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The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, stimulates insulin secretion and efficiently suppresses food intake to reduce body weight. As such, liraglutide is growing in popularity in the treatment of diabetes and chronic weight management. Within the brain, liraglutide has been shown to alter the activity of hypothalamic proopiomelanocortin (POMC) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons. Moreover, the acute activities of POMC and NPY neurons have been directly linked to feeding behavior, body weight, and glucose metabolism. Despite the increased usage of liraglutide and other GLP-1 analogues as diabetic and obesity interventions, the cellular mechanisms by which liraglutide alters the activity of metabolically relevant neuronal populations are poorly understood. In order to resolve this issue, we utilized neuron-specific transgenic mouse models to identify POMC and NPY neurons for patch-clamp electrophysiology experiments. We found that liraglutide directly activated arcuate POMC neurons via TrpC5 channels, sharing a similar mechanistic pathway to the adipose-derived peptide leptin. Liraglutide also indirectly increases excitatory tone to POMC neurons. In contrast, liraglutide inhibited NPY/AgRP neurons through post-synaptic GABA A receptors and enhanced activity of pre-synaptic GABAergic neurons, which required both TrpC5 subunits and K-ATP channels. In support of an additive role of leptin and liraglutide in suppressing food intake, leptin potentiated the acute effects of liraglutide to activate POMC neurons. TrpC5 subunits in POMC neurons were also required for the intact pharmacological effects of liraglutide on food intake and body weight. Thus, the current study adds to recent work from our group and others, which highlight potential mechanisms to amplify the effects of GLP-1 agonists in vivo. Moreover, these data highlight multiple sites of action (both pre- and post-synaptic) for GLP-1 agonists on this circuit. Taken together, our results identify critical molecular mechanisms linking GLP-1 analogues in arcuate POMC and NPY/AgRP neurons with metabolism. Model for direct and indirect effects of GLP-1 and its agonist (liraglutide) on arcuate POMC and NPY/AgRP neurons. Image 1 • Liraglutide directly activates arcuate POMC neurons, while also increasing pre-synaptic excitatory inputs to POMC neurons. • Leptin potentiates the acute effects of liraglutide to activate POMC neurons. • Liraglutide indirectly inhibits arcuate NPY/AgRP neurons via presynaptic TrpC 5 subunits and K ATP channels. • TrpC5 subunits in POMC neurons are required for the intact pharmacological effects of liraglutide. [ABSTRACT FROM AUTHOR]

• SHT inhibits colon cancer cells proliferation and colony formation ability. • STH arrests cell cycle at S and G2/M phase by regulating cell cycle-related genes. • SHT promotes apoptosis, activating both intrinsic and extrinsic pathways. • SHT modulates EGFR and MAPK pathways inducing cancer cells death. The aim of this work was to assess the phytochemical composition and anticancer effects of Strawberry-tree honey (STH) on cellular proliferation, cell cycle and apoptosis in human colon adenocarcinoma (HCT-116) and metastatic (LoVo) cancer cells. Kaempferol and gallic acid were the major phenolic compounds. STH showed higher cytotoxic and anti-colonogenic effects in a time- and dose-dependent manner; it arrested cell cycle in S and G2/M and regulated cell cycle genes, such as cyclin D1, cyclin E, CDK2, CDK4, p21Cip, p27Kip and p-RB. STH treatment promoted apoptosis by modulating key genes (p53, caspase-3, c-PARP) as well as intrinsic (Bax/Bcl2, Cyto C and caspase-9) and extrinsic (Fas L and caspase-8) apoptotic factors. STH also caused endoplasmic reticulum stress by increasing ATF-6 and XBP-1 expressions, suppressed EGFR, HER2 and downstream markers (p-Akt and p-mTOR) and elevated p-p38MAPK and p-ERK1/2. In conclusion, STH have shown a chemo-preventive action on different colon cancer cell models. [ABSTRACT FROM AUTHOR]

• STH induces oxidative stress and decreases antioxidant defenses in colon cancer cells. • STH suppresses NF-кB, p-IкBα and Nrf2 expression in colon cancer cells. • STH decreases mitochondrial respiration and glycolysis in colon cancer cells. • STH inhibits colon cancer cell migration, invasion and EMT. The aim of the present study was to evaluate the effects of Strawberry tree honey (STH) on oxidative stress, metabolic phenotype, migration, invasion and epithelial-mesenchymal transition in adenocarcinoma (HCT-116) and metastatic (LoVo) colon cancer cells as well as in human dermal fibroblasts (HDF). Significant oxidative stress was observed through the increase of intracellular ROS generation, lipid and protein damage and reduction of antioxidant enzyme activities in colon cancer cells; in HDF these effects were limited or none. The expression of NF-кB, p-IкBα, Nrf2 was suppressed after STH treatment in colon cancer cells. All the parameters of mitochondrial respiration and glycolysis were reduced after STH treatment in cancer cells, while they were unchanged in HDF. Wound-closure percentages and the expression of MMP-2, MMP-9, N-cadherin, β-catenin decreased, while those of E-cadherin increased after STH treatment in colon cancer cells. Thus, STH can be used for its potential in cancer prevention. [ABSTRACT FROM AUTHOR]

Abstract Objective Hypothalamic Pro-opiomelanocortin (POMC) and Neuropeptide Y/Agouti-Related Peptide (NPY / AgRP) neurons are critical nodes of a circuit within the brain that sense key metabolic cues as well as regulate metabolism. Importantly, these neurons retain an innate ability to rapidly reorganize synaptic inputs and electrophysiological properties in response to metabolic state. While the cellular properties of these neurons have been investigated in the context of obesity, much less is known about the effects of exercise training. Methods In order to further investigate this issue, we utilized neuron-specific transgenic mouse models to identify POMC and NPY/AgRP neurons for patch-clamp electrophysiology experiments. Results Using whole-cell patch-clamp electrophysiology, we found exercise depolarized and increased firing rate of arcuate POMC neurons. The increased excitability of POMC neurons was concomitant with increased excitatory inputs to these neurons. In agreement with recent work suggesting leptin plays an important role in the synaptic (re)organization of POMC neurons, POMC neurons which express leptin receptors were more sensitive to exercise-induced changes in biophysical properties. Opposite to effects observed in POMC neurons, NPY neurons were shunted toward inhibition following exercise. Conclusions Together, these data support a rapid reorganization of synaptic inputs and biophysical properties in response to exercise, which may facilitate adaptations to altered energy balance and glucose metabolism. Highlights • Exercise inhibited arcuate NPY neurons. • Exercise activated arcuate POMC neurons. • Leptin receptor expressing POMC neurons are much more sensitive to response to exercise. • Exercise effects are transient, lasting only hours for NPY, while sustainable for days in POMC neurons. [ABSTRACT FROM AUTHOR]

Abstract The development of chemo-sensitizers is urgently needed to overcome 5-fluorouracil (5-FU) therapeutic resistance and adverse toxicity in colorectal cancer. This work aims to evaluate the synergic effects of 5-FU and Manuka honey (MH), a rich source of bioactive compounds, in enhancing the anticancer effects of this drug on human colon cancer HCT-116 and LoVo cells. Compared to 5-FU alone, MH synergistically enhanced the chemotherapeutic effects of 5-FU, by reducing cell proliferation through the suppression of EGFR, HER2, p-Akt and p-mTOR expression, and promoting apoptosis by the modulation pro-apoptotic (p53, Bax, Cyto c, FasL caspase-3, −8, −9 and cleave-PARP) and anti-apoptotic (Bcl-2) markers. The activations of p-p38MAPK and p-Erk1/2 pathways and ROS production were also involved in this process. Downregulation of transcription factor (NF-κB and Nrf2) and antioxidant enzyme activity (SOD, catalase, glutathione peroxidase and glutathione reductase) and expression (SOD, catalase and HO-1) were more evident after the combined treatment, leading to more cell death by oxidative stress. Moreover, additive effects were also observed by increasing lipid and protein oxidation and arresting cell cycle. All the parameters of mitochondrial respiration and glycolysis function decreased and both cells entered the quiescent stage after the combined treatments. MH also influenced the anti-metastasis effects of 5-FU by decreasing migration ability, suppressing the expression of MMP-2, MMP-9 and increasing N-cadherin and E-cadherin. In conclusion, MH could be a useful preventive or adjuvant agent in the treatment of colorectal cancer with 5-FU. Graphical abstract fx1 Highlights • Manuka honey enhances 5-FU-induced oxidative stress in colon cancer cells. • Manuka honey enhances 5-FU-induced apoptosis, regulating intrinsic and extrinsic pathway. • Manuka honey and 5-FU combination affects mitochondrial respiration and glycolysis. • Manuka honey enhances 5-FU-induced anti-metastatic effects, controlling MMP-2, MMP-9, and EMT markers expression. [ABSTRACT FROM AUTHOR]

Abstract The redox-system is altered by oxidative stress that is initiated by oxidative agents such as lipopolysaccharides (LPS) and reactive oxygen species (ROS), which are strongly involved in chronic inflammation. Even if Manuka honey (MH) is a good source of polyphenol rich antioxidants, its antioxidant and anti-inflammatory effects are still elusive. The aim of the present work was to explore the protective effects of MH against E.coli LPS stimulated oxidative stress and inflammatory condition and the underlying mechanisms on murine RAW 264.7 macrophages. Pre-treatment with MH markedly inhibited LPS induced ROS and nitrite accumulation and increased the protection against cellular biomolecules such as lipids, proteins, and DNA. Stimulation by LPS suppressed both antioxidant enzyme activities and expressions, and Keap1-Nrf2 signaling pathway which was significantly (p < 0.05) increased in the presence of MH. The pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, and other inflammatory mediators (iNOS) were enhanced after LPS treatment, whereas MH suppressed the expression of these inflammatory markers. Moreover, MH also inhibited the expression of TLR4/NF-кB via IкB phosphorylation in LPS-stressed RAW 264.7 macrophages. In conclusion, MH acted as a natural agent for preventing oxidative and inflammatory-related diseases. Graphical abstract Image 1 Highlights • Manuka honey protected RAW 264.7 macrophages against LPS induces oxidative stress. • Manuka honey improved antioxidant enzyme activities and expressions. • Manuka honey enhanced oxidative defense by activation of Keap1-Nrf2signaling. • Manuka honey suppressed LPS stimulated inflammatory mediators. • Manuka honey suppressed LPS induced TLR4/NF-кB signaling. [ABSTRACT FROM AUTHOR]

The effects of ground pistachio kernel extracts have been evaluated on cellular viability, intracellular reactive oxygen species (ROS) production and cell death in MCF-7 breast cancer cells. Results showed a significant decrease in cell viability in a dose and time dependent manner. 48 h-treatments with different concentrations of the extracts induced intracellular ROS generation and showed that cell death was in an apoptosis-independent manner. It was also found that 48 h-treatments led to a dose dependent reduction in both extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) with respect to untreated cells. Therefore, a considerable alteration of cell bioenergetics would occur as consequence of such treatments. Combination of oxidative stress and bioenergetic alterations could be responsible, at least in part, of the cell death observed in the present model. In conclusion, pistachio kernel extract showed promising beneficial effects that could be exploited as a “natural adjuvant” in combination with chemotherapy treatment. [ABSTRACT FROM AUTHOR]

Excessive amounts of free radicals are deleterious for cells, resulting in cell damage, affecting the wound healing process and causing premature ageing or even neoplastic transformation. Here the capacity of Manuka honey (MH) to protect against oxidative damage and improve the process of skin wound healing was investigated. Up to 16 compounds were identified in MH, with leptosin derivatives and methyl syringate as the major ones. MH protected against apoptosis, intracellular ROS production, and lipid and protein oxidative damage. MH also protected mitochondrial functionality, promoted cell proliferation and activated the AMPK/Nrf2/ARE signalling pathway, as well as the expression of the antioxidant enzymes such as SOD and CAT. Here we describe for the first time that one of the possible mechanisms by which MH exhibits its ability to promote wound healing could be due to its capacity to improve the antioxidant response by activating AMPK phosphorylation and the ARE response. [ABSTRACT FROM AUTHOR]

Uterine leiomyomas, or fibroids, are estrogen dependent benign tumor in women, however, they have limited treatment options. Simvastatin, a drug commonly used to treat high cholesterol. Recently we demonstrated that simvastatin alters estrogen signaling by reducing the expression and trafficking of the estrogen receptor-α (ER-α) in human uterine leiomyoma cells. Caveolae are invaginations of the plasma membrane where ER-α is known to localize and directly interacts with the caveolar protein caveolin-1 (CAV1). This study examines the effects of simvastatin on plasma membrane caveolae and the expression and palmitoylation of CAV1 in human leiomyomas which may influence ER-α signaling. We performed in vitro experiments using primary and immortalized human uterine leiomyoma cells. The caveolae were quantified using transmission electron microscopy. Additionally, we examined the impact of simvastatin treatment (40 mg orally per day for 12 weeks) on human leiomyoma tissue obtained from a randomized controlled trial. The CAV1 protein and mRNA levels were determined using quantitative real-time polymerase chain reactions, western blotting, and immunofluorescence analyses. Simvastatin decreased the number of caveolae in primary leiomyoma cells and reduced CAV1 abundance in whole cells and remarkably the plasma protein fraction. It also decreased CAV1 palmitoylation, a post-translational modification associated with CAV1 activation. The effects of simvastatin on CAV1 were recapitulated in human leiomyoma tissue samples. Our results identify caveolae and CAV1 as novel targets of simvastatin which may contribute to the recently described effects of simvastatin on ER-α signaling and plasma membrane trafficking. Simvastatin decreases caveolae formation and CAV1 palmitoylation in leiomyoma cells and reduces CAV1 abundance in both leiomyoma cells and human tissue, thus highlighting these membrane components as new targets of simvastatin. Palm, palmitate; CAV1, caveolin-1; ER-α, estrogen receptor α, PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; MAPK, mitogen-activated protein kinase. [Display omitted] [ABSTRACT FROM AUTHOR]

Colorectal cancer remains a challenging health burden worldwide. This study aimed to assess the potentiality of Strawberry tree honey (STH), a polyphenol-enriched food, to increase the effectiveness of 5-Fluorouracil (5-FU) in adenocarcinoma (HCT-116) and metastatic (LoVo) colon cancer cell lines. The combined treatment reduced cell viability and caused oxidative stress, by increasing oxidative biomarkers and decreasing antioxidant defence, in a more potent way compared to 5-FU alone. The expression of endoplasmic reticulum (ATF-6, XBP-1) and MAPK (p-p38 MAPK, p-ERK1/2) markers were also elevated after the combined treatment, enhancing the cell cycle arrest through the modulation of regulatory genes (i.e., cyclins and CDKs). Apoptotic gene (i.e., caspases) expressions were also increased after the combined treatment, while those of proliferation (i.e., EGFR), cell migration, invasion (i.e., matrix metallopeptidase) and epithelial–mesenchymal transition (N-cadherin, β-catenin) were suppressed. Finally, the combined treatment led cell metabolism towards a quiescent stage, by reducing mitochondrial respiration and glycolysis. In conclusion, this work represents an initial step to highlight the possibility to use STH in combination with 5-FU in the treatment of colon cancer, even if further in vitro an in vivo studies are strongly needed to confirm the possible chemo-sensitizing effects of STH. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Uterine leiomyomas, the most common tumors of the female reproductive system, are characterized by excessive deposition of disordered stiff extracellular matrix and fundamental alteration in the mechanical signaling pathways. Specifically, these alterations affect the normal dynamic state of responsiveness to mechanical cues in the extracellular environment. These mechanical cues are converted through integrins, cell membrane receptors, to biochemical signals including cytoskeletal signaling pathways to maintain mechanical homeostasis. Leiomyoma cells overexpress β1 integrin and other downstream mechanical signaling proteins. We previously reported that simvastatin, an antihyperlipidemic drug, has antileiomyoma effects through cellular, animal model, and epidemiologic studies.Objective: This study aimed to examine the hypothesis that simvastatin might influence altered mechanotransduction in leiomyoma cells.Study Design: This is a laboratory-based experimental study. Primary leiomyoma cells were isolated from 5 patients who underwent hysterectomy at the Department of Gynecology and Obstetrics of the Johns Hopkins University Hospital. Primary and immortalized human uterine leiomyoma cells were treated with simvastatin at increasing concentrations (0.001, 0.01, 0.1, and 1 μM, or control) for 48 hours. Protein and mRNA levels of β1 integrin and extracellular matrix components involved in mechanical signaling were quantified by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. In addition, we examined the effect of simvastatin on the activity of Ras homolog family member A using pull-down assay and gel contraction.Results: We found that simvastatin significantly reduced the protein expression of β1 integrin by 44% and type I collagen by 60% compared with untreated leiomyoma cells. Simvastatin-treated cells reduced phosphorylation of focal adhesion kinase down to 26%-60% of control, whereas it increased total focal adhesion kinase protein expression. Using a Ras homolog family member A pull-down activation assay, we observed reduced levels of active Ras homolog family member A in simvastatin-treated cells by 45%-85% compared with control. Consistent with impaired Ras homolog family member A activation, simvastatin treatment reduced tumor gel contraction where gel area was 122%-153% larger than control. Furthermore, simvastatin treatment led to reduced levels of mechanical signaling proteins involved in β1 integrin downstream signaling, such as A-kinase anchor protein 13, Rho-associated protein kinase 1, myosin light-chain kinase, and cyclin D1.Conclusion: The results of this study suggest a possible therapeutic role of simvastatin in restoring the altered state of mechanotransduction signaling in leiomyoma. Collectively, these findings are aligned with previous epidemiologic studies and other reports and support the need for clinical trials. [ABSTRACT FROM AUTHOR]

Worldwide, colorectal cancer (CRC) remains a major cancer type and leading cause of death. Unfortunately, current medical treatments are not sufficient due to lack of effective therapy, adverse side effects, chemoresistance and disease recurrence. In recent decades, epidemiologic observations have highlighted the association between the ingestion of several phytochemical-enriched foods and nutrients and the lower risk of CRC. According to preclinical studies, dietary phytochemicals exert chemopreventive effects on CRC by regulating different markers and signaling pathways; additionally, the gut microbiota plays a role as vital effector in CRC onset and progression, therefore, any dietary alterations in it may affect CRC occurrence. A high number of studies have displayed a key role of growth factors and their signaling pathways in the pathogenesis of CRC. Indeed, the efficiency of dietary phytochemicals to modulate carcinogenic processes through the alteration of different molecular targets, such as Wnt/β-catenin, PI3K/Akt/mTOR, MAPK (p38, JNK and Erk1/2), EGFR/Kras/Braf, TGF-β/Smad2/3, STAT1-STAT3, NF-кB, Nrf2 and cyclin-CDK complexes, has been proven, whereby many of these targets also represent the backbone of modern drug discovery programs. Furthermore, epigenetic analysis showed modified or reversed aberrant epigenetic changes exerted by dietary phytochemicals that led to possible CRC prevention or treatment. Therefore, our aim is to discuss the effects of some common dietary phytochemicals that might be useful in CRC as preventive or therapeutic agents. This review will provide new guidance for research, in order to identify the most studied phytochemicals, their occurrence in foods and to evaluate the therapeutic potential of dietary phytochemicals for the prevention or treatment of CRC by targeting several genes and signaling pathways, as well as epigenetic modifications. In addition, the results obtained by recent investigations aimed at improving the production of these phytochemicals in genetically modified plants have been reported. Overall, clinical data on phytochemicals against CRC are still not sufficient and therefore the preventive impacts of dietary phytochemicals on CRC development deserve further research so as to provide additional insights for human prospective studies. [ABSTRACT FROM AUTHOR]

Objective: To test whether mechanical substrate stiffness would influence progesterone receptor B (PRB) signaling in fibroid cells. Uterine fibroids feature an excessive extracellular matrix, increased stiffness, and altered mechanical signaling. Fibroid growth is stimulated by progestins and opposed by anti-progestins, but a functional interaction between progesterone action and mechanical signaling has not been evaluated.Design: Laboratory studies.Setting: Translational science laboratory.Patient(s)/animal(s): Human fibroid cell lines and patient-matched fibroid and myometrial cell lines.Intervention(s): Progesterone receptor B-dependent reporter assays and messenger RNA quantitation in cells cultured on stiff polystyrene plates (3GPa) or soft silicone plates (930KPa). Pharmacologic inhibitors of extracellular signal-related protein kinase (ERK) kinase 1/2 (MEK 1/2; PD98059), p38 mitogen-activated protein kinase (SB202190), receptor tyrosine kinases (RTKs; nintedanib), RhoA (A13), and Rho-associated coiled-coil kinase (ROCK; Y27632).Main Outcome Measure(s): Progesterone-responsive reporter activation.Result(s): Fibroid cells exhibited higher PRB-dependent reporter activity with progesterone (P4) in cells cultured on stiff vs. soft plates. Mechanically induced PRB activation with P4 was decreased 62% by PD98059, 78% by nintedanib, 38% by A13, and 50% by Y27632. Overexpression of the Rho-guanine nucleotide exchange factor (Rho-GEF), AKAP13, significantly increased PRB-dependent reporter activity. Collagen 1 messenger RNA levels were higher in fibroid cells grown on stiff vs. soft plates with P4.Conclusion(s): Cells cultured on mechanically stiff substrates had enhanced PRB activation via a mechanism that required MEK 1/2 and AKAP13/RhoA/ROCK signaling pathways. These studies provide a framework to explore the mechanisms by which mechanical stiffness affects progesterone receptor activation. [ABSTRACT FROM AUTHOR]

A protracted pro-inflammatory state is the common denominator in the development, progression and complication of the common chronic diseases. Dietary antioxidants represent an efficient tool to counteract this inflammatory state. The aim of the present work was to evaluate the effects of strawberry extracts on inflammation evoked by E. Coli lipopolysaccharide in Human Dermal Fibroblast, by measuring reactive oxygen species production, apoptosis rate, antioxidant enzymes activity, mitochondria functionality and also investigating the molecular pathway involved in inflammatory and antioxidant response. The results demonstrated that strawberry pre-treatment reduced intracellular reactive oxygen species levels, apoptotic rate, improved antioxidant defences and mitochondria functionality in lipopolysaccharide -treated cells. Strawberry exerted these protective activities through the inhibition of the NF-kB signalling pathway and the stimulation of the Nrf2 pathway, with a mechanism AMPK-dependent. These results confirm the health benefits of strawberry in the prevention of inflammation and oxidative stress condition in lipopolysaccharide-treated cells. [ABSTRACT FROM AUTHOR]

• The melanocortin system is conserved across species and an important regulator of metabolism. • Melanocortin neurons have diverse projections and heterogenous molecular profiles. • The melanocortin circuit rapidly adapts to metabolic signals/challenges and energy state. • Exercise (during and after) exerts opposing effects on POMC and NPY/AgRP neurons. • Defining flexibility of relevant neural circuits may advance therapeutics of metabolic disease. Dysfunction in neurophysiological systems that regulate food intake and metabolism are at least partly responsible for obesity and related comorbidities. An important component of this process is the hypothalamic melanocortin system, where an imbalance can result in severe obesity and deficits in glucose metabolism. Exercise offers many health benefits related to cardiovascular improvements, hunger control, and blood glucose homeostasis. However, the molecular mechanism underlying the exercise-induced improvements to the melanocortin system remain undefined. Here, we review the role of the melanocortin system to sense hormonal, nutrient, and neuronal signals of energy status. This information is then relayed onto secondary neurons in order to regulate physiological parameters, which promote proper energy and glucose balance. We also provide an overview on the effects of physical exercise to induce biophysical changes in the melanocortin circuit which may regulate food intake, glucose metabolism and improve overall metabolic health. [ABSTRACT FROM AUTHOR]

The aim of the present work was to evaluate the phenolic profile of the ‘Brava’ extra virgin olive oil and assess its potential as a “natural adjuvant” in combination with chemotherapy treatment. The total phenol content of the phenolic extracts was 764 mg gallic acid equivalents/kg and the total antioxidant capacity was 2309, 1881 and 2088 μM trolox equivalents/kg determined by Diphenyl-1-picrylhydrazyl free radical method, Ferric Reducing Antioxidant Power and Trolox Equivalent Antioxidant Capacity assay, respectively. Secoiridoids comprised 83% of the total phenolic compounds. The main secoiridoid from oleuropein was the main isomer of oleuropein aglycone (74 mg/kg). The main secoiridoid from ligstroside was the main isomer of ligstroside aglycone (214 mg/kg). These phenolic extracts showed a significant decrease in cell viability on MCF-7 breast cancer cells in a dose and time dependent manner. 48 h-treatments with different concentrations of the extracts induced intracellular ROS generation and cell death. [ABSTRACT FROM AUTHOR]

During the process of beeswax recycling, many industrial derivatives are obtained. These matrices may have an interesting healthy and commercial potential but to date they have not been properly studied. The aim of the present work was to evaluate the proximal and phytochemical composition, the antioxidant capacity and cytotoxic effects of two by-products from beeswax recycling process named MUD 1 and MUD 2 on liver hepatocellular carcinoma. Our results showed that MUD 1 presented the highest ( P  < .05) fiber, protein, carbohydrate, polyphenol and flavonoid concentration, as well as the highest ( P  < .05) total antioxidant capacity than the MUD 2 samples. MUD1 exerted also anticancer activity on HepG2 cells, by reducing cellular viability, increasing intracellular ROS levels and affecting mitochondrial functionality in a dose-dependent manner. We showed for the first time that by-products from beeswax recycling process can represent a rich source of phytochemicals with high total antioxidant capacity and anticancer activity; however, further researches are necessary to evaluate their potentiality for human health by in vivo studies. [ABSTRACT FROM AUTHOR]

Dietary polyphenols have been recently proposed as activators of the AMP-activated protein kinase (AMPK) signaling pathway and this fact might explain the relationship between the consumption of polyphenol-rich foods and the slowdown of the progression of aging. In the present work, the effects of strawberry consumption were evaluated on biomarkers of oxidative damage and on aging-associated reductions in mitochondrial function and biogenesis for 8 weeks in old rats. Strawberry supplementation increased antioxidant enzyme activities, mitochondrial biomass and functionality, and decreased intracellular ROS levels and biomarkers of protein, lipid and DNA damage (P < 0.05). Furthermore, a significant (P < 0.05) increase in the expression of the AMPK cascade genes, involved in mitochondrial biogenesis and antioxidant defences, was also detected after strawberry intake. These in vivo results were then verified in vitro on HepG2 cells, confirming the involvement of AMPK in the beneficial effects exerted by strawberry against aging progression. [ABSTRACT FROM AUTHOR]

A common denominator in the pathogenesis of most chronic inflammatory diseases is the involvement of oxidative stress, related to ROS production by all aerobic organisms. Dietary antioxidants from plant foods represent an efficient strategy to counteract this condition. The aim of the present study was to evaluate the protective effects of strawberry extracts on inflammatory status induced by E. Coli LPS on RAW 264.7 macrophages by measuring the main oxidative and inflammatory biomarkers and investigating the molecular pathways involved. Strawberry pre-treatment efficiently counteracted LPS-induced oxidative stress reducing the amount of ROS and nitrite production, stimulating endogenous antioxidant enzyme activities and enhancing protection against lipid, protein and DNA damage ( P < 0.05). Strawberry pre-treatment exerted these protective effects primarily through the activation of the Nrf2 pathway, which is markedly AMPK-dependent and also by the modulation of the NF-kB signalling pathway. Finally, an improvement in mitochondria functionality was also detected. The results obtained in this work highlight the health benefit of strawberries against inflammatory and oxidative stress in LPS-stimulated RAW 264.7 macrophages, investigating for the first time the possible involved molecular mechanisms. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox), one of the most used chemotherapeutic agents, is known to generate oxidative stress and block DNA synthesis, which result in severe dose-limiting toxicity. A strategy to protect against Dox toxic effects could be to use dietary antioxidants of which fruits and vegetable are a rich source. In this context, strawberry consumption is associated with the maintenance of good health and the prevention of several diseases, thanks to the antioxidant capacities of its bioactive compounds. The aim of the present study was to evaluate the protective effects of strawberry consumption against oxidative stress induced by Dox in rats. Animals were fed with strawberry enriched diet (15% of the total calories) for two months and Dox (10 mg/kg; i.p.) was injected at the end of the experimental period. Strawberry consumption significantly inhibited ROS production and oxidative damage biomarkers accumulation in plasma and liver tissue and alleviated histopathological changes in rat livers treated with Dox. The reduction of antioxidant enzyme activities was significantly mitigated after strawberry consumption. In addition, strawberry enriched diet ameliorated liver mitochondrial antioxidant levels and functionality. In conclusion, strawberry intake protects against Dox-induced toxicity, at plasma, liver and mitochondrial levels thanks to its high contents of bioactive compounds. [ABSTRACT FROM AUTHOR]

The start-up and subsequent operation of nitritation process was carried out in an airlift reactor (ALR) over 253 days under the HRT shortening condition. The nitrogen loading rate (NLR) of the ALR was finally raised to 4.07 kg m −3 d −1 by shortening the HRT from 22.7 to 2.1 h under 350 mg l −1 of influent ammonium. The improvement of removal efficiency and nitrite accumulation to 98.7% and 92.4% elevated the ammonium removal rate (ARR) and nitrite production rate (NPR) to 3.89 and 2.81 kg m −3 d −1 , respectively. The settling property of the nitritation biomass was improved substantially under the high hydraulic loading condition. Scanning electronic microscopy (SEM), Energy-dispersive X-ray spectroscopy (EDS) and Fourier transform infrared spectroscopy (FTIR) were used to evaluate the physicochemical characteristics of the biomass. The attachment of chemical precipitates on biomass surface was an important reason contributing to the enhancement of nitritation performance through increasing the sludge settleability. The taxonomic complexities of microbial communities from phylum to species level were dealt with the high-throughput pyrosequencing of 16S rRNA gene sequence. It was revealed that Lactobacillus , Thermomonas , Ignavibacterium and Aquimonas were the most abundant genera in the biomass. The low abundance of Nitrospira and Candidatus Brocadia confirmed the possible occurrence of nitrite oxidation as well as anammox in the ALR. [ABSTRACT FROM AUTHOR]

Chemokines play pivotal roles in tissue recruitment and retention of leukocytes, with CX3CR1 recently identified as a chemokine receptor that selectively targets mouse kidney dendritic cells (DCs). We have previously demonstrated increased tubulointerstitial recruitment of human transforming growth factor-β (TGF-β)-producing DCs in renal fibrosis and chronic kidney disease (CKD). However, little is known about the mechanism of human DC recruitment and retention within the renal interstitium. We identified CD1c+ DCs as the predominant source of profibrotic TGF-β and highest expressors of the fractalkine receptor CX3CR1 within the renal DC compartment. Immunohistochemical analysis of diseased human kidney biopsies showed colocalization of CD1c+ DCs with fractalkine-positive proximal tubular epithelial cells (PTECs). Human primary PTEC activation with interferon-γ and tumor necrosis factor-α induced both secreted and surface fractalkine expression. In line with this, we found fractalkine-dependent chemotaxis of CD1c+ DCs to supernatant from activated PTECs. Finally, in comparison with unactivated PTECs, we showed significantly increased adhesion of CD1c+ DCs to activated PTECs via a fractalkine-dependent mechanism. Thus, TGF-β-producing CD1c+ DCs are recruited and retained in the renal tubulointerstitium by PTEC-derived fractalkine. These cells are then positioned to play a role in the development of fibrosis and progression of chronic kidney disease. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that repetitive hypoxia occurs during menstrual cycles due to vasoconstriction and myometrial contraction. It is unknown if hypoxia contributes to the development of uterine leiomyoma, the most common tumor of the female reproductive system. This study aims to characterize the response to hypoxia in leiomyoma and myometrial cells; and determine if an aberrant leiomyoma response to hypoxia may contribute to leiomyomatogenesis. Primary and immortalized leiomyoma and myometrial cells were cultured under normoxic and hypoxic conditions. Expression levels of vascular endothelial growth factor-A (VEGF-A), adrenomedullin (ADM), endothelin-1 (ET-1), and hypoxia-inducible factor-1 alpha (HIF-1α) were measured by qRT-PCR, western blotting and ELISA. Cell proliferation was assessed using MTT assay and proliferating-cell-nuclear-antigen (PCNA) expression. KC7F2 (HIF-1α inhibitor) was used to examine the regulating mechanisms. As expected, hypoxia induced HIF-1α expression in both leiomyoma and myometrial cells. However, hypoxia induced VEGF-A, ET-1 and ADM expression and VEGF-A secretion into the culture media in leiomyoma but not myometrial cells. MTT assay and PCNA expression showed that hypoxia induces proliferation in leiomyoma, but not myometrial cells. HIF-1α inhibitor abrogated the hypoxia-induced VEGF-A, ET-1, ADM, and PCNA expression in leiomyoma cells. This study suggests an aberrant leiomyoma cellular response to hypoxia compared to myometrium. This differential response to menstruation-related repetitive hypoxia episodes may lead to selective proliferation of hypoxia-adaptive leiomyoma cells and contribute to leiomyoma growth. Thus, in addition to adding to our understanding of leiomyoma pathobiology, the study proposes angiogenic factors as a potential leiomyoma therapeutic target. An illustration showing the mechanism by which hypoxia induces angiogenesis and proliferation in leiomyoma cells. HIF-1α, hypoxia inducible factor-1 alpha; HRE, hypoxia response element; VEGF-A, vascular endothelial growth factor-A; ET-1, endothelin-1; ADM, adrenomedullin. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The plant pleiotropic drug resistance (PDR) family of ATP-binding cassette (ABC) transporters is potentially involved in diverse biological processes. Currently, little is known about their actual physiological functions. A Panax ginseng PDR transporter gene (PgPDR1) was cloned and the cDNA has an open reading frame of 4344 bp. The deduced amino acid sequence contained the characteristic domains of PDR transporters: Walker A, Walker B, and ABC signature. Genomic DNA hybridization analysis indicated that one copy of PgPDR1 gene was present in P. ginseng. Subcellular localization showed that PgPDR1-GFP fusion protein was specifically localized in the cell membrane. Promoter region analysis revealed the presence of cis-acting elements, some of which are putatively involved in response to hormone, light and stress. To understand the functional roles of PgPDR1, we investigated the expression patterns of PgPDR1 in different tissues and under various conditions. Quantitative real-time PCR (qRT-PCR) and Western blotting analysis showed that PgPDR1 was expressed at a high level in the roots and leaves compared to seeds and stems. The expression of PgPDR1 was up-regulated by salicylic acid (SA) or chilling, down-regulated by ABA, and regulated differently at transcript and protein levels by MeJA. These results suggest that PgPDR1 might be involved in responding to environmental stresses and hormones. [Copyright &y& Elsevier]

Abstract: This study explores driver adaptation to inclement weather at two temporal scales. The first part of the paper asks whether drivers become acclimatized to weather conditions. This issue is addressed using data for 23 Canadian cities, based on the relationship between exposure to rain, heavy rain, snow, heavy snow, and icy pavement conditions vis-à-vis the risk of collision. The results do not provide strong evidence that drivers become acclimatized to local weather patterns, which underscores the need to look at driver adaptations on shorter time scales with a view to identifying situations or driver groups where risks are particularly elevated. The second part of the paper focuses on the issue of speed – both from the perspective of posted speed limits, and also in terms of driving speeds. The focus is narrowed to one part of Canada and to winter-weather conditions. The risk analysis confirms that days with snow, freezing rain, or other frozen forms of precipitation have elevated collision rates; and it provides evidence that relative risk is higher in rural areas than in nearby cities. The analysis also suggests that collision rates increase as the posted speed limit increases. These findings further highlight the importance of driving speed in weather-related collision occurrence, and that driving above posted speed limits occurs even during inclement weather. [Copyright &y& Elsevier]