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PMID:  Carcinogenesis. 2019 Mar 12 ;40(1):93-101. PMID: 30418550Abstract Title:  Urolithin A gains in antiproliferative capacity by reducing the glycolytic potential via the p53/TIGAR axis in colon cancer cells.Abstract:  Polyphenols have shown promising bioactivity in experimental in vitro and in vivo models for cancer chemoprevention. However, consumed orally, they are often transformed by gut microbes into new active principles with so far incompletely deciphered molecular mechanisms. Here, enterolacton, S-equol and urolithin A as representatives of metabolites of lignans, isoflavones and ellagitannins, respectively, were examined for their impact on HCT116 colon cancer cell growth, cooperativity with oxaliplatin and p53 dependency in vitro. Whereas enterolacton and S-equol (≤60 µM) did not elicit growth inhibition or positive cooperativity with oxaliplatin, urolithin A showed an IC50 value of 19 µM (72 h) and synergism with oxaliplatin. Urolithin A induced p53 stabilization and p53 target gene expression, and absence of p53 significantly dampened the antiproliferative effect of urolithin A (IC50(p53-/-) = 38 µM). P53 was dispensable for the G2/M arrest in HCT116 cells but required for induction of a senescence-like phenotype upon long-term exposure and for the observed synergism with oxaliplatin. Moreover, extracellular flux analyses and knockdown approachesuncovered a reduced glycolytic potential via the p53/TIGAR axis which was linked to the higher susceptibility of wildtype cells to urolithin A. Overall, the p53 status turned out to be an important determinant for the potential benefit of dietary ellagitannins in cancer chemoprevention or use in adjuvant therapy.

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Posted: April 20, 2019, 1:13 pm
PMID:  Obesity (Silver Spring). 2019 Apr ;27(4):612-620. Epub 2019 Feb 15. PMID: 30768775Abstract Title:  Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis.Abstract:  OBJECTIVE: Urolithin A (UroA) is a major metabolite of ellagic acid produced following microbial catabolism in the gut. Emerging evidence has suggested that UroA modulates energy metabolism in various cells. However, UroA's physiological functions related to obesity and insulin resistance remain unclear.METHODS: Male mice were intraperitoneally administrated either UroA or dimethyl sulfoxide (vehicle) along with a high-fat diet for 12 weeks. Insulin sensitivity was evaluated via glucose and insulin tolerance tests and acute insulin signaling. The effects of UroA on hepatic triglyceride accumulation, adipocyte size, mitochondrial DNA content, and proinflammatory gene expressions were determined. The impact of UroA on macrophage polarization and mitochondrial respiration were assessed in bone marrow-derived macrophages.RESULTS: Administration of UroA (1) improved systemic insulin sensitivity, (2) attenuated triglyceride accumulation and elevated mitochondrial biogenesis in the liver, (3) reduced adipocyte hypertrophy and macrophage infiltration into the adipose tissue, and (4) altered M1/M2 polarization in peritoneal macrophages. In addition, UroA favored macrophage M2 polarization and mitochondrial respiration in bone marrow-derived macrophages.CONCLUSIONS: UroA plays a direct role in improving systemic insulin sensitivity independent of its parental compounds. This work supports UroA's role in the metabolic benefits of ellagic acid-rich foods and highlights the significance of its microbial transformation in the gut.

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Posted: April 20, 2019, 1:06 pm
PMID:  J Neuroinflammation. 2019 Mar 14 ;16(1):62. Epub 2019 Mar 14. PMID: 30871577Abstract Title:  Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice.Abstract:  BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by an abnormal accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and impaired neurogenesis. Urolithin A (UA), a gut-microbial metabolite of ellagic acid, has been reported to exert anti-inflammatory effects in the brain. However, it is unknown whether UA exerts its properties of anti-inflammation and neuronal protection in theAPPswe/PS1ΔE9 (APP/PS1) mouse model of AD.METHODS: Morris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia, Aβ deposition, and neurogenesis. The expression of inflammatory mediators were measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The modulating effects of UA on cell signaling pathways were assayed by Western blotting.RESULTS: We demonstrated that UA ameliorated cognitive impairment, prevented neuronal apoptosis, and enhanced neurogenesis in APP/PS1 mice. Furthermore, UA attenuated Aβ deposition and peri-plaque microgliosis and astrocytosis in the cortex and hippocampus. We also found that UA affected critical cell signaling pathways, specifically by enhancing cerebral AMPK activation, decreasing the activation of P65NF-κB and P38MAPK, and suppressing Bace1 and APP degradation.CONCLUSIONS: Our results indicated that UA imparted cognitive protection by protecting neurons from death and triggering neurogenesis via anti-inflammatory signaling in APP/PS1 mice, suggesting that UA might be a promising therapeutic drug to treat AD.

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Posted: April 20, 2019, 12:57 pm
PMID:  Life Sci. 2019 Mar 31. Epub 2019 Mar 31. PMID: 30943382Abstract Title:  Ellagic acid protects against diabetes-associated behavioral deficits in rats: Possible involved mechanisms.Abstract:  AIMS: Diabetes mellitus (DM), a chronic metabolic disease, is associated with behavioral deficits. It has been suggested that ellagic acid (EA), a natural polyphenol compound, has potent anti-diabetic, anti-inflammatory, and neuroprotective properties. The present study was aimed to explore the potential protective effects of EA against diabetes-associated behavioral deficits and verified possible involved mechanisms.MAIN METHODS: Fifty adult male Wistar rats were randomly divided into five groups: i.e., CON: normal rats treated with vehicle (5 ml/kg/day; P.O.), EA: normal rats treated with EA (50 mg/kg/day; P.O.), STZ: diabetic rats treated with vehicle (5 ml/kg/day; P.O.), STZ + INS: diabetic rats treated with insulin (6 IU/rat/day; S.C.), STZ + EA: diabetic rats treated with EA (50 mg/kg/day; P.O.). All the groups were under treatment for eight consecutive weeks. During the seventh and eighth weeks, behavioral functions of the rats were assessed by commonly used behavioral tests. Subsequently, pro- and anti-inflammatory cytokines, neurotrophic factors, and also histological changes were evaluated in both cerebral cortex and hippocampus of the rats.KEY FINDINGS: Chronic EA treatment attenuated anxiety/depression-like behaviors, improved exploratory/locomotor activities, and ameliorated cognitive deficits in diabetic rats. These results were accompanied by decreased blood glucose levels, modulation of inflammation status, improved neurotrophic support, and amelioration of neuronal loss in diabetic rats. In some aspects, treatment with EA was even more effective than insulin therapy.SIGNIFICANCE: The current work's data confirms that EA could potentially serve as a novel, promising, and accessible protective agent against diabetes-associated behavioral deficits, owing to its anti-hyperglycemic, anti-inflammatory, and neurotrophic properties.

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Posted: April 20, 2019, 12:11 pm
PMID:  Environ Toxicol. 2019 Apr 5. Epub 2019 Apr 5. PMID: 30953405Abstract Title:  Ellagic acid ameliorates cisplatin induced hepatotoxicity in colon carcinogenesis.Abstract:  The clinical application of cisplatin (CP), one of the most extensively used antineoplastic drug, is restricted by its numerous side effects. CP's antitumor potential resides in the free generation of reactive oxygen species leading to oxidative stress. This stress is a source of the side effects associated with its use. Ellagic acid (EA), a polyphenol is known to possess multiple health benefits owing to its antioxidant properties. EA is largely metabolized by the colon microbiota of different mammals and therefore was a polyphenol of choice in the present study. The present study was thus carried out to explore the protective potential of EA on CP induced hepatotoxicity in colon tumor bearing mice. The administration of EA (10 mg/kg bwt po daily for 6 weeks) significantly ameliorated the toxicity caused by CP (5 mg/kg bwt ip once a week for 4 weeks). Activities of liver marker enzymes and lactate dehydrogenase were brought back to normal. EA cotreatment also led to a marked reduction in the extent of peroxidative damage to liver tissue as was evident from the improvement in the histopathological changes observed and FT-IR analysis. The present study, therefore, suggests that the administration of EA reduces the CP-induced hepatotoxicity, thereby emerging out as a potential candidate for chemopreventive action.

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Posted: April 20, 2019, 11:52 am
PMID:  Iran J Basic Med Sci. 2018 Dec ;21(12):1232-1237. PMID: 30627366Abstract Title:  Effect of gallic acid on chronic restraint stress-induced anxiety and memory loss in male BALB/c mice.Abstract:  Objectives: Long-term exposure to stress leads to memory deficits and certain mood disorders such as depression and anxiety. We aimed to study the effect of gallic acid (GA) on chronic restraint stress (CRS) induced anxiety and memory deficits in male BALB/c mice.Materials and Methods: Ninety male BALB/c mice were assigned to nine groups including caged control (CC): food-water deprived (FWD), under chronic restraint stress (CRS), CRS+ gallic acid (5, 10, and 20 mg/kg), and gallic acid (5, 10, and 20 mg/kg). Behavioral assays were performed after 21 days of daily treatment with CRS and GA. Serum and brain levels of malondialdehyde (MDA) and total antioxidant capacity (TCA) and serum corticosterone level were also measured.Results: Treatment of CRS mice with GA significantly improved passive avoidance memory in the shuttle box and ameliorated anxiety-like behaviors in the elevated plus maze (EPM) and open filed test (OFT). GA treatment significantly reduced elevated levels of serum and brain MDA and increased brain TCA. CRS and GA did not affect serum corticosterone levels. Treatment of healthy mice with GA had some adverse effects and induced some anxiety and oxidative stress.Conclusion: GA exerted protective effects against stress-induced mood and memory deficit disorders.

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Posted: April 20, 2019, 11:36 am
PMID:  Biomed Res Int. 2018 ;2018:1682743. Epub 2018 Dec 2. PMID: 30627538Abstract Title:  Gallic Acid Attenuates Dimethylnitrosamine-Induced Liver Fibrosis by Alteration of Smad Phosphoisoform Signaling in Rats.Abstract:  Dimethylnitrosamine (DMN) is a potent hepatotoxin, carcinogen, and mutagen. In our previous study, a candidate gallic acid (GA) that widely exists in food and fruit was selected for its capability to alleviate DMN toxicity in vivo. We aimed to investigate the therapeutic potential of GA against DMN-induced liver fibrosis. During the first four weeks, DMN was administered to rats via intraperitoneal injection every other day, except the control group. GA or silymarin was given to rats by gavage once daily from the second to the sixth week. GA significantly reduced liver damage in serum parameters and improved the antioxidant capacity in liver and kidney tissues. Cytokines involved in liver fibrosis were measured at transcriptional and translational levels. These results indicate that GA exhibits robust antioxidant and antifibrosis effects and may be an effective candidate natural medicine for liver fibrosis treatment.

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Posted: April 20, 2019, 11:30 am
PMID:  J Tradit Complement Med. 2019 Jan ;9(1):45-53. Epub 2018 Apr 27. PMID: 30671365Abstract Title:  Antifibrotic effects of gallic acid on hepatic stellate cells:mechanistic study.Abstract:  Few studies reported the antifibrotic effects of gallic acid (GA) despite its known hepatoprotective and antioxidant activities. Accordingly, this study investigated the antifibrotic effects of GA through clarifying its mechanisms on hepatic stellate cells' (HSCs) activation, proliferation and/or apoptosis.effects of GA on HSC-T6 activation/proliferation, morphology and safety on hepatocytes were assessed., hepatic fibrosis was inducedchronic thioacetamide (TAA)-intoxication. TAA-intoxicated rats were treated with silyamrin or GA. At end of experiment, liver functions, hepatic MDA, GSH, PDGF-BB, TGF-β1, TIMP-1 and hydroxyproline were determined. Histological analysis and Sirius red staining of hepatic sections, expressions of alpha-smooth muscle actin (α-SMA), proliferating cellular nuclear antigen (PCNA) and caspase-3 were examined., GA resulted in a concentration and time-dependent inhibition in HSCs activation, proliferation (IC= 45 and 19 μg/mL at 24 and 48 h respectively); restored the quiescent morphology of some activated HSCs plus its safety on hepatocytes., GA reduced ALT, AST, MDA, PDGF-BB levels, collagen deposition and fibrosis score (S1 vs S4); increased caspase-3 expression and restored GSH stores, TGF-β1 level, α-SMA and PCNA expressions. In conclusion, GA counteracted the progression of hepatic fibrosis through reduction of HSCs proliferation/activation mutually with their apoptosis induction.

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Posted: April 20, 2019, 10:55 am
PMID:  Molecules. 2019 Feb 10 ;24(3). Epub 2019 Feb 10. PMID: 30744145Abstract Title:  Total Phenols from Grape Leaves Counteract Cell Proliferation and Modulate Apoptosis-Related Gene Expression in MCF-7 and HepG2 Human Cancer Cell Lines.Abstract:  Grape leaves influence several biological activities in the cardiovascular system, acting as antioxidants. In this study, we aimed at evaluating the effect of ethanolic and water extracts from grape leaves grown in Algeria, obtained by accelerator solvent extraction (ASE), on cell proliferation. The amount of total phenols was determined using the modified Folin-Ciocalteu method, antioxidant activities were evaluated by the 2,2-diphenyl-l-picrylhydrazyl free radical (DPPH*) method andOH radical scavenging using electron paramagnetic resonance (EPR) spectroscopy methods. Cell proliferation of HepG2 hepatocarcinoma, MCF-7 human breast cancer cells and vein human umbilical (HUVEC) cells, as control for normal cell growth, was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay (MTT). Apoptosis- related genes were determined by measuring Bax and Bcl-2 mRNA expression levels. Accelerator solvent extractor yield did not show significant difference between the two solvents (ethanol and water) (>0.05). Total phenolic content of water and ethanolic extracts was 55.41± 0.11 and 155.73 ± 1.20 mg of gallic acid equivalents/g of dry weight, respectively. Ethanolic extracts showed larger amounts of total phenols as compared to water extracts and interesting antioxidant activity. HepG2 and MCF-7 cell proliferation decreased with increasing concentration of extracts(0.5, 1, and 2 mg/mL) added to the culture during a period of 1⁻72 h. In addition, the expression of the pro-apoptotic gene Bax was increased and that of the anti-apoptotic gene Bcl-2 was decreased in a dose-dependent manner, when both MCF-7 and HepG2 cells were cultured with one of the two extracts for 72 h. None of the extracts elicited toxic effects on vein umbilical HUVEC cells, highlighting the high specificity of the antiproliferative effect, targeting only cancer cells. Finally, our results suggested that ASE crude extract from grape leaves represents a source of bioactive compoundssuch as phenols, with potential antioxidants activity, disclosing a novel antiproliferative effect affecting only HepG2 and MCF-7 tumor cells.

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Posted: April 20, 2019, 12:44 am
PMID:  Oncol Rep. 2019 Mar ;41(3):1779-1788. Epub 2019 Jan 22. PMID: 30747218Abstract Title:  Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non‑small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway.Abstract:  Gallic acid (3,4,5‑trihydroxybenzoic acid; GA), a plant‑derived natural phenolic compound, has been reported to prevent the development and progression of various types of cancers. However, there has been little elaboration of the anticancer effects and underlying mechanisms of GA alone and/or in combination withcisplatin in non‑small cell lung cancer (NSCLC). The aim of the present study was to investigate the anticancer effects of GA on NSCLC A549 cells and its auxiliary effects on the anticancer activity of cisplatin. The results revealed that GA inhibited the proliferation and induced the apoptosis of NSCLC A549 cells in dose‑ and time‑dependent manners, which was associated with upregulated B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax) and downregulated Bcl‑2. Notably, the results also indicated that GA enhanced the anticancer effects of cisplatin in the inhibition of cancercell proliferation and the induction of cell apoptosis following elevated Bax expression and suppressed Bcl‑2 expression. Furthermore, the results of the present study also demonstrated that GA exerted independent anticancer effects on NSCLC A549 cells, and facilitated the anticancer effects of cisplatin by modulating the JAK/STAT3 signaling pathway and downstream apoptotic molecules. These results may serve as a rationale for further basic studies and preclinical investigations on the anticancer effects of GA and its auxiliary effects on cisplatin function in human NSCLC.

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Posted: April 20, 2019, 12:37 am
PMID:  Drug Chem Toxicol. 2019 Mar 25:1-12. Epub 2019 Mar 25. PMID: 30907158Abstract Title:  Gallic acid ameliorates sodium arsenite-induced renal and hepatic toxicity in rats.Abstract:  Chronic exposure to toxic inorganic arsenic results in the adverse health effects including skin lesions, cardiovascular diseases, diabetes, neurological disorders, and liver and kidney diseases. Gallic acid (GA) is an important phenolic compound, which could protect different tissues from oxidative stress induced damage. The present study investigated effects of GA against sodium arsenite (SA)-induced renal and hepatic toxicity. Thirty-five rats were randomly divided in to five groups; group 1 was treated with normal saline (2 ml/kg/day, p.o.; for 21 days); group 2 was exposed to SA (10 mg/kg/day, p.o.; for 14 days); groups 3 and 4 were treated with GA (10 and 30 mg/kg/day, respectively; for 7 days) prior to exposure to SA, and treatment was continued up to 21 days in parallel with SA administration; group5 was treated with GA (30 mg/kg/day, p.o.; for 21 days). The level of MDA, IL-1β, NO and glutathione (GSH) and the activity of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) were evaluated in kidney and liver tissues. Histopathological parameters and serum levels ofALT, AST, ALP, Cr and BUN were also assessed. Treatment with GA remarkably improved SA-induced alteration of hematological and histopathological parameters; these protective effects were associated with the reduction of SA-induced elevation of MDA, IL-1β and NO levels as well as reduction of GSH level and GPx, SOD and CAT activity. Our results suggest that GA may inhibit SA-induced kidney and liver toxicity through scavenging reactive free radicals and increasing intracellular antioxidant capacity.

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Posted: April 20, 2019, 12:16 am
PMID:  Metab Brain Dis. 2017 08 ;32(4):1279-1286. Epub 2017 Jun 2. PMID: 28573601Abstract Title:  Gallic acid and p-coumaric acid attenuate type 2 diabetes-induced neurodegeneration in rats.Abstract:  The brain of diabetics revealed deterioration in many regions, especially the hippocampus. Hence, the present study aimed to evaluate the effects of gallic acid and p-coumaric acid against the hippocampal neurodegeneration in type 2 diabetic rats. Adult male albino rats were randomly allocated into four groups: Group 1 served as control ones and others were induced with diabetes. Group 2 considered as diabetic, and groups 3 and 4 were further orally treated with gallic acid (20 mg/kg b.wt./day) and p-coumaric acid (40 mg/kg b.wt./day) for six weeks. Diabetic rats revealed significant elevation in the levels of serum glucose, blood glycosylated hemoglobin and serum tumor necrosis factor-α, while the level of serum insulin was significantly declined. Furthermore, the brain of diabetic rats showed a marked increase in oxidative stress and a decrease of antioxidant parameters as well as upregulation the protein expression of Bax and downregulation the protein expression of Bcl-2 in the hippocampus. Treatment of diabetic rats with gallic acid and p-coumaric acid significantly ameliorated glucose tolerance, diminished the brain oxidative stress and improved antioxidant status, declined inflammation and inhibited apoptosis in the hippocampus. The overall results suggested that gallic acid and p-coumaric acid may inhibit hippocampal neurodegeneration via their potent antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, both compounds can be recommended as hopeful adjuvant agents against brain neurodegeneration in diabetics.

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Posted: April 19, 2019, 11:46 pm
PMID:  Pan Afr Med J. 2018 ;30:205. Epub 2018 Jul 10. PMID: 30574224Abstract Title:  Low laser therapy as an effective treatment of recurrent aphtous ulcers: a clinical case reporting two locations.Abstract:  Apthous ulcers, commonly referred to as canker sores, are the most common ulcerative lesions of the oral mucosa. These are usually painful and are associated with redness and occasional bleeding from the affected area(s). Low Level Laser Therapy (LLLT) has shown excellent results in relieving the pain and complete remission of the oral ulcers. Through a clinical case, we report two locations of oral ulcers treated successfully with diode laser.

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Posted: April 19, 2019, 11:35 pm
PMID:  Int J Oral Maxillofac Surg. 2018 Dec 24. Epub 2018 Dec 24. PMID: 30591391Abstract Title:  Photobiomodulation with low-level laser therapy reduces oral mucositis caused by head and neck radio-chemotherapy: prospective randomized controlled trial.Abstract:  The objective of this study was to assess the effectiveness of photobiomodulation with low-level laser therapy (LLLT) as a preventive and therapeutic procedure for the treatment of oral and oropharyngeal mucositis caused by radio-chemotherapy in patients diagnosed with oral squamous cell carcinoma (SCC). An experimental, prospective, double-blind, randomized controlled study was conducted involving patients diagnosed with oral SCC undergoing oncological treatment. The variables analyzed included grade, appearance, and remission of mucositis. A final sample of 26 patients was included: 11 (42.3%) in the study group and 15 (57.7%) in the control group; their average age was 60.89±9.99years. Statistically significant differences between the groups were observed from week 5 of oncological treatment; 72.7% of the laser group showed normal mucosa (mucositis grade 0), while in the control group, 20.0% showed grade 0 mucositis and 40.0% showed grade 2 mucositis (P0.05). The tolerance evaluation did not show any statistically significant difference between the groups regarding the occurrence of side effects or adverse events during the trial (P>0.05). Photobiomodulation with LLLT reduces the incidence and severity of mucositis in patients treated with radiotherapy±chemotherapy.

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Posted: April 19, 2019, 11:30 pm
PMID:  Lasers Med Sci. 2018 Oct 19. Epub 2018 Oct 19. PMID: 30341668Abstract Title:  Effect of 650-nm low-level laser irradiation on c-Jun, c-Fos, ICAM-1, and CCL2 expression in experimental periodontitis.Abstract:  This study was designed to investigate the effect of 650-nm low-level laser irradiation (LLLI) as an adjunctive treatment of experimental periodontitis. To investigate possible LLLI-mediated anti-inflammatory effects, we utilized an experimental periodontitis (EP) rat model and analyzed c-Jun, c-Fos, ICAM-1, and CCL2 gene expressions on PB leukocytes and in the gingival tissue. Total RNA was isolated from the gingivae and peripheral blood (PB) leukocytes of normal, EP, scaling, and root planing (SRP)-treated EP and LLLI + SRP-treated EP rats, and gene expressions were analyzed by real-time PCR. The productions of c-Jun, c-Fos, ICAM-1, and CCL2 in gingivae were analyzed immunohistochemically. Tartrate-resistant acid phosphatase (TRAP) staining was used to determine osteoclast activity in alveolar bone. The c-Jun and ICAM-1 messenger RNA (mRNA) levels were significantly decreased in the EP rat gingival tissue treated by SRP + LLLI than by SRP, the c-Jun, ICAM-1, and c-Fos mRNA levels on PB leukocytes reduced after LLLI treatment but did not show any significant differences in both groups. There was no significant difference in CCL2 mRNA levels on PB leukocytes and in gingivae between the SRP + LLLI and the SRP groups. The c-Fos mRNA levels in gingivae did not show significant difference in both groups. Immunohistochemistry showed that the CCL2, ICAM-1, c-Jun, and c-Fos productions were significantly reduced in rats of the SRP + LLLI group compared with the only SRP group. LLLI significantly decreased the number of osteoclasts as demonstrated by TRAP staining. The 650-nm LLLI might be a useful treatment modality for periodontitis.

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Posted: April 19, 2019, 11:23 pm
PMID:  Lasers Med Sci. 2019 Feb 7. Epub 2019 Feb 7. PMID: 30729351Abstract Title:  Efficacy of low-level laser for treatment of cancer oral mucositis: a systematic review and meta-analysis.Abstract:  Review effectiveness of low-level laser therapy (LLLT) in the curative treatment of oral mucositis (OM) in patients receiving cancer therapy. A systematic review with meta-analysis was performed using Medline, Embase, and Cochrane Library databases according to PRISMA guidelines, to identify randomized controlled trials (RCT) on OM in patients during and/or after cancer therapy and in which the therapeutic approach was LLLT, with wavelengths between 632 and 970 nm. We considered grade of OM as a dichotomous variable (such as an improvement or not in severe OM on the seventh day of therapy), with the analysis of subgroups of adult patients or children and adolescents and as a continuous variable with determination of the time for the complete resolution and the subgroup analysis occurred with the strata of the samples by treatment only with chemotherapy or chemotherapy and radiotherapy. This paper's protocol was registered a priori at https://www.crd.york.ac.uk/PROSPERO . We found five RCT (total of 315 patients) with adequate methodology. LLLT waseffective, presenting a 62% risk reduction of severe mucositis on the seventh day of evaluation (RR = 0.38 [95% CI, 0.19-0.75]). When we analyzed subgroups, RR was 0.28 (95% CI 0.17-0.46) in the adult studies and 0.90 (95% CI, 0.46-1.78) in the studies with children and adolescents. We demonstrated a mean reduction of 4.21 days in the time of complete resolution of OM (CI - 5.65 to - 2.76) in favor of LLLT. There is moderate evidence that LLLT is effective in resolving OM lesions in adult patients undergoing cancer therapy. LLLT demonstrates potential for decreasing the resolution time of OM lesions by approximately 4.21 days.

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Posted: April 19, 2019, 11:12 pm
PMID:  Melanoma Res. 2019 Mar 6. Epub 2019 Mar 6. PMID: 30855528Abstract Title:  Low-level laser irradiation potentiates anticancer activity of p-coumaric acid against human malignant melanoma cells.Abstract:  p-Coumaric acid (PCA) is a kind of phenolic compound, and as one of the cinnamic acid derivatives, it has many biological functions such as antioxidants, anti-inflammatory, antiplatelet, and anticancer activity. Low-level laser irradiation has received increasing interest in the fields of tissue regeneration and wound healing. In this study, the effect of low-level laser irradiation on human fibroblast cells (human dermal fibroblast) and human melanoma cancer cells (A375 and SK-MEL-37) treated with PCA was investigated. The human dermal fibroblast, A375, and SK-MEL-37 cells were exposed to low-level laser at 660-nm wavelength with 3 J/cm for 90 s, and then the cells were treated with different concentrations of PCA (0-1000 μg/ml for 24 h), separately. In another experiment, first the cells were treated by PCA and then irradiated with low-level laser as described before. The effect of various irradiation energy (1-6 J/cm) on the melanoma cells, which were then treated by PCA, was studied. The cell viability using MTT assay and lactate dehydrogenase assay was determined. Morphological changes owing to apoptosis induction by irradiation and PCA were detected by fluorescence microscopy using acridine orange/ethidium bromide double staining. The results showed that pretreatment with low-level laser irradiation and then PCA reduced the survival and growth of melanoma cells more than the early treatment with PCA and then low-level laser irradiation. Lactate dehydrogenase activity was reduced significantly by preirradiation and then PCA treatment in comparison with the dark group in melanoma cells. The cell cytotoxicity at different irradiation energy and then IC50 concentration of PCA was increased up to 3 J/cm and then decreased following increasing irradiation energy. The morphology study with light microscopy and apoptotic assay using acridine orange/ethidium bromide dual staining confirmed the MTT results. This study showed that low-level laser irradiation alone is not able to kill human normal fibroblast and human melanoma cancer cells. Preirradiation followed by treatment with PCA did not change the cell viability in human fibroblast significantly but reduced the cell viability in melanoma cells presumably through the apoptosis pathway.

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Posted: April 19, 2019, 10:55 pm
PMID:  World J Gastroenterol. 2019 Feb 28 ;25(8):955-966. PMID: 30833801Abstract Title:  Procyanidin B2 protects against diet-induced obesity and non-alcoholic fatty liver diseasethe modulation of the gut microbiota in rabbits.Abstract:  BACKGROUND: Procyanidins have beneficial effects on metabolic syndrome and antimicrobial activity, but the mechanisms underlying these effects are unclear.AIM: To investigate the effects of procyanidin B2 (PB2) on non-alcoholic fatty liver disease and to explore the possible mechanism.METHODS: Thirty male New Zealand white rabbits were randomized into three groups. All of them were fed either a high-fat-cholesterol diet (HCD) or chow diet. HCD-fed rabbits were treated with vehicle or PB2 daily for 12 wk. Body weight and food intake were evaluated once a week. Serum biomarkers, such as total cholesterols, triglycerides, and aspartate transaminase, were detected. All rabbits were sacrificed and histological parameters of liver were assessed by hematoxylin and eosin-stained sections. Moreover, several lipogenic genes and gut microbiota (by 16S rRNA sequencing) were investigated to explore the possible mechanism.RESULTS: The HCD group had higher body weight, liver index, serum lipid profile, insulin resistance, serum glucose, and hepatic steatosis compared to the CHOW group. PB2 treatment prevented HCD-induced increases in body weight and hypertriglyceridemia in association with triglyceride accumulation in the liver. PB2 also ameliorated low-grade inflammation, which was reflected by serum lipopolysaccharides and improved insulin resistance. In rabbit liver, PB2 prevented the upregulation of steroid response element binding protein 1c and fatty acid synthase and the downregulation of carnitine palmitoyltransferase, compared to the HCD group. Moreover, HCD led to a decrease ofin gut microbiota. PB2 significantly improved the proportions ofat the phylum level andat the genus level.CONCLUSION: Our results indicate the possible mechanism of PB2 to improve HCD-induced features of metabolic syndrome and provide a new dietary supplement.

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Posted: April 19, 2019, 10:25 pm
PMID:  Fundam Clin Pharmacol. 2019 Mar 12. Epub 2019 Mar 12. PMID: 30861604Abstract Title:  Procyanidin B2 from lotus seedpod regulate NO/ADMA/DDAH pathway to treat insomnia in rats.Abstract:  Recent studies show that nitric oxide/asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase (NO/ADMA/DDAH) pathway may contribute to the development of sleep disorder. The objective of this study was to explore the inhibitory effect of procyanidin B2 from lotus seedpod (LSPC), a naturally occurring catechin compound, on insomnia and the mechanisms involved. The experiments were performed in brain from Sprague-Dawley rat control and insomniac rats treated or not with LSPC (15, 30, and 45 mg/kg, intragastrically) for 7 days. LSPC treatment reduced walking time and forelimb lifting-up frequency, cerebral levels of noradrenaline, glutamic acid, ADMA, sleep latency, and 8-isoprostane; increased sleep duration, cerebral concentrations of 5-hydroxytryptamine, γ-aminobutyric acid, andNO concomitantly with upregulated cerebral expression of DDAH 1, DDAH2, and neuronal NO synthases in insomniac rats. The present results suggest that LSPC may regulate NO/ADMA/DDAH pathway by inhibiting oxidative stress to treat insomnia in rats when sleep evaluation was achieved on the basis of behavioral criteria.

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Posted: April 19, 2019, 10:05 pm
PMID:  Front Oncol. 2016 ;6:244. Epub 2016 Nov 16. PMID: 27900284Abstract Title:  Effect of Pantethine on Ovarian Tumor Progression and Choline Metabolism.Abstract:  Epithelial ovarian cancer remains the leading cause of death from gynecologic malignancy among women in developed countries. New therapeutic strategies evaluated with relevant preclinical models are urgently needed to improve survival rates. Here, we have assessed the effect of pantethine on tumor growth and metabolism using magnetic resonance imaging and high-resolution proton magnetic resonance spectroscopy (MRS) in a model of ovarian cancer. To evaluate treatment strategies, it is important to use models that closely mimic tumor growth in humans. Therefore, we used an orthotopic model of ovarian cancer where a piece of tumor tissue, derived from an ovarian tumor xenograft, is engrafted directly onto the ovary of female mice, to maintain the tumor physiological environment. Treatment with pantethine, the precursor of vitamin B5 and active moiety of coenzyme A, was started when tumors were ~100 mmand consisted of a daily i.p. injection of 750 mg/kg in saline. Under these conditions, no side effects were observed. High-resolutionH MRS was performed on treated and control tumor extracts. A dual-phase extraction method based on methanol/chloroform/water was used to obtain lipid and water-soluble fractions from the tumors. We also investigated effects on metastases and ascites formation. Pantethine treatment resulted in slower tumor progression, decreased levels of phosphocholine and phosphatidylcholine, and reduced metastases and ascites occurrence. In conclusion, pantethine represents a novel potential, well-tolerated, therapeutic tool in patients with ovarian cancer. Furtherpreclinical studies are needed to confirm the beneficial role of pantethine and to better understand its mechanism of action.

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Posted: April 19, 2019, 9:40 pm
PMID:  Med Sci Monit Basic Res. 2017 Nov 27 ;23:368-372. Epub 2017 Nov 27. PMID: 29176546Abstract Title:  Pantethine Down-Regulates Leukocyte Recruitment and Inflammatory Parameters in a Mouse Model of Allergic Airway Inflammation.Abstract:  BACKGROUND Migration of leukocytes into airways is the hallmark of allergic asthma. The aim of this study was to target the pathological process using pantethine, a pleiotropic natural compound which has been recently shown to down-regulate chemokine-driven T cell migration. MATERIAL AND METHODS Mice were sensitized to the Leishmania LACK antigen, then treated or not treated with pantethine and exposed to LACK or saline aerosol. After sacrifice of the animals, cells in the bronchoalveolar lavage were analyzed and inflammatory parameters were determined to evaluate inflammation seriousness. RESULTS As compared to untreated animals, pantethine-treated animals displayed a moderated response to the allergen, as documented by decreased infiltration of inflammatory cells (all types), in addition to reduced levels of lung Th2 cytokines and circulating LACK-specific IgE. CONCLUSIONS These data reveal the potential therapeutic importance of pantethine to moderate allergic asthma pathology. The compound has been previously shown to exert a broad range of protective activity in animals and in humans, with few or no adverse effects.

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Posted: April 19, 2019, 9:31 pm
PMID:  Oncotarget. 2017 Dec 12 ;8(65):109217-109227. Epub 2017 Nov 24. PMID: 29312602Abstract Title:  Tanshinone IIA inhibits angiogenesis in human endothelial progenitor cellsand.Abstract:  Accumulating evidence reports that bone marrow-derived endothelial progenitor cells (EPCs) regulate angiogenesis, postnatal neovascularization and tumor metastasis. It has been suggested that understanding the molecular targets and pharmacological functions of natural products is important for novel drug discovery. Tanshinone IIA is a major diterpene quinone compound isolated from Danshen () and is widely used in traditional Chinese medicine (TCM). Evidence indicates that tanshinone IIA modulates angiogenic functions in human umbilical vein endothelial cells. However, the anti-angiogenic activity of tanshinone IIA in human EPCs has not been addressed. Here, we report that tanshinone IIA dramatically suppresses vascular endothelial growth factor (VEGF)-promoted migration and tube formation of human EPCs, without cytotoxic effects. We also show that tanshinone IIA markedly inhibits VEGF-induced angiogenesis in the chick embryo chorioallantoic membrane (CAM) model. Importantly, tanshinone IIA significantly attenuated microvessel formation and the expression of EPC-specific markers in theMatrigel plug assay in mice. Further, we found that tanshinone IIA inhibits EPC angiogenesis through the PLC, Akt and JNK signaling pathways. Our report is the first to reveal that tanshinone IIA reduces EPC angiogenesis bothand. Tanshinone IIA is a promising natural product worthy of further development for the treatment of cancer and other angiogenesis-related pathologies.

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Posted: April 19, 2019, 9:03 pm
PMID:  Cancer Med. 2018 02 ;7(2):397-407. Epub 2018 Jan 6. PMID: 29316373Abstract Title:  Tanshinone IIA induces cell death via Beclin-1-dependent autophagy in oral squamous cell carcinoma SCC-9 cell line.Abstract:  Tanshinone IIA (TAN) is one of the major functional compounds of Salvia miltiorrhiza Bunge and possesses the ability to suppress the growth of multiple cancer cell types via its apoptosis- and autophagy-inducing functions. In this study, the effect of TAN therapy on the survival of oral squamous cell carcinoma (OSCC) was evaluated, and the underlying mechanism involved in the treatment was investigated. Human oral squamous cell carcinoma cell SCC-9 was used for in vitro assays and induction in an OSCC xenograft mouse model. The tumor cells were subjected to TAN administration at different concentrations. Then the apoptosis and autophagy processes in SCC-9 cells were evaluated and the activities of Beclin-1/Atg7/Atg12-Atg5 and PI3K/Akt/mTOR pathways were determined. In addition, by knocking down the expression of Beclin-1 in SCC-9 cells, the study also assessed the role of the indicator in the anti-OSCC effect of TAN. Results of in vitro assays were further validated with an OSCC xenograft mouse model. Administration of TAN-induced cell apoptosis and upregulated the expression of cleaved-caspase-3. Simultaneously, the autophagy process in SCC-9 cells was initiated by TAN, which was signaled by the formation of autophagosomes and increase in the ratio of LC3 II/LC3I. The above processes were associated with the activation of Beclin-1/Atg7/Atg12-Atg5 signaling and inhibition of PI3K/Akt/mTOR signaling. Our results also inferred a partially Beclin-1-dependent mechanism of action of TAN in OSCC cells: knockdown of the Beclin-1 blocked the effect of TAN on SCC-9 cells both in vivo and in vitro. Our study provided a preliminary explanation of the mechanism involved in TAN effect: the agent exerted its autophagy-inducing effect against OSCC in a multipronged manner, by both inducing the Beclin-1/Atg7/Atg12-Atg5 pathway and suppressing the PI3K/Akt/mTOR pathway.

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Posted: April 19, 2019, 8:48 pm
PMID:  Iran J Basic Med Sci. 2018 Jan ;21(1):83-88. PMID: 29372041Abstract Title:  Tanshinone IIA inhibits AGEs-induced proliferation and migration of cultured vascular smooth muscle cells by suppressing ERK1/2 MAPK signaling.Abstract:  Objectives: Vascular smooth muscle cells (VSMCs) play a key role in the pathogenesis of diabetic vascular disease. Our current study sought to explore the effects of tanshinone IIA on the proliferation and migration of VSMCs induced by advanced glycation end products (AGEs).Materials and Methods: In this study, we examined the effects of tanshinone IIA by cell proliferation assay and cell migration assay. And we explored the underlying mechanism by Western blotting.Results: AGEs significantly induced the proliferation and migration of VSMCs, but treatment with tanshinone IIA attenuated these effects. AGEs could increase the activity of the ERK1/2 and p38 pathways but not the JNK pathway. Treatment with tanshinone IIA inhibited the AGEs-induced activation of the ERK1/2 pathway but not the p38 pathway.Conclusion: Tanshinone IIA inhibits AGEs-induced proliferation and migration of VSMCs by suppressing the ERK1/2 MAPK signaling pathway.

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Posted: April 19, 2019, 8:36 pm
PMID:  Onco Targets Ther. 2018 ;11:1777-1785. Epub 2018 Mar 29. PMID: 29636623Abstract Title:  Synergistic antitumor effects of tanshinone IIA and sorafenib or its derivative SC-1 in hepatocellular carcinoma cells.Abstract:  Introduction: Hepatocellular carcinoma (HCC) is the most common form of hepatic malignancy in the world. We aimed to determine the effect of tanshinone IIA (Tan-IIA) in combination with sorafenib or its derivative SC-1 on cytotoxicity, apoptosis, and metastasis in human HCC cells.Materials and methods: Cytotoxicity was detected by MTT assay. Apoptosis and sub-G1 populations were analyzed by flow cytometry. Cell migration and invasion were evaluated by Transwell assay. Protein expression was detected by Western blot.Results: Tan-IIA combined with sorafenib or SC-1 exerted synergistic cytotoxicity in HCC cells. Elevated proportions of sub-G1 and caspase activation were observed in the combinative treatments; in addition, marked inhibition of cell migration and invasion, which could be mediated by the modulation of epithelial-mesenchymal transition was observed. pSTAT3 levels were significantly reduced as well.Conclusion: A combination therapy using Tan-IIA and sorafenib or SC-1 could be a promising approach to target HCC, and further preclinical investigations are warranted to establish their synergetic advantage.

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Posted: April 19, 2019, 7:52 pm
Content Was Refreshed: 20 Apr 2019 | 19:59:22

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