammatory and antioxidant properties of curcumin have been shown. In this study, anti-inflammatory, antioxidant, and immunomodulatory effects of curcumin in sensitized rat were evaluated.METHODS: Six groups of rats including control (C), ovalbumin-sensitized (as a rat model of asthma, S), S groups treated with curcumin (Cu 0.15, 0.30, and 0.60 mg/mL), and 1.25μg/mL dexamethasone (S + D) were studied. Curcumin and dexamethasone were given in animals' drinking water during sensitization period. Total and differential WBC count, PLA2, TP, IFN-γ, IL-4, IgE, oxidant, and antioxidant biomarker levels in bronchoalveolar lavage fluid (BALF) were examined.RESULTS: Total WBC, neutrophil and eosinophil counts, levels of PLA2, TP, IgE, IL-4, NO, NO, and MDA in BALF were increased but lymphocyte percentage, SOD, CAT, thiol, and IFN-γ levels and IFN-γ/IL-4 ratio decreased in S animals compared to controls (P 

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PMID: 

BMC Vet Res. 2020 Feb 5 ;16(1):44. Epub 2020 Feb 5. PMID: 32024502

Abstract Title: 

Betulinic acid shows anticancer activity against equine melanoma cells and permeates isolated equine skin in vitro.

Abstract: 

BACKGROUND: Equine malignant melanoma (EMM) is a frequently occurring dermoepidermal tumor in grey horses. Currently available therapies are either challenging or inefficient. Betulinic acid (BA), a naturally occurring triterpenoid, is a promising compound for cancer treatment. To evaluate the potential of BA as a topical therapy for EMM, its anticancer effects on primary equine melanoma cells and dermal fibroblasts and its percutaneous permeation through isolated equine skin were assessed in vitro.RESULTS: BA showed antiproliferative and cytotoxic effects on both primary equine melanoma cells and fibroblasts in a time- and dose-dependent manner. The lowest half-maximal inhibitory concentrations were obtained 96 h after the beginning of drug exposure (12.7 μmol/L and 23.6 μmol/L for melanoma cells eRGO1 and MelDuWi, respectively, in cytotoxicity assay). High concentrations of the compound were reached in the required skin layers in vitro.CONCLUSION: BA is a promising substance for topical EMM treatment. Further clinical studies in horses are necessary to assess safety and antitumoral effects in vivo.

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PMID: 

J Biomed Nanotechnol. 2020 Feb 1 ;16(2):235-251. PMID: 32252884

Abstract Title: 

The Antitumor Activity of Betulinic Acid-Loaded Nanoliposomes Against Colorectal Cancerandvia Glycolytic and Glutaminolytic Pathways.

Abstract: 

The purpose of this study is to develop betulinic acid loaded nanoliposomes to improve the chemotherapy effect of colorectal cancer. The cellular uptake and anti-tumor effects of betulinic acid loaded nanoliposomeswere characterized and evaluated, and their effects on glycolysis, glutamine decomposition and key anti-cancer targets were analyzed. Moreover, their anticancer efficacy was assessed. Compared with free betulinic acid, the cellular uptake and anti-tumor activity of betulinic acid-loaded nanoliposomes were significantly enhanced; these nanoliposomes significantly suppressed the proliferation and glucose uptake of colorectal cancer cells. Mechanistically, the anti-colorectal cancer effect of betulinic acid-loaded nanoliposomes was confirmed by their triggering of cellular apoptosis and regulating the potential glycolytic and glutaminolytic targets and pathways. After tumor proliferation was inhibited and colorectal cancer cells apoptosis, the anticancer effect of betulinic acid loaded nanoliposomeswas significantly enhanced. All in all, betulinic acid loaded nanoliposomes are expected to be an effective drug delivery system for colorectal cancer treatment.

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PMID: 

Cell Biochem Funct. 2020 Apr 13. Epub 2020 Apr 13. PMID: 32283563

Abstract Title: 

Betulinic acid triggers apoptosis and inhibits migration and invasion of gastric cancer cells by impairing EMT progress.

Abstract: 

Gastric cancer (GC) is one of the most prevalent types of malignancies. Betulinic acid (BA) is a natural pentacyclic triterpene with a lupine structure. However, to the best of our knowledge, there is no research study on the anti-tumour and anti-metastasis effect of BA on GC. In this study, we assessed the anti-cancer effect of BA on human GC cells in vitro and in vivo. We first investigated the cytotoxicity and anti-proliferation effect of BA on GC cells of SNU-16 and NCI-N87. The results indicated that BA had significant cytotoxic and inhibitory effects on GC cells in a dose- and time-dependent manner. To further study the cytotoxic action of BA on GC cells, we assessed the apoptotic induction effect of BA on SNU-16 cells and found that BA distinctly induced apoptosis in SNU-16 cells. In addition, BA inhibited the migratory and invasive abilities of SNU-16 cells. Western-blot analysis revealed that BA suppressed the migration and invasion of GC cells by impairing epithelial-mesenchymal transition progression. Furthermore, in vivo experiments showed that BA could delay tumour growth and inhibit pulmonary metastasis, which is consistent with the results of in vitro studies. Overall, we evaluated the anti-cancer effect of BA on human GC cells in vivo and in vitro, and the present study provides new evidence on the use of BA as a potential anti-cancer drug for GC treatment. SIGNIFICANCE OF THE STUDY: BA significantly suppressed proliferation and triggered apoptosis in GC cells. Additionally, BA remarkably inhibited migration and invasion of GC cells by impairing the epithelial-mesenchymal transition signalling pathway. It is worth noting that BA drastically retarded tumour growth in the xenograft mouse model of GC. Our results indicated that BA can be considered a candidate drug for GC therapy.

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PMID: 

Cancers (Basel). 2020 Apr 15 ;12(4). Epub 2020 Apr 15. PMID: 32326583

Abstract Title: 

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma.

Abstract: 

Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant origin, can cross the blood-brain barrier. Here, we investigated the antitumor effects of BA on typical glioblastoma cell lines and primary glioblastoma cells from patients, as well as corresponding temozolomide-resistant cells. Our findings verified that BA significantly reduced growth in all examined cells. Furthermore, gene-expression array analysis showed that the unfolded-protein response was significantly affected by BA. Moreover, BA treatment increased activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptotic pathway, and reduced specificity protein 1 (Sp1) expression. However, Sp1 overexpression reversed the observed cell-growth inhibition and PERK/CHOP signaling activation induced by BA. Because temozolomide-resistant cells exhibited significantly increased Sp1 expression, we concluded that Sp1-mediated PERK/CHOP signaling inhibition protects glioblastoma against cancer therapies; hence, BA treatment targeting this pathway can be considered as an effective therapeutic strategy to overcome such chemoresistance and tumor relapse.

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PMID: 

Mol Nutr Food Res. 2020 Apr 6:e1901315. Epub 2020 Apr 6. PMID: 32250024

Abstract Title: 

Lonicera caerulea L. Polyphenols Alleviate Oxidative Stress-Induced Intestinal Environment Imbalance and Lipopolysaccharide-Induced Liver Injury in HFD-Fed Rats by Regulating the Nrf2/HO-1/NQO1 and MAPK Pathways.

Abstract: 

SCOPE: This study investigates the modulatory effects of Lonicera caerulea L. polyphenols (LCPs) on the intestinal environment and lipopolysaccharide (LPS)-induced liver injury via the nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (HO-1)/NQO1 and mitogen-activated protein kinase (MAPK) pathways in a rat model of oxidative stress damage (OSD).METHODS AND RESULTS: To examine the prebiotic properties of LCP, a model of high-fat-diet-induced OSD is established using Sprague Dawley rats. In the colon, treatment with LCP for 8 weeks ameliorates enhanced intestinal permeability (glucagon-like peptide-2 content and occludin protein increase, whereas claudin-2 protein decreases), intestinal inflammation (levels of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, cyclooxygenase-2, and nuclear factor kappa-B p65 (NF-κB p65), decrease), and intestinal OSD (through regulation of the Nrf2/HO-1/NQO1 pathway). Moreover, LCP alleviates LPS-induced liver injury by suppressing the nuclear translocation of NF-κB p65 and activation of the MAPK signaling pathway. Additionally, Bacilli, Lactobacillales, Lactobacillaceae, Lactobacillus, Akkermansia, Actinobacteria, Proteobacteria, Rothia, and Blautia are found to be the key intestinal microbial taxa related to intestinal OSD and LPS-induced liver injury in rats.CONCLUSION: LCP treatment potentially modulates the intestinal environment and alleviates liver injury by suppressing oxidative-stress-related pathways and altering the composition of the intestinal microbiota.

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