Evaluation of the regulatory effect of carnosine and alpha-lipoic acid on the cytokine profile of the cerebral cortex of Wistar rats under induced obesity

BACKGROUND: The model of obesity under experimental conditions is reproduced by using high-calorie diets in animals. It has been established that metabolic disorders cause meta-inflammation not only in peripheral organs and tissues, but also in brain structures. The search for effective neuroprotective antioxidants to suppress inflammatory processes in the cerebral cortex in obesity is an urgent task due to the widespread prevalence of this disease.AIM: to evaluate the effect of minor biologically active substances — carnosine (CAR) and α-lipoic acid (ALA) on the cytokine profile of the frontal cortex of the left hemisphere of the brain in Wistar male rats with obesity induced by a high-calorie choline-deficient diet.MATERIALS AND METHODS: The studies were carried out on male Wistar rats with an initial body weight of 150±10 g. The animals were randomized by body weight into 5 groups. For 8 weeks, rats of the 1st (control) group received a complete modified diet of AIN93M; rats of the 2nd group consumed a high-calorie choline-deficient diet (HCHDR), the fat content of which was 45%, fructose — 20% of the energy value of the diet; rats of the 3rd group received HCHDR with the addition of CAR at a dose of 75 mg per 1 kg of body weight; rats of the 4th group received HCHDR with the addition of ALA at a dose of 75 mg per 1 kg of body weight; rats of the 5th group received HCHDR with the addition of the CAR + ALA complex in a total dose of 150 mg per 1 kg of body weight. Animals were removed from the experiment by decapitation under ether anesthesia. The levels of triglycerides (Tg) and free fatty acids (FFA) in blood plasma (mmol) were determined on a biochemical analyzer (Konelab 20i, Thermo Clinical Labsystems Oy, Finland). Content of cytokines and chemokines (pg/ml): GM-CSF, IL-10, IL-17A, IL-12p40, IL-12p70, IL-1α, IL-2, IL-4, IL-5, IFN-γ, MCP-1, M-CSF, MIP-1α, MIP-2, MIP-3α, RANTES, and TNF-α in cerebral cortex lysates were determined by multiplex immunoassay using a Luminex 200 analyzer (Luminex Corporation, USA). To assess the relationship between the level of cytokines in blood plasma and changes in their concentrations under the influence of HCCDR in lysates of the cortex of the frontal lobe of the left hemisphere of the brain, the ratio was calculated: the level of cytokines pg/ml in blood plasma [1]/the content of cytokines pg/ml in lysates (pl/ lys) for each sample.RESULTS: On the model of obesity in rats, the presence of an inflammatory process in the cerebral cortex was established, as evidenced by an increase in the content of pro-inflammatory factors: IL-2, M-CSF, MIP-1α and RANTES and a decrease in the content of immunoregulatory cytokines of varying severity: IL-10, IL17A, IL-12p40, IL-12p70, TNF-a, MIP-2 and MIP-3α in group 2 rats. (HCHDR) compared with the control group. Enrichment of HCHDR with biologically active substances: CAR, ALA or their complex, ensured the normalization of lipid metabolism, as evidenced by the decrease in the ratio of circulating Tg to FFA in the blood serum of rats to control values: 1st gr. (control) — 1,04±0.23; 2nd gr. (HCHDR) — 1,64±0.63; 3rd gr. (CAR) — 0,98±0.31; 4th gr. (ALA) — 0,86±0.31; 5th gr. (CAR+ALA) — 1,02±0.38. Enrichment of HCHDR with CAR, ALA or their complex led to a decrease in the content of pro-inflammatory and apoptosis-regulating cytokines and chemokines in the cortex of the frontal lobe of the rat brain: IL-1α, IL-2, IL-17A, M-CSF, MCP-1, MIP3α and RANTES, along with an increase in the level of the anti-inflammatory cytokine IL-10, which indicates the suppression of the inflammatory process induced by the consumption of HCHDR in rats.CONCLUSION: The data obtained indicate the prospect of using CAR and ALA or their complex as neuroprotective antioxidants to reduce the inflammatory process in brain structures in obesity

First-principles modeling of the polycyclic aromatic hydrocarbons reduction

Density functional theory modelling of the reduction of realistic nanographene molecules (C42H18, C48H18 and C60H24) by molecular hydrogen evidences for the presence of limits in the hydrogenation process. These limits caused the contentions between three-fold symmetry of polycyclic aromatic hydrocarbon molecules and two-fold symmetry of adsorbed hydrogen pairs. Increase of the binding energy between nanographenes during reduction is also discussed as possible cause of the experimentally observed limited hydrogenation of studied nanographenes.Comment: 18 pages, 7 figures, accepted to J. Phys. Chem.

Значение герминальной BRCA-мутации при формировании опухолевого микроокружения Эффективность PARP-ингибирования в поздней линии терапии метастатического кастрационно-резистентного рака предстательной железы

Metastatic castration-resistant prostate cancer is a difficult problem for a clinical oncologist. In addition, mutations in genes of homologous DNA recombination, including BRCA1/2, suggest an aggressive behavior and therapy resistance. Treatment options for such patients were significantly limited until new drugs - PARP inhibitors have been registered. Nevertheless, there is evidence that BRCA1/2 gene mutations are associated with increased mutational load, neoepitopes formation, increased number of tumor-infiltrating lymphocytes and a response to the immune response checkpoints blockade. Studies have shown that BRCA2-mutated prostate cancer demonstrates high level of immune cells infiltration compared to tumors without mutation, in particular with respect to CD4+, CD8+ and FOXP3+ T-lymphocytes. It should be noted that studies have shown a tendency of CD8+ T-lymphocytes/FOXP3+ T-cells ratio decreasing in BRCA2-mutated tumors. Thus, the mutational status of BRCA2 presumably forms the immune phenotype of prostate cancer with an increase of intratumoral immune cells, but with immunosuppressive properties. At the same time, the use of immune checkpoint blockers in advanced prostate cancer has been unsuccessful in terms of overall survival. Despite the fact that immune checkpoint blocker's efficacy is often associated with a high intracellular CD4+ and CD8+ T lymphocytes, their presence is clearly insufficient for response. Studies showed that PARP inhibitors effect tumor microenvironment significantly. Anti-PD-1/PD-L1 combination with PARP inhibitors is being actively studied due to their properties of modulating the tumor microenvironment. Thus, future immunooncological strategies for primary prostate cancer therapy may include not only an increase in mutational load, but also an impact on the immunosuppressive microenvironment. The article presents clinical cases of 3 brothers, carriers of the germinal BRCA2 c.9371A>T mutation, suffering from prostate cancer with a burdened family history. The disease development under standard therapies was studied and markers of the tumor microenvironment were immunohistochemically evaluated. PARP inhibitor Olaparib efficacy in prostate cancer of older brother in late-line therapy for metastatic castration-resistant disease was analyzed.Метастатический кастрационно-резистентный рак предстательной железы является сложной проблемой для клинического онколога. Кроме этого, наличие мутации в генах гомологичной рекомбинации ДНК, в том числе BRCA1/2, предполагает агрессивное течение и резистентность к проводимой терапии. До регистрации новой группы препаратов - PARP-ингибиторов - опции лечения таких больных были существенно ограниченны. Тем не менее есть данные о том, что мутации генов BRCA1/2 связаны с повышенной мутационной нагрузкой, образованием неоэпитопов, увеличением количества инфильтрирующих опухоль лимфоцитов и ответом на блокаду контрольных точек иммунного ответа. В исследованиях показано, что BRCA2-мутированный рак предстательной железы обладает высоким уровнем инфильтрации иммунными клетками по сравнению с опухолями без мутации, в частности в отношении Т-лимфоцитов, экспрессирующих CD4, CD8 и FOXP3. Следует отметить, что в исследованиях наблюдалась тенденция к снижению отношения CD8+-Т-лимфоцитов к FOXP3+-Т-клеткам в BRCA2-мутированных опухолях. Таким образом, мутационный статус BRCA2 предположительно формирует иммунный фенотип рака предстательной железы с увеличением количества интратуморальных иммунных клеток, но с иммуносупрессивными свойствами. При этом использование блокаторов контрольных точек иммунитета при распространенном раке предстательной железы до сих пор было в значительной степени безуспешным в отношении показателей общей выживаемости пациентов. Несмотря на то что эффективность блокаторов контрольных точек иммунитета зачастую связана с высоким содержанием внутриопухолевых CD4+- и CD8+-Т-лимфоцитов, их присутствия явно недостаточно для ответа. Как показано в исследованиях, ингибиторы PARP способны оказывать существенное влияние на микроокружение опухоли. Активно изучается комбинация анти-PD-VPD-Lt с ингибиторами PARP за счет их свойств модулирования микроокружения опухоли. Таким образом, будущие онкоиммунологические стратегии первичной терапии рака предстательной железы могут включать не только повышение мутационной нагрузки, но и воздействие на иммуносупрессивное микроокружение. В статье представлены случаи развития рака предстательной железы у 3 братьев, носителей герминальной мутации гена BRCA2 c.9371A>T с отягощенным семейным анамнезом. Изучено клиническое течение заболевания при применении стандартных методов терапии, иммуногистохимически оценены маркеры микроокружения опухоли. Проанализирована эффективность использования PARP-ингибитора олапариба у одного из братьев в поздней линии терапии при метастатическом кастрационно-резистентном заболевании

Bedmap2: improved ice bed, surface and thickness datasets for Antarctica

We present Bedmap2, a new suite of gridded products describing surface elevation, ice-thickness and the seafloor and subglacial bed elevation of the Antarctic south of 60 S. We derived these products using data from a variety of sources, including many substantial surveys completed since the original Bedmap compilation (Bedmap1) in 2001. In particular, the Bedmap2 ice thickness grid is made from 25 million measurements, over two orders of magnitude more than were used in Bedmap1. In most parts of Antarctica the subglacial landscape is visible in much greater detail than was previously available and the improved datacoverage has in many areas revealed the full scale of mountain ranges, valleys, basins and troughs, only fragments of which were previously indicated in local surveys. The derived statistics for Bedmap2 show that the volume of ice contained in the Antarctic ice sheet (27 million km3) and its potential contribution to sea-level rise (58 m) are similar to those of Bedmap1, but the mean thickness of the ice sheet is 4.6% greater, the mean depth of the bed beneath the grounded ice sheet is 72m lower and the area of ice sheet grounded on bed below sea level is increased by 10 %. The Bedmap2 compilation highlights several areas beneath the ice sheet where the bed elevation is substantially lower than the deepest bed indicated by Bedmap1. These products, along with grids of data coverage and uncertainty, provide new opportunities for detailed modelling of the past and future evolution of the Antarctic ice sheets

Bedmap2: improved ice bed, surface and thickness datasets for Antarctica

We present Bedmap2, a new suite of gridded products describing surface elevation, ice-thickness and the seafloor and subglacial bed elevation of the Antarctic south of 60° S. We derived these products using data from a variety of sources, including many substantial surveys completed since the original Bedmap compilation (Bedmap1) in 2001. In particular, the Bedmap2 ice thickness grid is made from 25 million measurements, over two orders of magnitude more than were used in Bedmap1. In most parts of Antarctica the subglacial landscape is visible in much greater detail than was previously available and the improved data-coverage has in many areas revealed the full scale of mountain ranges, valleys, basins and troughs, only fragments of which were previously indicated in local surveys. The derived statistics for Bedmap2 show that the volume of ice contained in the Antarctic ice sheet (27 million km3) and its potential contribution to sea-level rise (58 m) are similar to those of Bedmap1, but the mean thickness of the ice sheet is 4.6% greater, the mean depth of the bed beneath the grounded ice sheet is 72 m lower and the area of ice sheet grounded on bed below sea level is increased by 10%. The Bedmap2 compilation highlights several areas beneath the ice sheet where the bed elevation is substantially lower than the deepest bed indicated by Bedmap1. These products, along with grids of data coverage and uncertainty, provide new opportunities for detailed modelling of the past and future evolution of the Antarctic ice sheets

Translocation t(1;11)(p32;q23) with MLL-EPS15 fusion gene formation in acute leukemias: a review and 6 new case reports. Approaches to minimal residual disease monitoring

We performed clinical and laboratory characterization of patients with rare translocation t(1;11)(p32;q23) leading to MLL-EPS15 fusion gene formation. Study cohort consisted of 33 primary acute leukemia (AL) cases including 6 newly diagnosed and 27 patients previously described in literature. Among study group patients t(1;11)(p32;q23) was found most frequently in infant AL cases (median age 8 months). In acute lymphoblastic leukemia (ALL) male/female ratio was 1:3, in acute myeloid leukemia (AML) it was 1:1. Additional cytogenetic aberrations in 38 % of patients were revealed. The most frequent breakpoint position in EPS15 gene was intron 1. Four different types of MLLEPS15 fusion gene transcripts were detected. Primers-probe-plasmid combination for MLL-EPS15 fusion gene transcript monitoring by realtime quantitative polymerase chain reaction (RQ-PCR) was developed and successfully applied. In 3 patients RQ-PCR was done on genomic DNA for absolute quantification of MLL-EPS15 fusion gene. High qualitative concordance rate (92 %) was noted between minimal residual disease data obtained in cDNA and genomic DNA for MLL-EPS15 fusion detection.</p

Friends with Benefits: Social Coupons as a Strategy to Enhance Customers’ Social Empowerment

Businesses often seek to leverage customers’ social networks to acquire new customers and stimulate word-of-mouth recommendations. While customers make brand recommendations for various reasons (e.g., incentives, reputation enhancement), they are also motivated by a desire for social empowerment—to feel an impact on others. In several multi-method studies, we show that facilitating sharing of social coupons (i.e., coupon sets that include one for self-use and one to be shared) is a unique marketing strategy that facilitates social empowerment. Firms benefit from social coupons because customers who share spend more and report greater purchase intentions than those who do not. Furthermore, we demonstrate that social coupons are most effective when the sharer’s brand relationship is new versus established. For customers with an established relationship, sharing with a receiver who also has an established relationship maximizes potential impact. Together, these studies connect social empowerment to relationship marketing and provide guidance to managers targeting social coupons