PMID: 

J Med Food. 2019 Nov 20. Epub 2019 Nov 20. PMID: 31747348

Abstract Title: 

Effect of Ursolic Acid on Insulin Resistance and Hyperinsulinemia in Rats with Diet-Induced Obesity: Role of Adipokines Expression.

Abstract: 

Excess of visceral adipose tissue (VAT) characteristic of obesity leads to a proinflammatory state disrupting the insulin signaling pathway, triggering insulin resistance (IR) and inflammation, the main processes contributing to obesity comorbidities. Ursolic acid (UA), a pentacyclic triterpenoid occurring in a variety of plant foods, exhibits anti-inflammatory properties. The aim of this study was to evaluate UA effects on IR, hyperinsulinemia, and inflammation in experimental diet-induced obesity. Forty male Wistar rats were randomly assigned to eight groups ( = 5). One group was used for time 0. Three groups were labeled as OBE (control): receiving high-fat diet (HFD; fat content 45.24% of energy) during 3, 6, or 9 weeks; three groups UA-PREV: exposed to simultaneous HFD and UA during 3, 6, or 9 weeks to evaluate UA preventive effects; one group UA-REV: receiving HFD for 6 weeks, followed by simultaneous HFD and UA for three additional weeks to analyze UA reversal effects. Measurements were performed after 3, 6, or 9 weeks of treatment. Adiposity was calculated by weighing VAT after sacrifice. Serum markers were quantified through colorimetricand enzyme-linked immunosorbent assay methods. VAT adipokines RNAm expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction. Data were analyzed by Kruskal-Wallis and Mann-Whitneytests. UA significantly decreased adiposity, IR, hyperinsulinemia, triacylglycerides, and cholesterol levels, and also VAT mRNA expression of MCP-1 (monocyte chemoattractant protein-1), IL (interleukin)-1and IL-6, concomitantly increasing adiponectin levels. UA metabolic effects demonstrated in this study support its potential therapeutic utility to improve IR, hyperinsulinemia, and inflammation observed in obesity and diabetes.

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PMID: 

Diabetes Metab Syndr Obes. 2019 ;12:2597-2608. Epub 2019 Dec 9. PMID: 31849504

Abstract Title: 

Ursolic Acid Treatment Alleviates Diabetic Kidney Injury By Regulating The ARAP1/AT1R Signaling Pathway.

Abstract: 

Purpose: This study aimed to investigate whether ursolic acid (UA) mitigates renal inflammation, oxidative stress and fibrosis by regulating the angiotensin II type 1 receptor-associated protein (ARAP1)/angiotensin II type 1 receptor (AT1R) signaling pathway and subsequently alleviating renal damage.Methods: db/db mice were divided randomly into a diabetic nephropathy (DN) group and a UA treatment group. Light microscopy and electron microscopy were used to observe pathological changes in renal tissues. Immunohistochemistry (IHC) was employed to examine changes in the expression of ARAP1, AT1R, 8-hydroxydeoxyguanosine (8-OHdG), NADPH oxidase 2 (NOX2), the extracellular matrix protein fibronectin (FN), IL-1β and IL-18 in renal tissues. Western blotting and RT-qPCR were used to detect the respective changes in the protein and mRNA levels of ARAP1, AT1R, NOX4, NOX2, transforming growth factor-β1 (TGF-β1), FN, collagen IV, IL-1β and IL-18 in renal tissues and mesangial cells. In addition, immunofluorescence staining was employed to examine changes in FN and NOX2 expression in mesangial cells.Results: UA treatment effectively reduced the body weights and blood glucose levels of db/db mice (p

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PMID: 

Environ Toxicol. 2019 Dec 19. Epub 2019 Dec 19. PMID: 31855318

Abstract Title: 

The miRNA-149-5p/MyD88 axis is responsible for ursolic acid-mediated attenuation of the stemness and chemoresistance of non-small cell lung cancer cells.

Abstract: 

Although the inhibitory roles of ursolic acid (UA) have been established in various tumors, its effects on the stemness of non-small cell lung cancer (NSCLC) cells are still unclear. Here, we constructed NSCLC cells with paclitaxel resistance (A549-PR) and showed that A549-PR exhibited a remarkably stronger stemness than the parental A549 cells, which is evident by the increase of spheroid formation capacity, stemness marker expression, and ALDH1 activity. Additionally, UA significantly reduced the stemness and paclitaxel resistance of A549-PR cells. Mechanistic investigations revealed that UA inhibited the miR-149-5p/MyD88 signaling, which is responsible for UA-mediated effects on the stemness of A549-PR cells. Notably, miR-149-5p/MyD88 axis promoted the stemness of A549 cells, while inhibition of this axis attenuated the stemness of A549-PR cells. Therefore, these results suggest that UA could attenuate the stemness and chemoresistance of NSCLC cells through targeting miR-149-5p/MyD88 axis.

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PMID: 

J Control Release. 2020 Jan 8 ;320:168-178. Epub 2020 Jan 8. PMID: 31926193

Abstract Title: 

Solubilization and delivery of Ursolic-acid for modulating tumor microenvironment and regulatory T cell activities in cancer immunotherapy.

Abstract: 

Ursolic acid (UA) is a potent triterpenoid compound found in plants and fruits with activities modulating key cell signaling pathways involving STATs, NF-κB, and TRAIL. But it's highly hydrophobic and very poorly soluble in nature. It had been prepared as nanocrystals, solid dispersion and loaded in nanoparticles but the achieved systemic exposure and circulation half-life were not ideal. We reported the development of UA-liposomes made by HPβCD assisted active loading. Compared to lipid suspensions of UA (Lipid-UA) with similar lipid composition, the novel process enabled the formation of UA-Ca crystalline structures inside the liposomes and therefore sustained release of UA in vivo. While the UA-liposomes were not generally toxic towards 4T1 triple negative breast cancer cells, they could effectively modulate CD4CD25Foxp3T cells from 4T1 tumor bearing mouse by inhibiting STAT5 phosphorylation and IL-10 secretion. In vivo administration of UA-liposomes at 10 mg/kg dose led to reduced numbers of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) residing in tumor tissues. These changes signified the correction of the tumor mediated immune-suppressive microenvironment. The UA-liposomes treatment alone was already effective in deterring tumor growth. Such a formulation may be highly promising as an immunotherapy agent and be combined with chemotherapeutics or targeted drugs.

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PMID: 

Free Radic Biol Med. 2020 Jan 23. Epub 2020 Jan 23. PMID: 31981623

Abstract Title: 

Ellagic acid protects Caco-2 cell monolayers against inflammation-induced permeabilization.

Abstract: 

Chronic intestinal inflammation involves a cycle of oxidative stress, activation of redox sensitive transcription factors, and barrier permeabilization. The latter can lead to systemic inflammation and its associated co-morbidities. Diet can play a major role in the modulation of intestinal inflammation. Among plant bioactives, ellagic acid (EA) was reported to inhibit inflammatory bowel disease in animal models. This work investigated the mechanisms by which EA inhibits tumor necrosis factor alpha (TNFα)-induced inflammation, oxidative stress, and loss of barrier integrity. Caco-2 cells differentiated into an intestinal epithelial cell monolayer were incubated with TNFα (10 ng/ml), in the presence of different EA concentrations. TNFα triggered interleukin (IL) 6 and 8 release into the medium, which was inhibited by EA in a dose-dependent manner (IC = 17.3 μM for IL-6). TNFα also led to: i) increased ICAM-1 and NLRP3 expression; ii) loss of epithelial barrier function; iii) increased oxidant production from NOX and mitochondrial origin; iv) NF-κB and ERK1/2 activation; and v) increased MLCK gene expression and MLC phosphorylation. EA (10-40 μM) inhibited all these adverse effects of TNFα. EA mainly acted through NF-κB and ERK1/2 inhibition, breaking the cycle of inflammation, oxidative stress, redox-sensitive pathway (e.g. NF-κB, ERK1/2) activation and intestinal permeabilization. This suggests that consumption of EA, via foods or supplements, may afford a strategy to mitigate intestinal inflammation and its associated co-morbidities.

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PMID: 

Inflammopharmacology. 2020 Feb ;28(1):1-18. Epub 2019 Dec 2. PMID: 31792765

Abstract Title: 

Modulation of cell signaling pathways by Phyllanthus amarus and its major constituents: potential role in the prevention and treatment of inflammation and cancer.

Abstract: 

The causal and functional connection between inflammation and cancer has become a subject of much research interest. Modulation of cell signaling pathways, such as those involving mitogen activated protein kinases (MAPKs), nuclear factor kappaβ (NF-κB), phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt), and Wnt, and their outcomes play a fundamental role in inflammation and cancer. Activation of these cell signaling pathways can lead to various aspects of cancer-related inflammation. Hence, compounds able to modulate inflammation-related molecular targets are sought after in anticancer drug development programs. In recent years, plant extracts and their metabolites have been documented with potential in the prevention and treatment of cancer and inflammatory ailments. Plants possessing anticancer and anti-inflammatory properties due to their bioactive constituents have been reported to modulate the molecular and cellular pathways which are related to inflammation and cancer. In this review we focus on the flavonoids (astragalin, kaempferol, quercetin, rutin), lignans (phyllanthin, hypophyllanthin, and niranthin), tannins (corilagin, geraniin, ellagic acid, gallic acid), and triterpenes (lupeol, oleanolic acid, ursolic acid) of Phyllanthus amarus, which exert various anticancer and anti-inflammatory activities via perturbation of the NF-κB, MAPKs, PI3K/Akt, and Wnt signaling networks. Understanding the underlying mechanisms involved may help future research to develop drug candidates for prevention and new treatment for cancer and inflammatory diseases.

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PMID: 

Drug Chem Toxicol. 2020 Jan 3:1-10. Epub 2020 Jan 3. PMID: 31899970

Abstract Title: 

Effect ofandleaf extracts on selected biochemical indices inmodel of neurotoxicity.

Abstract: 

Aluminum (Al)-induced toxicity in fruit fly (is one of the established models for studying neurotoxicity and neurodegenerative diseases. Alkaloid phytochemicals have been reported to exhibit neuroprotective effects. Therefore, the aim of this study is to determine the effect of alkaloid extracts ofandleaves on Al-induced toxicity in wild typeThe flies were exposed to diets containing 40 mM AlCl, and the alkaloid extracts (0.1 and 1 mg/ml). Thereafter, the flies were assessed for learning and memory, as well as locomotor performance 14 days post-treatment. This was followed by homogenizing the flies and the homogenates were assayed for acetylcholinesterase, monoamine oxidase and catalase activities, as well as the malondialdehyde content. The results showed that the alkaloid extracts of both leaves could ameliorate the aluminum-induced behavioral and biochemical impairments in the flies. The HPLC analysis of the alkaloid contents revealed that there is an abundance of Amaryllidaceae alkaloids, caffeine and carpaine. Thus, alkaloid extracts from these leaves could serve as promising therapeutic candidates for the management of neurodegenerative disease.

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PMID: 

J Bodyw Mov Ther. 2020 Jan ;24(1):15-18. Epub 2019 May 4. PMID: 31987536

Abstract Title: 

Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial.

Abstract: 

OBJECTIVE: This study examined the effects of treatment with Phyllanthus amarus nanoparticle gel applied by phonophoresis (PP) and ultrasound therapy (UT) in patients with symptomatic knee osteoarthritis (OA) using a randomized, double-blind, controlled trial.METHODS: Patients with knee OA (n = 40; mean age ± SD, 64.30 ± 9.71 years), who had visual analogue scale (VAS) scores for knee pain intensity of 68.00 ± 9.58 (UT group) and 71.00 ± 8.74 (PP group, respectively) before treatment, were randomly allocated into two groups. Both groups were treated with an ultrasound program in continuous mode, 1.0 W/cm, 10 min per session, for 10 sessions. Nanoparticles of P. amarus were used in the PP group, whereas a nondrug coupling gel was used in the UT group. The 6-min walk test (6-MWT) was performed to evaluate functional capacity. The VAS and the 6-MWT were evaluated before and after 10 treatment sessions in both groups using a double-blind procedure.RESULTS: VAS and 6-MWT showed significant improvement after treatment in both groups (p 

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PMID: 

Biomolecules. 2020 Jan 5 ;10(1). Epub 2020 Jan 5. PMID: 31948119

Abstract Title: 

Bothand Metformin Extract Improved the Function and Histological Structure of Thyroid Gland in Polycystic Ovary Syndrome Rats through Antioxidant Mechanism.

Abstract: 

There is increasing proof that polycystic ovary syndrome (PCOS) is associated with the increased frequency of thyroid disturbances. Chamomile (L.) herb and metformin showed therapeutic efficacy against polycystic ovary syndrome (PCOS). This study aimed to investigate the possible therapeutic effect of both chamomile flower extract and metformin against thyroid damage associated with PCOS in rats. The PCOS model was developed in rats by injecting estradiol valerate, and it was confirmed to be associated with thyroid hypofunction biochemically and pathologically. Treatment of PCOS rats with both chamomile extract and metformin resulted in an improvement in serum level of thyroid hormones (TSH,

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PMID: 

Complement Ther Med. 2020 Jan ;48:102284. Epub 2019 Dec 17. PMID: 31987240

Abstract Title: 

Chamomile (Matricaria recutita L.) and diabetes mellitus, current knowledge and the way forward: A systematic review.

Abstract: 

Chamomile, as a rich source of phenolic compounds and terpenoids, seems to be an effective approach in the management of chronic conditions such as diabetes mellitus. The aim of this systematic review was to evaluate evidence from animal and human studies of the effects of chamomile on metabolic risk markers and complications of diabetes mellitus. The literature search was conducted in PubMed, SCOPUS, Embase, ProQuest and Google Scholar electronic and were considered the articles published on April 2019. Original studies that investigated the effect of chamomile in diabetes mellitus which met the inclusion criteria were eligible. After screening 208 citations, 15 studies were included. The results of these studies demonstrated a significant effect of chamomile administration on metabolic profiles. All 12 studies that examined the impact of chamomile supplementation on glycemic control indicated this feature. Four of the five studies appraising the impact of chamomile on lipid profiles showed that it improved dyslipidemia. Six studies showed that chamomile markedly decreased oxidative stress particularly malondialdehyde. Altogether, four chamomile studies evaluating diabetes complications, including renal and hepatic profiles, found significant decreases compared to controls. These findings extend the novel functions of chamomile in the improvement of glycemic and lipid profiles and oxidative stress indicators in diabetes mellitus and related complications. In-depth studies focusing on underlying mechanisms are warranted to make useful conclusions.

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