A step toward precision gerontology: Lifespan effects of calorie and protein restriction are consistent with predicted impacts on entropy generation.

Understanding aging is a key biological goal. Precision gerontology aims to predict how long individuals will live under different treatment scenarios. Calorie and protein restriction (CR and PR) extend lifespan in many species. Using data from C57BL/6 male mice under graded CR or PR, we introduce a computational thermodynamic model for entropy generation, which predicted the impact of the manipulations on lifespan. Daily entropy generation decreased significantly with increasing CR level, but not PR. Our predictions indicated the lifespan of CR mice should increase by 13 to 56% with 10 to 40% CR, relative to ad libitum-fed animals. This prediction was broadly consistent with the empirical observation of the lifespan impacts of CR in rodents. Modeling entropy fluxes may be a future strategy to identify antiaging interventions.

Postweaning Social Isolation Alters Puberty Onset by Suppressing Electrical Activity of Arcuate Kisspeptin Neurons.

INTRODUCTION: Postweaning social isolation (PWSI) in rodents is an advanced psychosocial stress model in early life. Some psychosocial stress, such as restrain and isolation, disrupts reproductive physiology in young and adult periods. Mechanisms of early-life stress effects on central regulation of reproduction need to be elucidated. We have investigated the effects of PWSI on function of arcuate kisspeptin (ARCKISS1) neurons by using electrophysiological techniques combining with monitoring of puberty onset and estrous cycle in male and female Kiss1-Cre mice. METHODS: Female mice were monitored for puberty onset with vaginal opening examination during social isolation. After isolation, the estrous cycle of female mice was monitored with vaginal cytology. Anxiety-like behavior of mice was determined by an elevated plus maze test. Effects of PWSI on electrophysiology of ARCKISS1 neurons were investigated by the patch clamp method after intracranial injection of AAV-GFP virus into arcuate nucleus of Kiss1-Cre mice after the isolation period. RESULTS: We found that both male and female isolated mice showed anxiety-like behavior. PWSI caused delay in vaginal opening and extension in estrous cycle length. Spontaneous-firing rates of ARCKISS1 neurons were significantly lower in the isolated male and female mice. The peak amplitude of inhibitory postsynaptic currents to ARCKISS1 neurons was higher in the isolated mice, while frequency of excitatory postsynaptic currents was higher in group-housed mice. CONCLUSION: These findings demonstrate that PWSI alters pre- and postpubertal reproductive physiology through metabolic and electrophysiological pathways.

Investigation of effects of transferrin-conjugated gold nanoparticles on hippocampal neuronal activity and anxiety behavior in mice.

Gold nanoparticles (GNPs) have been widely used in medicine such as imaging, drug delivery and therapeutics due to their multifunctional properties. Alterations in neuronal function may contribute to various neurological diseases. Transferrin plays a primary role in iron transportation and delivery and has recently been utilized for drug delivery to the brain. We have investigated effects of transferrin-conjugated GNPs (Tf-GNPs) on anxiety and locomotor behavior in vivo and also hippocampal neuronal activity ex vivo. Electrophysiological effects of Tf-GNP on hippocampal neurons were determined by patch clamp method. Fifteen male young adult C57BL/6 mice were randomly divided into three groups as control (200 µL PBS), GNP (bare GNP; 2.2 µg/g in PBS) and Tf-GNPs (2.2 µg/g Tf-GNP). Animals intraperitoneally received the respective treatments for seven consecutive days and were subjected to elevated plus maze (EPM) and open field tests (OFT). Ex vivo, firing frequency of the neurons significantly increased by GNP treatment (p < 0.001). In vivo, animals in Tf-GNP group showed significantly longer distance in open arms but significantly lower number of entries to the open arms in EPM (p < 0.05). Mice received bare GNPs had significantly higher locomotor activity in OFT (p < 0.05), while Tf-GNP did not alter the locomotor activity significantly (p = 0.051). Animals in Tf-GNP group spent significantly longer time in the peripheral zone in OFT (p < 0.05). The present findings have shown that Tf-GNP induces anxiety-like behavior without altering spontaneous firing rate of hippocampal neurons. We suggest that neurobiological effects of Tf-GNP should be pre-determined before using in medical applications.

The effect of maternal period nutritional status on oro-sensorial fat perception and taste preference in rats.

CD36 and GPR120 play an important role in the perception and preference for fat-rich food consumption. We aimed to investigate the relationship between oro-gustatory perception of lipids, fatty taste preference, and maternal (Gestation + Lactation)-maturation period nutrition status in offspring Sprague-Dawley rats. In our study, mother rats were fed with control (C) or high-fat diets (HFD) during gestation (21 days) and lactation (21 days) periods. After weaning, the offspring were fed with control (C) or high-fat diets (HFD) during the maturation (120 days) period. Daily calorie intake and weekly body weight measurements were monitored. Two-bottle preference (TBPT) and licking tests measured the fat perceptions and preferences. Plasma levels of insulin, leptin, glucose, and triglyceride were measured. The protein and mRNA expressions of CD36 and GPR120 in the circumvallate papillae (CVP) were determined. The 48 h TBPT results revealed that maternal HFD-exposed offspring rats significantly preferred 2% rapeseed oil solution regardless of the type of maturation diet. According to the licking test, C/C group (C diet exposed group in maternal and maturation periods) offspring licked 0.1% oleic acid-containing water more than C/HFD (C diet exposed in maternal period and HFD exposed group in maturation period) and HFD/HFD group. (HFD exposed group in maternal and maturation periods) groups. Plasma insulin and leptin concentrations significantly increased in HFD/HFD groups compared to C/C group. CD36 protein expressions were significantly lower in HFD/HFD than C/HFD and HFD/C groups. GPR120 and GNAT3 mRNA expressions in HFD/C group were significantly higher than in C/HFD group. Our results suggest that HFD exposure during maternal and maturation period may play a role in fat perception/preference through oral lipid sensors.

The Effects of Chronic Asprosin Administration on Sense of Smell and Sexual Behavior in Female Rats.

INTRODUCTION: Asprosin is an adipokine released from white adipose tissue during fasting and acts through the olfactory receptor. It is known that adipokines play roles in reproductive physiology in mammals. However, there are very few studies conducted on role of asprosin in reproductive functions. There are no studies on its relationship with sexual motivation. It was shown in the literature that administration of asprosin to male mice improves olfaction. It is also known that there is a strong correlation between smell and sexual desire. In view of this, it was hypothesized that chronic administration of asprosin would improve olfactory performance and increase sexual incentive motivation in female rats for male partners. METHODS: This hypothesis was tested by applying the hidden cookie test, sexual incentive test, active research test, and sexual behavior test. The changes in serum hormone levels in female rats that chronically received asprosin were also measured and compared. RESULTS: Chronic asprosin exposure increased olfactory performance, male preference ratio, male investigation preference ratio, activity index, and anogenital investigation behavior. Also, serum oxytocin and estradiol levels increased following chronic administration of asprosin in female rats. CONCLUSION: These data suggest that chronic administration of asprosin can result in increased sexual incentive motivation for opposite sex in female rats over increased olfactory performance and changes in reproductive hormones.

Clinicopathological and prognostic significance of PD-L1 expression in colon adenocarcinoma tumor budding.

OBJECTIVE: In this study, we investigated the relationship between programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) expression in colon adenocarcinoma tumor budding. METHODS: This study included 122 patients with colon adenocarcinomas. The largest sample of formaldehyde-fixed paraffin-embedded tumor tissues was selected for analysis. Expression of membranous PD-L1 (clone 22C3) and the Combined Positive Score (CPS) in tumor tissues was calculated and graded according to the percentages of peritumoral and intratumoral tumor cells (0 %, 1 %, 1-5 %, >5 %). The effects of these factors on the prognosis were analyzed. RESULTS: Tumor budding was associated with adverse clinicopathological features and poor overall survival. PD-L1 (CPS%) peritumoral tumor budding (1 %/<1 %) was statistically significant in the univariate model (p = 0.004). Age, organ metastases (liver, lung, liver, lung, and peritoneum), and metastases were statistically significant in the multivariate model (p = 0.001, p = 0.004, p = 0.001, p = 0.002, p = 0.004, and p = 0.032, respectively). PD-L1 positive staining was mostly observed around the tumor and during tumor budding. PD-L1 peritumoral tumor budding rates and patients' survival rates differed significantly (log-rank = 12.07, p = 0.007). CONCLUSION: We found that patients with PD-L1 (CPS%) > 1 % in tumor budding had a shortened life expectancy and demonstrated the importance of including tumor budding areas in the samples used for biomarker evaluation. We previously reported that PD-L1 expression in tumor budding is associated with more aggressive cancer biology and poor survival, although overall survival is of limited statistical significance.

Thermodynamic Assessment of the Effects of Intermittent Fasting and Fatty Liver Disease Diets on Longevity.

Organisms uptake energy from their diet and maintain a highly organized structure by importing energy and exporting entropy. A fraction of the generated entropy is accumulated in their bodies, thus causing ageing. Hayflick's entropic age concept suggests that the lifespan of organisms is determined by the amount of entropy they generate. Organisms die after reaching their lifespan entropy generation limit. On the basis of the lifespan entropy generation concept, this study suggests that an intermittent fasting diet, which means skipping some meals without increasing the calories uptake in the other courses, may increase longevity. More than 1.32 million people died in 2017 because of chronic liver diseases, and a quarter of the world's population has non-alcoholic fatty liver disease. There are no specific dietary guidelines available for the treatment of non-alcoholic fatty liver diseases but shifting to a healthier diet is recommended as the primary treatment. A healthy obese person may generate 119.9 kJ/kg K per year of entropy and generate a total of 4796 kJ/kg K entropy in the first 40 years of life. If obese persons continue to consume the same diet, they may have 94 years of life expectancy. After age 40, Child-Pugh Score A, B, and C NAFLD patients may generate 126.2, 149.9, and 272.5 kJ/kg K year of entropy and have 92, 84, and 64 years of life expectancy, respectively. If they were to make a major recommended shift in their diet, the life expectancy of Child-Pugh Score A, B, and C patients may increase by 29, 32, and 43 years, respectively.

Apelin Receptor Signaling Protects GT1-7 GnRH Neurons Against Oxidative Stress In Vitro.

Hypothalamic-pituitary-adrenal (HPA) axis regulates stress response in the body and abnormal increase in oxidative stress contributes to the various disease pathogenesis. Although hypothalamic distribution of Apelin receptor (APLNR) has been studied, the potential regulatory role in hormone releasing function of hypothalamus in response to stress is not well elucidated yet. To determine whether APLNR is involved in the protection of the hypothalamus against oxidative stress, gonadotropin-releasing hormone (GnRH) cells were used as an in vitro model system. GT1-7 mouse hypothalamic neuronal cell line was subjected to H2O2 and hypoxia induced oxidative stress under various circumstances including APLNR overexpression, knockdown and knockout. Overexpression and activation of APLNR in GnRH producing neurons caused an increase in cell proliferation under oxidative stress. In addition, blockage of APLNR function by siRNA reduced GnRH release. Activation of APLNR initiated AKT kinase pathway as a proliferative response against hypoxic culture conditions and blocked apoptosis. Although expression and activation of APLNR have not been related to GnRH neuron differentiation during development, positive contribution of activated APLNR signaling to GnRH release in mouse embryonic stem cell derived GnRH neurons was observed in the present study. Sustained overexpression and complete deletion of APLNR in mouse embryonic stem cell derived GnRH neurons reduced GnRH release in vitro. The present findings suggest that expression and activation of APLNR in GnRH releasing GT1-7 neurons might induce a protective mechanism against oxidative stress induced cell death and APLNR signaling may play a role in GnRH neurons.

Long-term chronic caloric restriction alters miRNA profiles in the brain of ageing mice.

Calorie restriction (CR) has been shown to be one of the most effective methods in alleviating the effects of ageing and age-related diseases. Although the protective effects of CR have been reported, the exact molecular mechanism still needs to be clarified. This study aims to determine differentially expressed (DE) miRNAs and altered gene pathways due to long-term chronic (CCR) and intermittent (ICR) CR in the brain of mice to understand the preventive roles of miRNAs resulting from long-term CR. Ten weeks old mice were enrolled into three different dietary groups; ad libitum, CCR or ICR, and fed until 82 weeks of age. miRNAs were analysed using GeneChip 4.1 microarray and the target of DE miRNAs was determined using miRNA target databases. Out of a total 3,163 analysed miRNAs, 55 of them were differentially expressed either by different CR protocols or by ageing. Brain samples from the CCR group had increased expression levels of mmu-miR-713 while decreasing expression levels of mmu-miR-184-3p and mmu-miR-351-5p compared to the other dietary groups. Also, current results indicated that CCR showed better preventive effects than that of ICR. Thus, CCR may perform its protective effects by modulating these specific miRNAs since they are shown to play roles in neurogenesis, chromatin and histone regulation. In conclusion, these three miRNAs could be potential targets for neurodegenerative and ageing-related diseases and may play important roles in the protective effects of CR in the brain.

Surface plasmon resonance aptasensor for soluble ICAM-1 protein in blood samples.

Intercellular Adhesion Molecule-1 (ICAM-1) is considered to be a cancer biomarker in the assessment of metastatic potential in patients and an early indicator of atherosclerosis. A labelless biosensor based on the surface plasmon resonance (SPR) signal from the specific affinity interaction of an aptamer and a soluble ICAM-1 protein was developed for blood samples. The developed aptasensor provided real-time information on the concentration of the ICAM-1 protein in blood when integrated to a purification step based on a magnetic pull-down separation. The SPR aptasensor was highly specific with a limit of detection of 1.4/0.2 ng ml-1, which was achieved through aptamer-functionalized silica-coated magnetic nanoparticles.

Investigation of obesogenic effects of hexachlorobenzene, DDT and DDE in male rats.

Obesity has become a very important public health problem and is increasing globally. Genetics, individual and environmental factors play roles in the etiology of this complex disorder. Recently, several environmental pollutants have been suggested to have obesogenic activities. Peroxisome proliferator activating receptor gamma (PPARγ), uncoupling protein-1 (UCP1) and their expression in white adipose tissue (WAT) and brown adipose tissue (BAT) play key roles in adipogenesis. UCP3 and irisin were reported to play roles in non-shivering thermogenesis. Our primary aim was to investigate obesogenic effects of hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) in rats. In addition, thermoregulatory effects of HCB, DDT and DDE were also investigated by analyzing the levels of Ucp3 and irisin. Thirty-two adult male Sprague-Dawley rats were randomly divided into four groups as control, HCB, DDT and DDE. Animals were administered with organochlorine pesticides (OCPs; 5 mg/kg bw) by oral gavage every other day for five weeks. At the end of the experimental period, the animals were sacrificed, BAT and WAT samples were collected to analyze Pparγ, Ucp1 and Ucp3 levels. Moreover, skeletal muscle samples were collected to examine Ucp3 and irisin levels. Serum glucose, cholesterol and triglyceride levels were also determined. Body weight and core temperature of the animals were not significantly affected by any of the OCP administration. Serum glucose, cholesterol and triglyceride levels were similar among the experimental groups. Pparγ expression was significantly elevated by HCB administration only in WAT (p < 0.05). On the other hand, both Pparγ and Ucp1 expressions were diminished in WAT and BAT (p < 0.01) by DDT treatment, while in WAT, DDE significantly decreased Pparγ expression without altering its expression in BAT (p < 0.001). Ucp3 and irisin levels in skeletal muscle were not altered. Our findings show that both DDT and DDE reduce the browning of WAT by suppressing white adipocytes and thus may have obesogenic activity in male rats without altering thermoregulation. In addition, HCB, DDT and DDE-induced alterations in expression of Pparγ and Ucp1 in WAT implicates differential regulation of adipogenic processes.

What is the protective effect of preischemic kisspeptin-10 administration against ischemia/reperfusion injury of striatum on mice?

BACKGROUND: Kisspeptin is a neuropeptide with a primary role on the onset of puberty and has beneficial effects on ischemia/ reperfusion (I/R) injury. In this study, we aimed to investigate the effect of kisspeptin administration on striatal I/R injury in mice. METHODS: Forty adult C57/BL6 mice were randomly divided into four groups: Sham, Kisspeptin, I/R, and I/R + Kisspeptin groups. The groups were administered with either physiological saline (Sham and I/R groups) or kisspeptin (Kisspeptin and I/R + Kisspeptin groups) intraperitoneally 40 min before the operation. A microdialysis probe was placed in the right striatum according to stereotaxic coordinates. During the experimental period, artificial cerebrospinal fluid was passed through the micropump. Then, transient cerebral ischemia was established by compressing both common carotid arteries with an aneurysm clip for 15 min and animals were reperfused for 2 h. Throughout the process of microdialysis (before, during and after I/R period), samples were collected to measure dopamine (DA), noradrenaline (NA), and 3,4-dihydroxyphenylglycine (DHPG) at intervals of 20 min continuously. At the end of the reperfusion period, the animals were decapitated, striatum was dissected, half of the animals were used for oxidative stress analyses (reduced glutathione, glutathione S-transferase (GST), superoxide dismutase (SOD), malondialdehyde (MDA), and the other half were used for histopathology analyses. RESULTS: Number of glial cells was significantly increased in kisspeptin-administered groups. DA levels in ischemic animals were decreased by kisspeptin administration (p < 0.0001). NA levels were reduced in animals administered with kisspeptin without I/R injury (p < 0.05). DHPG levels reduced during the reperfusion period in ischemic animals (p < 0.05). Kisspeptin did not exhibit a significant antioxidant activity in the ischemic animals, while GST and SOD levels were reduced in the I/R + kisspeptin group compared to the kisspeptin group (p < 0.05). DISCUSSION: Our results suggest that kisspeptin may be regulating the neurotransmitter release and metabolism, as well as inflammatory response in brain upon I/R injury.

Inflammatory Cytokines are in Action: Brain Plasticity and Recovery after Brain Ischemia Due to Delayed Melatonin Administration.

OBJECTIVES: Post-ischemic inflammation leads to apoptosis as an indirect cause of functional disabilities after the stroke. Melatonin may be a good candidate for the stroke recovery because of its anti-inflammatory effects. Therefore, we investigated the effect of melatonin on inflammation in the functional recovery of brain by evaluating ipsilesional and contralesional alterations. MATERIALS AND METHODS: Melatonin (4 mg/kg/day) was intraperitoneally administered into the mice from the 3rd to the 55th day of the post-ischemia after 30 min of middle cerebral artery occlusion. RESULTS: Melatonin produced a functional recovery by reducing the emigration of the circulatory leukocytes and the local microglial activation within the ischemic brain. Overall, the expression of the inflammation-related genes reduced upon melatonin treatment in the ischemic hemisphere. On the other hand, the expression level of the inflammatory cytokine genes raised in the contralateral hemisphere at the 55th day of the post-ischemia. Furthermore, melatonin triggers an increase in the iNOS expression and a decrease in the nNOS expression in the ipsilateral hemisphere at the earlier times in the post-ischemic recovery. At the 55th day of the post-ischemic recovery, melatonin administration enhanced the eNOS and nNOS protein expressions. CONCLUSIONS: The present molecular, biological, and histological data have revealed broad anti-inflammatory effects of melatonin in both hemispheres with distinct temporal and spatial patterns at different phases of post-stroke recovery. These outcomes also established that melatonin act recruitment of contralesional rather than of ipsilesional.

Interaction of the mTERT telomerase catalytic subunit with the c-Abl tyrosine kinase in mouse granulosa cells.

Context: Oocyte and granulosa cells (GCs) have bidirectional communication and GCs play an important role in folliculogenesis and proliferation of GCs is very important for the development of ovulatory follicle. DNA double-strand breaks activate c-Abl protein tyrosine kinase and c-Abl has a functional role in repairement of DNA and control of telomere.Objective: In this study, we hypothesized that c-Abl has a regulative role on mTERT in mouse ovarian granulosa cells (GCs) and we aimed to detect c-Abl and mTERT interaction in mouse primary culture of GCs.Materials and methods: Mouse ovarian granulosa cell were cultured and siRNA-mediated knockdown approach was used to knockdown c-Abl expression.Results: We showed c-Abl and mTERT immunolocalization in vivo and in vitro mouse GCs. c-Abl and mTERT were constitutively expressed in mouse granulosa cells and c-Abl presented more intense expression in granulosa cells than mTERT expression. The interaction of the c-Abl-mTERT is supported by the exhibition that c-Abl siRNA knockdown cells show decreased mTERT expression. We also present an interaction between c-Abl and mTERT by immunoprecipitation. In addition, our results indicated that the down-regulation of c-Abl was also accompanied by reduced expression of proliferating cell nuclear antigen (PCNA) in GCs.Conclusions: We suggest that mTERT may associate with the c-Abl in mouse GCs and the interactions between c-Abl and mTERT suggest a role for c-Abl in the regulation of telomerase function and proliferation in mouse granulosa cells.

Endocrine disrupting chemicals: exposure, effects on human health, mechanism of action, models for testing and strategies for prevention.

Endocrine Disrupting Chemicals (EDCs) are a global problem for environmental and human health. They are defined as "an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action". It is estimated that there are about 1000 chemicals with endocrine-acting properties. EDCs comprise pesticides, fungicides, industrial chemicals, plasticizers, nonylphenols, metals, pharmaceutical agents and phytoestrogens. Human exposure to EDCs mainly occurs by ingestion and to some extent by inhalation and dermal uptake. Most EDCs are lipophilic and bioaccumulate in the adipose tissue, thus they have a very long half-life in the body. It is difficult to assess the full impact of human exposure to EDCs because adverse effects develop latently and manifest at later ages, and in some people do not present. Timing of exposure is of importance. Developing fetus and neonates are the most vulnerable to endocrine disruption. EDCs may interfere with synthesis, action and metabolism of sex steroid hormones that in turn cause developmental and fertility problems, infertility and hormone-sensitive cancers in women and men. Some EDCs exert obesogenic effects that result in disturbance in energy homeostasis. Interference with hypothalamo-pituitary-thyroid and adrenal axes has also been reported. In this review, potential EDCs, their effects and mechanisms of action, epidemiological studies to analyze their effects on human health, bio-detection and chemical identification methods, difficulties in extrapolating experimental findings and studying endocrine disruptors in humans and recommendations for endocrinologists, individuals and policy makers will be discussed in view of the relevant literature.

MCH Neuron Activity Is Sufficient for Reward and Reinforces Feeding.

BACKGROUND: Melanin-concentrating hormone (MCH)-expressing neurons have been implicated in regulation of energy homeostasis and reward, yet the role of their electrical activity in short-term appetite and reward modulation has not been fully understood. OBJECTIVES: We investigated short-term behavioral and physiological effects of MCH neuron activity manipulations. METHODS: We used optogenetic and chemogenetic approaches in Pmch-cre transgenic mice to acutely stimulate/inhibit MCH neuronal activity while probing feeding, locomotor activity, anxiety-like behaviors, glucose homeostasis, and reward. RESULTS: MCH neuron activity is neither required nor sufficient for short-term appetite unless stimulation is temporally paired with consumption. MCH neuronal activation does not affect short-term locomotor activity, but inhibition improves glucose tolerance and is mildly anxiolytic. Finally, using two different operant tasks, we showed that activation of MCH neurons alone is sufficient to induce reward. CONCLUSIONS: Our results confirm diverse behavioral/physiological functions of MCH neurons and suggest a direct role in reward function.

Thermodynamic assessment of allocation of energy and exergy of the nutrients for the life processes during pregnancy.

Thermodynamic analyses are performed to quantify allocation of the nutritional energy and exergy to most of the life processes by pregnant mice. In these analyses, 'internal work performance' is calculated for the first time in the literature for metabolism during pregnancy and found substantially higher than the 'external work performance'. Variation of the daily entropy generation rates and the daily internal work performance rates during the course of pregnancy showed a highly similar phasic behaviour. With the progression of the pregnancy, external work performance decreased and second law efficiency increased significantly. On the 13th day of pregnancy, net energy extracted from the food at the cellular energy metabolism subsystem was 15·0 kJ; approximately 3 kJ of it was employed for daily internal work performance, 0·8 kJ was allocated to daily external work performance and 0·8 kJ was stored in the adipose tissue without entering into the cellular energy metabolism subsystem. Heat generation in association with internal and external work performance was 9·1 and 2·2 kJ, respectively. Energy, pertinent to the first law, and exergy (useful energy), pertinent to the second law, balances are described graphically, and comparison of these plots showed that the total exergy of the nutrients allocated to internal and external work performance and heat generation is substantially smaller in magnitude when compared with those of energy balance.

Hexagonal boron nitrides reduce the oxidative stress on cells.

The molecular stress caused by a drug administered to treat a disorder on healthy cells appears as a side effect. In this study, we aim to understand the potential of hexagonal boron nitrides (hBNs) as a therapeutic agent to relieve the cellular stress exerted by drugs. First, the cytotoxicity of hBNs and their possible degradation product, boric acid (BA), on the embryonic mouse hippocampal cell line mHippo E-14 was assessed in a wide concentration range (4.4-440 µg ml-1) of boron including hBNs and BA for 24 and 72 h exposure. Then, cell cycle, reactive oxygen species generation, cell death mechanism and apoptotic body formation in nuclei with hBN and BA exposure were evaluated at increased concentrations and incubation times. Finally, the cells, exposed to doxorubicin (DOX), an anti-cancer chemotherapy drug, to exert oxidative stress, were treated with hBNs and BA. The results indicate that hBNs decrease the oxidative stress at the concentrations that are nontoxic to cells. The study suggests that hBNs can open new venues for their investigation to reduce or eliminate the adverse effects of toxic drugs used in the treatment of several fatal diseases including neurological disorders and cancer with their slow degradation feature.

Effects of anticoagulant drugs on wound healing process in a rat model: a comparative study.

OBJECTIVE: This study aims to compare the efficacy of enoxaparin, rivoraxaban and dabigatran on wound healing using a rat model. METHOD: Sprague-Dawley female rats (n=56), 10-12 weeks old, weight 245±30g, were used in this study. The rats were divided into four equally-sized groups. A type 1 (secondary wound healing) and type 2 (primary wound healing) wound was opened surgically on each rat in each group. Anticoagulent drugs enoxaparin, rivoraxaban and dabigatran and physiological saline solution were administered to Groups 1, 2, 3 and 4, respectively. After wound healing was scored tissue samples were taken from euthanised rats at days five and 10 and examined histologically. Since time was used as a classification (days five and 10), a time effect was included. RESULTS: There was no statistically significant difference in total score distribution in rats between type 1 secondary wounds for days five and 10 (p>0.05). There was no statistically significant difference in the overall score distribution in rats between type 2 primary wounds for days five and 10 (p>0.05). CONCLUSION: In addition to the use of low molecular weight heparin with well-known anticoagulation activity, the new generation oral medications are used efficiently in thromboembolic diseases. However, there was no evidence observed in this study that these drugs could be either beneficial or harmful to wound healing.

Inactivation of Magel2 suppresses oxytocin neurons through synaptic excitation-inhibition imbalance.

Prader-Willi and the related Schaaf-Yang Syndromes (PWS/SYS) are rare neurodevelopmental disorders characterized by overlapping phenotypes of high incidence of autism spectrum disorders (ASD) and neonatal feeding difficulties. Based on clinical and basic studies, oxytocin pathway defects are suggested to contribute disease pathogenesis but the mechanism has been poorly understood. Specifically, whether the impairment in oxytocin system is limited to neuropeptide levels and how the functional properties of broader oxytocin neuron circuits affected in PWS/SYS have not been addressed. Using cell type specific electrophysiology, we investigated basic synaptic and cell autonomous properties of oxytocin neurons in the absence of MAGEL2; a hypothalamus enriched ubiquitin ligase regulator that is inactivated in both syndromes. We observed significant suppression of overall ex vivo oxytocin neuron activity, which was largely contributed by altered synaptic input profile; with reduced excitatory and increased inhibitory currents. Our results suggest that dysregulation of oxytocin system goes beyond altered neuropeptide expression and synaptic excitation inhibition imbalance impairs overall oxytocin pathway function.