PMID: 

Saudi J Biol Sci. 2020 Jan ;27(1):163-172. Epub 2019 Jun 19. PMID: 31889831

Abstract Title: 

Phytochemical profiling, antioxidant and HepG2 cancer cells' antiproliferation potential in the kernels of apricot cultivars.

Abstract: 

Phytochemical composition, in vitro antioxidant and antiproliferative activity against HepG2 cells were studied in the kernels of apricot cultivars grown in the northern areas of Pakistan. Relatively, the kernel of Habbi cultivar/AP-12 depicted significant potential to scavenge DPPH and ABTS+ free radicals as well as oxygen radical absorbance capacity along with highest contents of total flavonoids, phenolics, chlorogenic and syringic acids on dry weight basis. The average concentration of quercetin ranged 0.072-1.343 mg/100 g, and of EGCG from 0.713 to 6.521 mg/100 g with maximum concentration in Hulappa/AP-3 and Kho Chali-Khatta 3/AP-17, respectively. Amygdalin content was highest (1145 mg/100 g) in the kernel of Balaani/AP-14. Highest inhibition of HepG2 cells was found in the kernel of Waflu Chuli/AP-9 (EC50 = 15.70 ± 3.77 mg/mL). The PCA showed significant contributions of polyphenols and flavonoids towards biochemical assays, while CA revealed similarities and associations among various cultivars. Our study revealed that Habbi, Waflu Chuli, Thukdeena and Balaani kernels are rich sources of bioactive compounds and possess significant antioxidant and anticancer activity and can contribute considerably in the prevention and treatment of chronic health disorders.

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PMID: 

Environ Sci Pollut Res Int. 2020 Jan 8. Epub 2020 Jan 8. PMID: 31916166

Abstract Title: 

Hepatic ameliorative role of vitamin B17 against Ehrlich ascites carcinoma-induced liver toxicity.

Abstract: 

Vitamin B17 (VB17), also known as amygdalin and laetrile, is a type of carbohydrate occurring naturally in many plants, such as apricot kernels which have obtained a great interest in cancer therapy. This study aimed to investigate the hepatic protective potential of VB17 against Ehrlich ascites carcinoma (EAC)-bearing mice-induced liver injury, DNA damage, apoptotic P53, and PCNA alterations. A total of 100 female mice were divided into 5 groups (1st group, control group; 2nd group, VB17 group; 3rd group, EAC group; 4th group, pre-treated EAC with VB17; 5th group, co-treated EAC with VB17). Results showed that the presence of VB17 in pre-treated and co-treated groups lead to decreased DNA damage, microsomal protein, NADPH cytochrome c reductase, alpha-fetoprotein (AFP), AST, ALT, and ALP while showed increased cytochrome b5, cytochrome P450 amidopyrine N-demethylase, and aniline 4-hydroxylase compared with the EAC group. Many histopathological changes were observed in liver sections in EAC as moderate fibrosis and marked diffuse necrosis of hepatic tissue, marked inflammatory cells, and congested blood sinusoids. On the other hand, there was a moderate degree of improvement in hepatocytes in liver sections in pre-treated VB17+EAC, while a mild degree of improvement in hepatocytes, moderate cellular infiltrations, and moderate cytoplasmic vacuolization of hepatocytes in liver sections in co-treated EAC+VB17. In addition, there was a depletion in hepatic P53 and PCNA protein expression compared with the EAC group. It could be concluded that VB17 has a potential hepatoprotective effect against EAC cell-induced liver toxicity.

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PMID: 

Mol Biol Rep. 2020 Feb 5. Epub 2020 Feb 5. PMID: 32026321

Abstract Title: 

Bitter apricot ethanolic extract induces apoptosis through increasing expression of Bax/Bcl-2 ratio and caspase-3 in PANC-1 pancreatic cancer cells.

Abstract: 

Pancreatic cancer is the fourth common cause of cancer death. Surgery and chemotherapy are the common treatment strategies for pancreatic cancer patients; however, the response rate is less than 20% at advanced stages. In recent years, growing interest has been dedicated to natural products. Bitter apricot seeds possess a number of pharmacological properties including antitumor activity and amygdalin from bitter apricot seeds can induce apoptosis. In this study, we investigated the cyto/genotoxic effects of bitter apricot ethanolic extract (BAEE) and amygdalin on human pancreatic cancer PANC-1 and normal epithelial 293/KDR cells. BAEE was assessed using high-performance liquid chromatography for the confirmation of the structure. The biological impacts of BAEE and amygdalin on PANC-1 and 293/KDR cells were evaluated by MTT assay, DAPI staining, AnnexinV/PI and Real-time qPCR analysis. BAEE and amygdalin inhibited cancer cell growth in a dose- and time-dependent manner. DAPI staining and flow cytometric analysis revealed fragmented nuclei and elevated numbers of early and late apoptotic cells, respectively. Also, increased Bax/Bcl-2 ratio and upregulation of caspase-3 further confirmed the occurrence of apoptosis in PANC-1 cells, but not in non-cancerous 293/KDR cells. These results indicate that BAEE could mediate apoptosis induction in cancer cells through a mitochondria dependent pathway. These findings suggest that BAEE functions as a potent pro-apoptotic factor for human pancreatic cancer cells without a significant effect on 293/KDR cells. Though, the potent anti-cancer components of BAEE should be further identified. Moreover, in vivo investigations are required to confirm bitter apricot ethanolic extract's clinical value as an anti-tumor drug.

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PMID: 

Anticancer Agents Med Chem. 2020 Jan 19. Epub 2020 Jan 19. PMID: 31958042

Abstract Title: 

Anticancer effect of Amygdalin (vitamin B17) on hepatocellular carcinoma cell line(HepG2) in the presence and absence of Zinc.

Abstract: 

BACKGROUND: Amygdalin (Vitamin B-17) is a naturally occurring vitamin found in the seeds of the fruits of Prunus Rosacea family including apricot, bitter almond, cherry, and peach.OBJECTIVE: The purpose of this study was to examine the effect of amygdalin with and without zinc on hepatocellular carcinoma (HepG2) cell line.METHODS: MTT assay was used to evaluate the cytotoxicity of amygdalin without zinc, amygdalin + 20µmol zinc, and amygdalin + 800µmol zinc on HepG2 cell lines. The cell cycle distribution assay was determined by flow cytometry. Apoptosis was confirmed by Annexin V-FITC/PI staining assay. Moreover, the pathway of apoptosis was determined by the percentage of change in the mean levels of P53, Bcl2, Bax, cytochrome c, and caspase-3.RESULTS: Amygdalin without zinc showed a strong anti-HepG2 activity. Furthermore, HepG2 cell lines treatment with amygdalin + 20µmol zinc and amygdalin + 800µmol zinc showed a highly significant apoptotic effect than the effect of amygdalin without zinc. Amygdalin treatment induced the cell cycle arrest at G2/M and increased the levels of P53, Bax, cytochrome c, and caspase-3 significantly, while it decreased the level ofanti-apoptotic Bcl2.CONCLUSION: Amygdalin is a natural anti-cancer agent which can be used for the treatment of hepatocellular carcinoma. It promotes apoptosis via the intrinsic cell death pathway (the mitochondria-initiated pathway) and cell cycle arrest at G/M. The potency of amygdalin in HepG2 treatment increased significantly by the addition of zinc.

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PMID: 

Int J Biol Macromol. 2020 Jan 28 ;149:600-608. Epub 2020 Jan 28. PMID: 32004612

Abstract Title: 

Fucoidan from Laminaria japonica exerts antitumor effects on angiogenesis and micrometastasis in triple-negative breast cancer cells.

Abstract: 

Fucoidan is a fucose-rich polysaccharide that has gained attention for its various anticancer properties. However, the effect and underlying mechanism of fucoidan on triple-negative breast cancer (TNBC) are still unknown. Herein, we investigated the anticancer potential of fucoidan from Laminaria japonica. We found that fucoidan showed modest antiproliferative activity against TNBC cells, while it effectively reduced migratory and invasive capacities. Mechanistically, fucoidan suppressed activation of MAPK and PI3K followed by inhibition of AP-1 and NF-κB signaling in TNBC. Additionally, fucoidan downregulated expressions of proangiogenic factors in TNBC cells, and fucoidan blocked tumor-elicited tube formation by human umbilical vascular endothelial cells (HUVECs). We also observed that fucoidan blocked tumor adhesion and invasion towards HUVECs. Surprisingly, fucoidan robustly suppressed tube formation on HUVECs. Moreover, fucoidan inhibited in vivo angiogenesis and micrometastasis in a transgenic zebrafish model. Together, L. japonica fucoidan exhibits potent antitumor effects by its attenuation of invasiveness and proangiogenesis in TNBC.

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PMID: 

Neurotherapeutics. 2019 Oct ;16(4):1269-1282. PMID: 31420820

Abstract Title: 

Activation of the miR-34a-Mediated SIRT1/mTOR Signaling Pathway by Urolithin A Attenuates D-Galactose-Induced Brain Aging in Mice.

Abstract: 

Despite tremendous advances in modern medicine, effective prevention or therapeutic strategies for age-related neurodegenerative diseases such as Alzheimer's disease (AD) remain limited. Currently, accumulating evidence has demonstrated that microRNAs (miRNAs) are increasingly associated with age-related diseases and are emerging as promising therapeutic targets. Urolithin A, a metabolite compound resulting from the transformation of ellagitannins by gut bacteria, has been reported to have anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The present study primarily focused on the ameliorative effect of urolithin A on aging mice and on the exploration of the potential mechanisms of such an ameliorative effect on cognitive impairment and brain aging. In this study, we first tested the neuroprotective effect of urolithin A using an in vitro HO-induced PC12 cell oxidative damage model. The in vivoD-gal-induced brain aging model showed that urolithin A significantly suppressed the upregulation of miR-34a induced by D-gal. Moreover, target genes associated with miR-34a were also examined. Urolithin A supplementation ameliorated apoptosis induced by D-gal and rescued miR-34a overexpression-induced impaired autophagy in brain aging mice after a 2-month administration. Furthermore, urolithin A activated autophagy by upregulating the SIRT1 signaling pathway and downregulating the mTOR signaling pathway. In conclusion, urolithin A may exert neuroprotective effects and may aid in preventing D-gal-induced brain aging through activation of the miR-34a-mediated SIRT1/mTOR signaling pathway.

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PMID: 

J Ethnopharmacol. 2020 Mar 25 ;250:112479. Epub 2019 Dec 14. PMID: 31846746

Abstract Title: 

Pancreas protective effects of Urolithin A on type 2 diabetic mice induced by high fat and streptozotocin via regulating autophagy and AKT/mTOR signaling pathway.

Abstract: 

ETHNOPHARMACOLOGICAL RELEVANCE: Urolithin A (UroA), the main intestinal microflora metabolite of ellagic acid of berries, pomegranate,and some other traditional chinese herbals such as emblica officinalis,etc,has been reported to exhibit anti-inflammatory, anti-oxidative, anti-tumor and pro-autophagy effects.AIM OF THE STUDY: This study evaluated the anti-diabetic and pancreas-protective effects of UroA using a mice model of type 2 diabetes and preliminarily explored its effect on autophagy as well as the mechanism involved.MATERIALS AND METHODS: Type 2 diabetes model was induced by high-fat diet (HFD; 60% energy as fat) and low-dose streptozotocin (85 mg/kg) injection. Mice were administered with UroA (50 mg/kg/d) alone or UroA-chloroquine (autophagy inhibitor) combination for 8 weeks.RESULTS: UroA improved symptoms of diabetic mice such as high water intake volume, high urine volume, significantly decreased fasting blood glucose (FBG), after-glucose-loading glucose, glycated hemoglobin (GHb) levels, plasma C-peptide, malondialdehyde (MDA) and interleukin-1β level, increased reduced glutathione (GSH), interleukin-10 content, and glucose tolerance. UroA also improved pancreatic function indexes such as HOMA-β as evidenced by improved pathological and ultrastructural features of the pancreas assessed by light microscopy and transmission electron microscopy (TEM). Accordingly, UroA decreased mitochondrial swelling and myelin-like cytoplasmic inclusions. UroA significantly upregulated the protein levels of microtubule-associated protein 1 light chain 3-II (LC3II) and beclin1, downregulated sequestosome 1 (p62) accompanied by decreased expression of apoptotic protein cleaved caspase3 in pancreas of diabetic mice. In addition, it increased the phosphorylation level of protein kinase B (p-Akt) and mammalian target of rapamycin (p-mTOR). Most of these effects of UroA were reversed by treatment with autophagy inhibitor chloroquine.CONCLUSIONS: Our findings reveal that the pancreas protective effects of UroA against diabetes were partially mediated by its regulation of autophagy and AKT/mTOR signal pathway.

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PMID: 

Mol Nutr Food Res. 2020 Jan 24:e1900390. Epub 2020 Jan 24. PMID: 31976617

Abstract Title: 

Gut metabolite, Urolithin A decreases Actin Polymerization and Migration in Cancer Cells.

Abstract: 

SCOPE: Urolithin A (UA) is a gut-derived metabolite from ellagic acid found in pomegranates, berries and nuts can down-regulate cell proliferation and migration. Cell proliferation and cell motility require actin reorganization which is under control of ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1). The present study explored whether Urolithin A can modify actin cytoskeleton in cancer cells.METHODS: The effect of Urolithin A on globular over filamentous actin ratio was determined utilizing Western blotting, immunofluorescence and flow cytometry. Rac1 and PAK1 levels were measured by qRT-PCR and immunoblotting. As a result, a 24 hour treatment with Urolithin A (20μM) significantly decreased Rac1 and PAK1 transcript levels and activity, depolymerized actin and wound healing. The effect of Urolithin A on actin polymerization was mimicked by pharmacological inhibition of Rac1 and PAK1. The effect was also mirrored by knock down using siRNA.CONCLUSION: Urolithin A leads to disruption of Rac1 and Pak1 activity with subsequent actin depolymerization and migration. Thus, use of dietary Urolithin A in cancer prevention or as adjuvant therapy is promising. This article is protected by copyright. All rights reserved.

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PMID: 

J Diet Suppl. 2020 Jan 29:1-15. Epub 2020 Jan 29. PMID: 31992104

Abstract Title: 

Fisetin Improved Rotenone-Induced Behavioral Deficits, Oxidative Changes, and Mitochondrial Dysfunctions in Rat Model of Parkinson's Disease.

Abstract: 

Oxidative stress plays an important role in the pathogenesis of Parkinson's disease (PD), particularly the inhibition of mitochondrial complex-I. This study aimed to evaluate the effect of fisetin in the rotenone-induced rat model of PD. Rotenone was administered (2mg/kg s.c.) for 35days to induce PD in animals. Fisetin was administered at two doses (10mg/kg and 20mg/kg p.o.) for 25days to the animals that were given rotenone. Behavioral experiment, i.e. cylinder test, was performed to assess the motor asymmetry. Animals were euthanized, and mid brains were isolated for the estimation of tricarboxylic acid cycle enzymes, oxidative measures (lipid peroxidation (LPO), glutathione (GSH) and catalase) and complex-I activity. In addition, histopathological studies were conducted. Fisetin treatment improved motor function in the cylinder test and reversed the rotenone-induced changes in mitochondrial enzymes, striatal dopamine levels, antioxidant enzyme levels and histological changes. An important finding of this study was both the doses of fisetin significantly (

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PMID: 

Exp Clin Endocrinol Diabetes. 2020 Jan 2. Epub 2020 Jan 2. PMID: 31896157

Abstract Title: 

Luteolin Attenuates Diabetic Nephropathy through Suppressing Inflammatory Response and Oxidative Stress by Inhibiting STAT3 Pathway.

Abstract: 

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). DN has many pathological changes, but tubular injury is considered to be a crucial pathological feature and plays a key role in the progression of DN. Accumulating studies have confirmed that Luteolin (3,4,5,7-tetrahydroxyflavone, Lut) possesses anti-inflammatory and antioxidant activities, which may play a role in kidney protection in DN.OBJECTIVES: This paper described the effects of Lut on appropriated tubular injury in the kidneys of db/db mice and searched the possible mechanisms underlying the kidney protection effect in DN.METHODS: Twelve-week-old male C57BL/6 J db/db and C57BL/6 J db/m mice were used for the animal experiments. They were organized into the following five groups for the animal experiments: a db/m group (control, n=6); a db/db group(n=8) ; a db/db group receiving Lut (10 mg/kg/day, n=8)treatment by oral gavage; a db/db group receiving stattic (a selective STAT3 inhibitor,50 mg/Kg/day, n=8) treatment by oral gavage and a db/db group receiving both stattic and Lut treatment by oral gavage.RESULTS: In this study, we found that Lut might ameliorate glomerular sclerosis and interstitial fibrosis in DN mouse models through inhibiting the inflammatory response and oxidative stress. And it might play its biological function mainly through repressing the STAT3 activation.CONCLUSIONS: Lut attenuates DN mainly via suppression of inflammatory response and oxidative response. STAT3 pathway is the potential target, which ultimately reduces renal fibrosis and delays the progress of DN.

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