Angiogenesis Inhibition in the Second-Line Treatment of Metastatic Colorectal Cancer. A Definite Conclusion?

Publication date: Available online 29 July 2017
Source:Seminars in Oncology
Author(s): M. Ducreux, P. Österlund, J.P. Pignon




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Dual-frequency ultrasonic treatment on microstructure and mechanical properties of ZK60 magnesium alloy

Publication date: January 2018
Source:Ultrasonics Sonochemistry, Volume 40, Part A
Author(s): Xingrui Chen, Fangkun Ning, Jian Hou, Qichi Le, Yan Tang
Compared with other dual-frequency acoustic applications, melt-treatment with dual-frequency ultrasound was less researched, especially in magnesium field. In this present work, traditional single-frequency ultrasonic field (SUF) treatment and dual-frequency ultrasonic field (DUF) treatment were used to refine the as-cast microstructure and improve the mechanical properties of the ZK60 (Mg–Zn–Zr) magnesium alloy. The influences of DUF on the microstructure evolution and mechanical properties were systematically investigated, and the cavitation bubble's dynamic behaviors were investigated by numerical simulation. α-Mg grains and second phases were dramatically refined by introduced ultrasound, and DUF showed higher refinement efficiency than SUF. The DUF treatment promoted the formation of small α-Mg globular grains and changed the distribution and morphology of MgZn2 phases. Mechanical properties of the as-cast alloy were much promoted with DUF. Yield strength, ultimate tensile strength and elongation increased to 153MPa, 239MPa and 13.9% respectively after 1400W DUF treatment, which were 30.8%, 42.3% and 58.0% higher than the values obtained from untreated samples and 20.5%, 20.7% and 30.0% higher than 1200W SUF treated samples. The DUF can generate more and larger cavitation bubbles, and make more bubbles into instantaneous bubbles, improving refinement efficiency.



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Hypothalamic mitochondrial abnormalities occur downstream of inflammation in diet-induced obesity

Publication date: Available online 29 July 2017
Source:Molecular and Cellular Endocrinology
Author(s): Rodrigo S. Carraro, Gabriela F. Souza, Carina Solon, Daniela S. Razolli, Bruno Chausse, Roberta Barbizan, Sheila C. Victorio, Licio A. Velloso
Hypothalamic dysfunction is a common feature of experimental obesity. Studies have identified at least three mechanisms involved in the development of hypothalamic neuronal defects in diet-induced obesity: i, inflammation; ii, endoplasmic reticulum stress; and iii, mitochondrial abnormalities. However, which of these mechanisms is activated earliest in response to the consumption of large portions of dietary fats is currently unknown. Here, we used immunoblot, real-time PCR, mitochondrial respiration assays and transmission electron microscopy to evaluate markers of inflammation, endoplasmic reticulum stress and mitochondrial abnormalities in the hypothalamus of Swiss mice fed a high-fat diet for up to seven days. In the present study we show that the expression of the inflammatory chemokine fractalkine was the earliest event detected in this study. Its hypothalamic expression increased as early as 3 h after the introduction of a high-fat diet and was followed by the increase of cytokines. GPR78, an endoplasmic reticulum chaperone, was increased 6 h after the introduction of a high-fat diet, however the actual triggering of endoplasmic reticulum stress was only detected three days later, when IRE-1α was increased. Mitofusin-2, a protein involved in mitochondrial fusion and tethering of mitochondria to the endoplasmic reticulum, underwent a transient reduction 24 h after the introduction of a high-fat diet and then increased after seven days. There were no changes in hypothalamic mitochondrial respiration during the experimental period, however there were reductions in mitochondria/endoplasmic reticulum contact sites, beginning three days after the introduction of a high-fat diet. The inhibition of TNF-α with infliximab resulted in the normalization of mitofusin-2 levels 24 h after the introduction of the diet. Thus, inflammation is the earliest mechanism activated in the hypothalamus after the introduction of a high-fat diet and may play a mechanistic role in the development of mitochondrial abnormalities in diet-induced obesity.



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Gonadotropin-releasing hormone signaling: An information theoretic approach

Publication date: Available online 29 July 2017
Source:Molecular and Cellular Endocrinology
Author(s): Margaritis Voliotis, Kathryn L. Garner, Hussah Alobaid, Krasimira Tsaneva-Atanasova, Craig A. McArdle
Gonadotropin-releasing hormone (GnRH) is a peptide hormone that mediates central control of reproduction, acting via G-protein coupled receptors that are primarily Gq coupled and mediate GnRH effects on the synthesis and secretion of luteinizing hormone and follicle-stimulating hormone. A great deal is known about the GnRH receptor signaling network but GnRH is secreted in short pulses and much less is known about how gonadotropes decode this pulsatile signal. Similarly, single cell measures reveal considerable cell-cell heterogeneity in responses to GnRH but the impact of this variability on signaling is largely unknown. Ordinary differential equation-based mathematical models have been used to explore the decoding of pulse dynamics and information theory-derived statistical measures are increasingly used to address the influence of cell-cell variability on the amount of information transferred by signaling pathways. Here, we describe both approaches for GnRH signaling, with emphasis on novel insights gained from the information theoretic approach and on the fundamental question of why GnRH is secreted in pulses.



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A functional drug re-purposing screening identifies carfilzomib as a drug preventing 17β-estradiol: ERα signaling and cell proliferation in breast cancer cells

Publication date: Available online 29 July 2017
Source:Molecular and Cellular Endocrinology
Author(s): Claudia Busonero, Stefano Leone, Cinzia Klemm, Filippo Acconcia
Most cases of breast cancer (BC) are estrogen receptor α-positive (ERα+) at diagnosis. The presence of ERα drives the therapeutic approach for this disease, which often consists of endocrine therapy (ET). 4OH-Tamoxifen and faslodex (i.e., fulvestrant - ICI182,780) are two ETs that render tumor cells insensitive to 17β-estradiol (E2)-dependent proliferative stimuli and prevent BC progression. However, ET has limitations and serious failures in different tissues and organs. Thus, there is an urgent need to identify novel drugs to fight BC in the clinic. Re-positioning of old drugs for new clinical purposes is an attractive alternative for drug discovery. For this analysis, we focused on the modulation of intracellular ERα levels in BC cells as target for the screening of about 900 Food and Drug Administration (FDA) approved compounds that would hinder E2:ERα signaling and inhibit BC cell proliferation. We found that carfilzomib induces ERα degradation and prevents E2 signaling and cell proliferation in two ERα+ BC cell lines. Remarkably, the analysis of carfilzomib effects on a cell model system with an acquired resistance to 4OH-tamoxifen revealed that this drug has an antiproliferative effect superior to faslodex in BC cells. Therefore, our results identify carfilzomib as a drug preventing E2:ERα signaling and cell proliferation in BC cells and suggest its possible re-position for the treatment of ERα+ BC as well as for those diseases that have acquired resistance to 4OH-tamoxifen.



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A novel Brain Computer Interface for classification of social joint attention in Autism and comparison of 3 experimental setups: a feasibility study

Publication date: Available online 29 July 2017
Source:Journal of Neuroscience Methods
Author(s): Carlos P. Amaral, Marco A. Simões, Susana Mouga, João Andrade, Miguel Castelo-Branco
BackgroundWe present a novel virtual-reality P300-based Brain Computer Interface (BCI) paradigm using social cues to direct the focus of attention. We combined interactive immersive virtual-reality (VR) technology with the properties of P300 signals in a training tool which can be used in social attention disorders such as autism spectrum disorder (ASD).New methodWe tested the novel social attention training paradigm (P300-based BCI paradigm for rehabilitation of joint-attention skills) in 13 healthy participants, in 3 EEG systems. The more suitable setup was tested online with 4 ASD subjects. Statistical accuracy was assessed based on the detection of P300, using spatial filtering and a Naïve-Bayes classifier.ResultsWe compared: 1 − g.Mobilab+ (active dry-electrodes, wireless transmission); 2 − g.Nautilus (active electrodes, wireless transmission); 3 − V-Amp with actiCAP Xpress dry-electrodes. Significant statistical classification was achieved in all systems. g.Nautilus proved to be the best performing system in terms of accuracy in the detection of P300, preparation time, speed and reported comfort. Proof of concept tests in ASD participants proved that this setup is feasible for training joint attention skills in ASD.Comparison with Existing methodsThis work provides a unique combination of 'easy-to-use' BCI systems with new technologies such as VR to train joint-attention skills in autism.ConclusionsOur P300 BCI paradigm is feasible for future Phase I/II clinical trials to train joint-attention skills, with successful classification within few trials, online in ASD participants. The g.Nautilus system is the best performing one to use with the developed BCI setup.



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Acute Ethanol Modulation of Neurocircuit Function in the Nucleus of the Tractus Solitarius

Publication date: Available online 29 July 2017
Source:Brain Research Bulletin
Author(s): Michael A. Aimino, Caitlin Coker, Yuval Silberman
The nucleus of the tractus solitarius (NTS) is a brain stem region critical to many physiologic processes and has been implicated in addiction to multiple classes of abused drugs, including alcohol (EtOH). That said, the mechanism by which EtOH modulates NTS neurocircuit activity is not well characterized and has yet to be examined utilizing electrophysiologic methods in mouse models of alcohol use disorders. To begin to address this gap in knowledge, we sought to use whole-cell and cell-attached recordings to determine the mechanism of acute EtOH action on GABAergic and glutamatergic neurotransmission, as well as on action potential firing in the NTS of adult male, EtOH naïve mice. Bath application of EtOH (50mM) significantly enhanced the frequency of spontaneous inhibitory postsynaptic current events, while increasing the amplitude of these events in half of the neurons tested. This finding suggests a presynaptic mechanism of EtOH action on GABAergic transmission in the NTS as well as a postsynaptic mechanism in subsets of NTS neurons. EtOH application was further associated with a significant decrease in action potential firing in most, but not all, NTS neurons tested. EtOH induced a small but significant decrease in spontaneous excitatory postsynaptic current frequency, indicating that EtOH may also inhibit NTS glutamatergic signaling to some degree. Intriguingly, in vivo EtOH exposure (4g/kg IP) enhanced c-FOS colocalization with tyrosine hydroxylase via immunohistochemical methods, indicating that NTS norepinephrine neurons may be activated by acute EtOH exposure. Although future work is needed, the current data indicate that acute EtOH may enhance GABAergic signaling in local NTS circuits resulting in disinhibition of NTS norepinephrine neurons. Such a finding has important implications in understanding the role of the NTS in the development of alcoholism.



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The roles of sodium-glucose cotransporter 2 inhibitors in preventing kidney injury in diabetes

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Krit Jaikumkao, Anchalee Pongchaidecha, Varanuj Chatsudthipong, Siriporn C. Chattipakorn, Nipon Chattipakorn, Anusorn Lungkaphin
Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) worldwide. The early effective treatment of high plasma glucose could delay or prevent the onset of DN. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are new target treatments for ameliorating high plasma glucose and help to maintain glucose homeostasis in diabetic patients. Reduced renal glucose reabsorption by SGLT2 inhibition seems to have high potential to improve glycemic control in diabetes mellitus (DM) not only through glucose lowering but also through glucose-independent effects such as blood pressure-lowering and direct renal effects in diabetes. Of note, the important events in the pathogenesis of glucose-induced renal injury and DN including oxidative stress, inflammation, fibrosis and apoptosis conditions have shown to be ameliorate after the treatment with SGLT2 inhibitors. Interestingly, SGLT2 inhibitors have been reported to reduce albuminuria in DM via an activation of renal tubuloglomerular feedback by increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction and attenuated diabetes-induced renal hyperfiltration. These effects also help to conserve glomerular integrity. Thus, the treatment of diabetes mellitus using SGLT2 inhibitors could be one of the effective approach for the management of diabetic-associated kidney disease like DN. This review summarizes the up to date information and discusses the bidirectional relationship between the SGLT2 inhibitor treatments and the renal functions that are available from both basic research and clinical reports. The details of renal outcomes of SGLT2 inhibitors in DN are also provide in this review.



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Effects of long-term oral administration of methimazole on femur and tibia properties in male Wistar rats

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Marcin R. Tatara, Marcin Gołyński, Radosław P. Radzki, Marek Bieńko, Witold Krupski
Physiological concentrations of thyroid hormones are crucial for skeletal growth and development, physiological bone turnover and bone homeostasis maintenance. Methimazole (1-methyl-2-mercaptoimidazole) is an antithyroid drug used for the treatment of the hyperthyroidism in humans and animals. The aim of the study was to determine effects of long-term oral methimazole treatment in male Wistar rats on biochemical bone metabolism markers, as well as morphological, geometric, densitometric and mechanical properties of femur and tibia. Experimental rats were subjected to 90-day-long oral treatment with 0.05% water solution of methimazole and were kept under identical environmental conditions and received the same diet ad libitum as the control group. Serum concentration of osteocalcin (OC) and C-terminal telopeptides of type I collagen (CTX-I) was determined. Femur and tibia were evaluated using quantitative computed tomography (QCT), peripheral QCT (pQCT) and three-point bending test. Final body weight of the experimental group was significantly decreased by 30% (P=0.01). Methimazole treatment significantly decreased serum OC concentration by 21% (P=0.02) and increased CTX-I concentration by 17% (P=0.06). Methimazole decreased morphological, geometric and densitometric parameters of femur and tibia in rats. Mechanical evaluation of bones has shown significantly decreased maximum elastic strength and ultimate strength of femur in rats treated with methimazole by 36% and 40% when compared to the control group (P<0.05). In conclusion, this study has shown that long-term treatment with methimazole inhibits bone formation and accelerates bone resorption processes. The observed negative effects of methimazole treatment on body weight gain and skeletal properties may be considered as additional possible side effects in living organisms to those reported in the previous studies. It may be suggested that long-term antithyroid treatment should be combined with prevention of the negative effects of methimazole on bone tissue and whole body metabolism.



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Neuropharmacological and neuroprotective activities of some metabolites produced by cell suspension culture of Waltheria americana Linn.

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Jorge Mundo, Juana Villeda-Hernández, Maribel Herrera-Ruiz, María del Carmen Gutiérrez, Jesús Arellano-García, Ismael León-Rivera, Irene Perea-Arango
Waltheria americana is a plant used in Mexican traditional medicine to treat some nervous system disorders. The aims of the present study were to isolate and determine the neuropharmacological and neurprotective activities of metabolites produced by a cell suspension culture of Waltheria americana. Submerged cultivation of W. americana cells provided biomass. A methanol-soluble extract (WAsc) was obtained from biomass. WAsc was fractionated yielding the chromatographic fractions 4WAsc-H2O and WAsc-CH2Cl2. For the determination of anticonvulsant activity in vivo, seizures were induced in mice by pentylenetetrazol (PTZ). Neuropharmacological activities (release of gamma amino butyric acid (GABA) and neuroprotection) of chromatographic fractions were determined by in vitro histological analysis of brain sections of mice post mortem. Fraction 4WAsc-H2O (containing saccharides) did not produce neuronal damage, neurodegeneration, interstitial tissue edema, astrocytic activation, nor cell death. Pretreatment of animals with 4WAsc-H2O and WAsc-CH2Cl2 from W. americana cell suspensions induced an increase in: GABA release, seizure latency, survival time, neuroprotection, and a decrease in the degree of severity of tonic/tonic-clonic convulsions, preventing PTZ-induced death of up to 100% of animals of study. Bioactive compounds produced in suspension cell culture of W. americana produce neuroprotective and neuropharmacological activities associated with the GABAergic neurotransmission system.



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Rac2 deficiency attenuates CCl4-induced liver injury through suppressing inflammation and oxidative stress

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Yan Zou, Ji-bin Xiong, Ke Ma, Ai-Zhong Wang, Ke-Jian Qian
Oxidative stress is a leading cause to liver injury. Rac2 is a Ras-associated guanosine triphosphatase, an important molecule modulating a large number of cells and involved in the regulation of reactive oxygen species (ROS). For the study described here, we supposed that Rac2 knockout protects mice against CCl4-induced acute liver injury. We found that Rac2 expressed highly in CCl4-induced liver tissues. CCl4-treated Rac2 knockout (Rac2−/−) mice had reduced CD24 levels and steatosis. In addition, CCl4-induced high expression of pro-inflammatory cytokines and chemokine were reversed by Rac2 deficiency compared to CCl4-treated wild type (WT) mice. We also found that fibrosis-related signals of MMP-9, MMP-2 and TGF-β1 were also down-regulated in Rac2 knockout mice induced by CCl4. Significantly, oxidative stress induced by CCl4 was also suppressed owing to the lack of Rac2, evidenced by enhanced superoxide dismutase (SOD) activity, and reduced malondialdehyde (MDA) levels, superoxide radical, H2O2, xanthine oxidase (XO), xanthine dehydrogenase (XDH) and XO/XDH ratio. Moreover, c-Jun N-terminal protein kinase mitogen-activated protein kinases (JNK MAPK) was activated by CCl4, which was reversed in the liver of Rac2−/− mice through western blot and immunohistochemical analysis. In vitro, endotoxin (LPS) was treated to hepatocytes isolated from WT mice and Rac2−/− mice. The data further confirmed the role of Rac2 deficiency suppressed pro-inflammatory cytokines and chemokine, as well as fibrosis-related signals. Of note, production of ROS induced by LPS was reduced in Rac2−/− cells, accompanied with enhanced SOD1, SOD2 and reduced XO and phosphorylated-JNK expressions. Our results indicated that Rac2 played an essential role in acute liver injury induced by CCl4, providing the compelling information of the effects of Rac2 on liver injury, and revealing a novel regulatory mechanism for acute liver injury.



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Efavirenz loaded nanostructured lipid carrier engineered for brain targeting through intranasal route: In-vivo pharmacokinetic and toxicity study

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Varsha Pokharkar, Arpana Patil-Gadhe, Prathyusha Palla
Intranasal delivery is a potential platform that can be employed in targeting the antiretrovirals (ARVs) to reach HIV that harbors in the central nervous system. The objective of the study was to develop an optimized efavirenz (EFV) loaded nanostructured lipid carrier (ENLC) and deliver it through intranasal route for brain targeting. Factorial design (2³) was used to identify the key formulation variables influencing particle size and percent drug encapsulation of efavirenz in the NLC. Optimised ENLC-6 batch exhibited a spherical morphology with a mean particle size of 162nm, high drug encapsulation of 95.78±0.42% and in-vitro drug release of 92.45% at the end of 24h. Single dose in-vivo pharmacokinetic studies revealed significant therapeutic concentration of the drug in the CNS following IN administration with a Cmax value of 31.45±0.75 and T1/2 of 11.14h. A 10 fold increase (p<0.001) in% drug targeting efficiency (DTE) and 4.5 fold increase (p<0.001) in % drug targeting potential (DTP) for ENLC-6 was observed as compared to pure EFV. Sub-acute 28day IN toxicity in experimental animals indicated non-toxicity of encapsulated efavirenz over pure drug. Based on the findings we conclude that the intelligent choice of the lipdic carrier along with the strategic use of excipients can prove helpful for the efficient brain targeting of the encapsulated efavirenz which is devoid of toxicity. This may prove useful in the management of neuro-AIDS.

Graphical abstract

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Potential of the chlorogenic acid as multitarget agent: Insulin-secretagogue and PPAR α/γ dual agonist

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Maetzin Becerra Sanchez, Elizabeth Miranda-Perez, Juan Carlos Gomez Verjan, Maria de los Angeles Fortis Barrera, Julia Perez-Ramos, Francisco Javier Alarcon-Aguilar
The chlorogenic acid (CGA) is a natural product isolated from Cecropia obtusifolia, which possesses several pharmacological properties, such as: anti-carcinogenic, neuroprotective, antioxidant, anti-inflammatory, hypoglycemic, and hypolipidemic. In relation to its effects on the hyperglycemia and hypertriglyceridemia, few is known about the mechanisms in which this compound may be acting, therefore, the aim of the present study was to determine if CGA acts as an insulin secretagogue increasing intracellular calcium concentrations ([Ca²⁺]i) in RINm5F cells; or as an insulin sensitizer and lipid-lowering agent stimulating the expression of PPARγ and PPARα, respectively, in 3T3-L1 adipocytes. As results, RINm5F cells treated with 200μM of CGA showed an increase in [Ca²⁺]i of 9-times versus control and 4-times as compared to positive control; in addition, an increase in insulin secretion was observed similarly to those of positive control. CGA also significantly increased the mRNA expression of PPARγ (150%) and GLUT4 (220%), as well PPARα (40%) and FATP (25%) as it was appreciated by RT-PCR. Additionally, a chemoinformatic analysis suggested that CGA has suitable physicochemical properties to be considered as leader bioactive molecule for the development of novel agents with similar properties. Together, our results indicate that CGA possesses multiple mechanisms of action for the development of highly effective therapeutics in the treatment of metabolic diseases such as type 2 diabetes.



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Neuroprotective properties of anthocyanidin glycosides against H2O2-induced glial cell death are modulated by their different stability and antioxidant activity in vitro

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Gedas Ereminas, Daiva Majiene, Kastytis Sidlauskas, Valdas Jakstas, Liudas Ivanauskas, Gintautas Vaitiekaitis, Julius Liobikas
The neuroprotective effect of several anthocyanins in combination with their stability and antioxidant/pro-oxidant activity has been investigated against H2O2–induced oxidative stress in C6 glial cells. First it was found that delphinidin (Dp) 3-O-glucoside and 3-O-rutinoside were degraded within an hour, and at the same time stimulated the production of H2O2 in the micromolar concentration range. The stability of peonidin, pelargonidin (Pg), malvidin (Mv) and cyanidin (Cy) 3-O-glucosides and Cy 3-O-rutinoside was significantly higher than that of Dp 3-O-glycosides, with Pg3G showing the highest percent recovery over time. Based on these findings and chemical difference (according to the set of functional groups on the B-ring) of tested anthocyanins Cy3G, Mv3G and Pg3G were selected as candidates for the protection of glial cells against H2O2-induced oxidative stress. It was revealed that Cy3G (5–20μM) and Mv3G (10–20μM) but not Pg3G protected glial cells against H2O2–induced necrotic cell death. Moreover, these anthocyanins sustained the glutathione antioxidant defence system. Finally, to the extent of our knowledge we were the first to demonstrate the protective effect of Cy3G on the resting mitochondrial respiration rate in H2O2-affected glial cells. The results suggest that Cy3G, as the most prominent antioxidant among tested anthocyanins, could be a potential adjuvant for the prevention or reduction of necrotic glial cell death during the oxidative stress conditions met in neurodegenerative diseases. However, further elucidation of other possible mechanisms for anthocyanins to protect the nervous system is encouraged.



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Inhibition of Rad51 sensitizes breast cancer cells with wild-type PTEN to olaparib

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Qian Zhao, Jiawei Guan, Zhiwei Zhang, Jian Lv, Yulu Wang, Likun Liu, Qi Zhou, Weifeng Mao
PTEN is a tumor suppressor gene well characterized as a phosphatase. However, more evidences demonstrate PTEN functions in DNA repair independent of its phosphatase activity, which affects the efficacy of DNA damage anti-tumoral drugs in treating cancer cells with PTEN variations. Using BT549 breast cancer cells, we studied the roles of PTEN in DNA repair and in sensitization of breast cancer cells to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor. Comet assay showed PTEN promoted DNA repair. PTEN-deficient BT549 cells are sensitive to olaparib, which shows the synthetic lethality between PTEN and PARP1. We expressed PTEN in BT549 cells and found PTEN-proficient BT549 cells resist to olaparib. Western blot showed that PTEN up-regulated Rad51 expression, suggesting PTEN promotes DNA repair through Rad51-dependnent homologous recombination. We used 5μM olaparib or 5μM RI-1, a Rad51 inhibitor, to treat PTEN-proficient BT549 cells respectively. The immunofluorescent analysis showed the combination of olaparib and RI-1 induced more than 4-fold of γH2AX foci than either of them. MTT assay showed 5μM RI-1 did not change the survival of PTEN-proficient BT549 cells, however, this dose of RI-1 sensitized PTEN-proficient BT549 cells to olaparib. Consequently, these results demonstrate that inhibition of Rad51 can sensitize BT549 cells with wild type PTEN to olaparib, which would contribute to using PARP inhibitors in individual treatment of breast cancer patients with PTEN variations.

Graphical abstract

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Navel orange peel hydroethanolic extract, naringin and naringenin have anti-diabetic potentials in type 2 diabetic rats

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Osama M. Ahmed, Mohamed A. Hassan, Sanaa M. Abdel-Twab, Manal N. Abdel Azeem
The therapy of Type 2 Diabetes Mellitus (T2DM) stays a challenging issue. During the last decade, there has been an interest in the expansion of anti-diabetic drugs especially those of natural sources. Thus, the aim of this study was to assess the anti-hyperglycemic and the anti-hyperlipidemic effects as well as the anti-oxidant activities of navel orange hydroethanolic extract and its constituting flavonoids naringin and naringenin on nicotineamide (NA)/streptozotocin (STZ)-induced type 2 diabetic rats. To induce T2DM, 16h-fasted rats were intraperitoneally injected with STZ at dose of 50mg/kg body weight (b. w.), 15min after the intraperitoneal administration of NA (120mg/kg b. w.). The NA/STZ-induced type 2 diabetic rats were orally treated with navel orange peel hydroethanolic extract, naringin and narengenin at dose level of 100mg/kg b. w./day for 4 weeks. The treatments with navel orange peel hydroethanolic extract, naringin and narengenin potentially alleviated the lowered serum insulin and C-peptide levels, the depleted liver glycogen content, the elevated liver glucose-6-phosphatase and glycogen phosphorylase activities, the deteriorated serum lipid profile, and the suppressed liver antioxidant defense system of NA/STZ-induced type 2 diabetic rats. The treatments also enhanced the mRNA expression of insulin receptor β-subunit, GLUT4 and adiponectin in adipose tissue of STZ/NA-induced type 2 diabetic rats. In conclusion, the navel orange peel hydroethanolic extract, naringin and naringenin have potent anti-diabetic effects in NA/STZ-induced type 2 diabetic rats via their insulinotropic effects and insulin improving action which in turn may be mediated through enhancing insulin receptor, GLUT4 and adiponectin expression in adipose tissue.



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Kiwi fruit (Actinidia deliciosa) ameliorates gentamicin-induced nephrotoxicity in albino mice via the activation of Nrf2 and the inhibition of NF-κB (Kiwi & gentamicin-induced nephrotoxicity)

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Yomna I. Mahmoud
Gentamicin is a potent aminoglycoside antibiotic, but the risk of nephrotoxicity limits its prolonged use. The toxicity of gentamicin is believed to result from oxidative stress, a condition that could be counteracted by dietary antioxidants. This study determines the possible renoprotective effects of kiwifruit against the pathophysiological and ultrastructural alterations induced by gentamicin. Mice were intraperitoneally injected with gentamicin (100mg/kg body weight) for eight consecutive days, and kiwi juice was administered for 8days, either concomitant to or after gentamicin injection. Gentamicin caused nephrotoxicity evidenced by the significant elevation of serum creatinine and blood urea nitrogen levels, along with significant reduction of serum sodium and potassium ions, compared to normal controls. This was associated with proximal tubular necrosis, lysosomal accumulation and mitochondrial alterations, together with glomerular atrophy, mesangial hypercellularity, and inflammatory cell infiltration. Moreover, immunohistochemical results pointed to the relevant role of Nrf2 and NF-κB in gentamicin-induced nephrotoxicity. Kiwi administration, especially when given after gentamicin injection, significantly ameliorated gentamicin-induced pathophysiological alterations, increased the nuclear immunoreactivity of Nrf2 and decreased that of NF-κB. In short, kiwi fruit shows a promising role as a nephroprotective agent against gentamicin-induced nephrotoxicity via attenuating oxidative stress, inflammation and cell death.



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Rhein ameliorates adenomyosis by inhibiting NF-κB and β-Catenin signaling pathway

Publication date: October 2017
Source:Biomedicine & Pharmacotherapy, Volume 94
Author(s): Tingting Feng, Shaobin Wei, Yan Wang, Xianyun Fu, Ling Shi, Liyuan Qu, Xiaoxue Fan
In the present study, we examined the effects of rhein on pituitary gland implantation-induced adenomyosis, an animal model which mimics human adenomyosis. Oral administration of rhein dose-dependently attenuated hyperplastic and hypertrophic myometrium and improved adenomyosis. The activation of NF-κB and β-catenin signaling pathway was observed in the ectopic endometria. While, rhein dose dependently inhibited the expressions of p-p65, p-AKT and actived Rac1. As Rac1 activation controlled nuclear localization of β-catenin during canonical Wnt signaling, we found that the degradation complex of β-catenin was improved by rhein. In addition, β-catenin nuclear translocation and its downstream genes were markedly suppressed by different doses of rhein. At the same time, decreased activation of epithelial–mesenchymal transition (EMT)-associated proteins including Snail and ZEB1 was detected in rhein-treated mice, indicating that the activation of Wnt signaling pathway was suppressed by rhein. The in vitro study verified a negative regulation of rhein on β-catenin in stromal cells. Stimulation of IL-1β significantly increased the nuclear translocation of β-catenin and improved its target genes expressions. While, rhein remarkably abolished the enhancement in a dose dependent manner. Taken together, our results demonstrated the ability of rhein to inhibit Wnt/β-catenin activation and its potential use in the treatment of adenomyosis and other abnormal activation of β-catenin −associated diseases.



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Raising Awareness of Graves’ Orbitopathy with Early Warning Cards

Abstract

Background

Clinically significant Graves' orbitopathy (GO) develops in about 25% of those with Graves' disease (GD); most cases of GD in the UK are managed by endocrinologists. Despite this, patients report significant delays before a diagnosis of GO is made. Measures to increase awareness of the early signs of GO and establishing a fast-track referral pathway to specialist care should overcome these delays and potentially improve outcomes.

Aims

We aimed to determine whether issuing a "GO early warning card" to all GD patients raises awareness of GO and facilitates early diagnosis, what percentage of cards result in a telephone contact, the number of "false reports" from card carriers and patient perceptions of the cards.

Methods

We designed cards, detailing common GO symptoms and a telephone number for patients developing symptoms. Cards were distributed to 160 GD patients, without known GO, attending four endocrine clinics in the UK (December 2015 - March 2016). We recorded telephone contacts over twelve months from when the last card was distributed and gathered patient feedback.

Results

The early warning cards were well received by patients in general. Over twelve months, ten telephone contacts from nine patients, all related to ocular symptoms, were received (6% of cards issued). Nine calls resulted in an additional clinic review (for eight patients) and four diagnoses of GO were made.

Conclusions

This pilot study demonstrates that it is feasible to distribute GO early warning cards in clinic and that they can be used to facilitate an early diagnosis of GO.

This article is protected by copyright. All rights reserved.

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A distinct serum metabolic signature of distant metastatic papillary thyroid carcinoma

Summary

Background

Although the incidence rate for thyroid cancer seems to have begun stabilizing in recent years, an increased rate of advanced stage of this disease has been reported. Additionally, distant metastasis is one of the most important prognostic factors of patients with papillary thyroid carcinoma (PTC). Unfortunately, the underlying mechanisms of distant metastasis as well as cell status like metabolism changes in distant metastatic tumors have not been clearly elucidated.

Objective

To identify serum metabolic signature of distant metastatic PTC.

Design, patients and measurementsIn

this study, gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) was used to analyze the serum from 77 patients diagnosed with PTC (37 in distant metastasis group and 40 in ablation group). Principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA)scores plots were used to analyze the data.

Results

PCA and OPLS-DA analyses demonstrated an evident trend of separation between 40 serum samples from the ablation group and 37 samples from distant metastasis group. A total of 31 metabolites were identified which are related to amino acid, lipid, glucose, vitamin metabolism and diet/gut microbiota interaction. Pathway analysis showed 'alanine, aspartate and glutamate metabolism' and 'inositol phosphate metabolism' were the most relevant pathways.

Conclusion

Serum metabolomics profiling could significantly discriminate papillary thyroid cancer patients according to distant metastasis. Potential metabolic aberration in distant metastatic PTC could be involved in different biologic behaviors of tumor cells including proliferation, invasion/migration, and immune escape. Diet/gut microbiota produced metabolites could play an important role in these effects. This work may provide new clues to find the underlying mechanisms regarding to the distant metastasis of PTC as well as potential adjuvant therapy targets.

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