The mechanisms of melanogenesis inhibition by glabridin:molecular docking,PKA/MITF and MAPK/MITF pathways

Glabridin is the main ingredient of hydrophobic fraction in licorice extract and has been shown to have anti-melanogenesis activity in skins.However,the underlying mechanism(s)remain not completely understood.The aim of this study is thus to elucidate the possible mechanisms related to the melanogenesis suppression by glabridin in cultured B16 murine melanoma cells and in UVA radiation induced hyperpigmentation model of BALB/c mice as well.Molecular docking simulations revealed that between catalytic core residues and the compound.The treatment by glabridin significantly downregulated both transcriptional and/or protein expression of melanogenesis-related factors including melanocyte stimulating hormone receptor(MC1R),microphthalmia-associated transcription factor(MITF),tyrosinase(TYR),TYR-related protein-1(TRP-1)and TRP-2 in B16 cells.Both PKA/MITF and MAPK/MITF signaling pathways were found to be involved in the suppression of melanogenesis by glabridin in B16 cells.Also in vivo glabridin therapy significantly reduced hyperpigmentation,epidermal thickening,roughness and inflammation induced by frequent UVA exposure in mice skins,thus beneficial for skin healthcare.These data further look insights into the molecular mechanisms of melanogenesis suppression by glabridin,rationalizing the application of the natural compound for skin healthcare.

如何将小胶质细胞向有益功能重编程

小胶质细胞是一种非神经起源的脑细胞,它可以协调对各种损伤的炎症反应,包括围产期脑中的缺氧/缺血或母体/胎儿感染。实验研究已经证明小胶质细胞能够识别病原体或受损细胞,从而激活细胞毒性反应,从而加剧脑损伤。然而,小胶质细胞在对损伤的反应中显示出巨大的可塑性,并且还可以促进炎症和组织再生的消退。尽管小胶质细胞在脑病理学中起着关键作用,对于控制小胶质细胞不同表型的细胞机制的研究却才刚刚崭露头角。这篇文章回顾了推动小胶质细胞向有益功能发展的新兴策略,总结了涉及表型转换潜在的分子机制的研究。这些方法包括使用药理学试剂,细胞因子,脂质信使或微小RNA,以及免疫调节细胞的营养方法或疗法来处理小胶质细胞。对小胶质细胞向促再生功能重编程相关的分子机制的分析指出,能量代谢在塑造小胶质细胞功能中起到核心作用。因此,可以通过调控代谢途径,来预防炎性小胶质细胞的有害作用并控制脑病症中的过度炎症反应。

Macrophage regulation of graft-vs-host disease

Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy,but graft-vs-host disease(GVHD)has limited the survival quality and overall survival of hematopoietic stem cell transplantation.Understanding of the immune cells’reaction in pathophysiology of GVHD has improved,but a review on the role of macrophages in GVHD is still absent.Studies have observed that macrophage infiltration is associated with GVHD occurrence and development.In this review,we summarize and analyze the role of macrophages in GVHD based on pathophysiology of acute and chronic GVHD,focusing on the macrophage recruitment and infiltration,macrophage polarization,macrophage secretion,and especially interaction of macrophages with other immune cells.We could conclude that macrophage recruitment and infiltration contribute to both acute and chronic GVHD.Based on distinguishing pathology of acute and chronic GVHD,macrophages tend to show a higher M1/M2 ratio in acute GVHD and a lower M1/M2 ratio in chronic GVHD.However,the influence of dominant cytokines in GVHD is controversial and inconsistent with macrophage polarization.In addition,interaction of macrophages with alloreactive T cells plays an important role in acute GVHD.Meanwhile,the interaction among macrophages,B cells,fibroblasts,and CD4+T cells participates in chronic GVHD development.

Simulation study on performance optimization of a prototype scintillation detector for the GRANDProto35 experiment

As a proposed detector,the giant radio array for neutrino detection(GRAND)is primarily designed to discover and study the origin of ultra-high-energy cosmic rays,with ultra-high-energy neutrinos presenting the main method for detecting ultra-high-energy cosmic rays and their sources.The main principle is to detect radio emissions generated by ultra-high-energy neutrinos interacting with the atmosphere as they travel.GRAND is the largest neutrino detection array to be built in China.GRANDProto35,as the first stage of the GRAND experiment,is a coincidence array composed of radio antennas and a scintillation detector,the latter of which,as a traditional detector,is used to perform cross-validation with radio detection,thus verifying the radio detection efficiency and enabling study of the background exclusion method.This study focused on the implementation of the optimization simulation and experimental testing of the performance of the prototype scintillation detector used in GRANDProto35.A package based on GEANT4 was used to simulate the details of the scintillation detector,including the optical properties of its materials,the height of the light guide box,and position inhomogeneity.The surface of the scintillator and the reflective materials used in the detector was optimized,and the influence of light guide heights and position inhomogeneity on the energy and time resolutions of the detector was studied.According to the simulation study,the number of scintillator photoelectrons increased when changing from the polished surface to the ground surface,with the appropriate design height for the light guide box being 50 cm and the appropriate design area for the scintillator being 0.5 m^(2).The performance of the detector was tested in detail through a coincidence experiment,and the test results showed that the number of photoelectrons collected in the detector was$84 with a time resolution of~1 ns,indicating good performance.The simulation results were consistent with those obtained from the tests,which also verified the reliability of the simulation software.These studies provided a full understanding of the performance of the scintillation detector and guidance for the subsequent operation and analysis of the GRANDProto35 experimental array.

N-acetylcysteine and glycyrrhizin combination:Benefit outcome in a murine model of acetaminophen-induced liver failure

BACKGROUND Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries.Substantial progress has been made in understanding the mechanism of hepatocellular injury,but N-acetylcysteine remains the only effective treatment despite its short therapeutic window.Thus,other hepatoprotective drugs are needed for the delayed treatment of acetaminopheninduced hepatotoxicity.Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1(HMGB1)protein,a member of the family of damage-associated molecular pattern,known to play an important pathological role in various diseases.AIM To investigate the efficacy of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity.METHODS Eight-week-old C57BL/6J wild-type female mice were used for all our experiments.Mice fasted for 15 h were treated with acetaminophen(500 mg/kg)or vehicle(phosphate-buffered saline)by intraperitoneal injection and separated into the following groups:Glycyrrhizin(200 mg/kg);N-acetylcysteine(150 mg/kg);and N-acetylcysteine/glycyrrhizin.In all groups,mice were sacrificed 12 h following acetaminophen administration.The assessment of hepatotoxicity was performed by measuring plasma levels of alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase.Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections.Survival rates were compared between various groups using Kaplan-Meier curves.RESULTS Consistent with data published in the literature,we confirmed that intraperitoneal administration of acetaminophen(500 mg/kg)in mice induced severe liver injury as evidenced by increases in alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score.Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity of liver injury.Thus,the co-administration of glycyrrhizin and N-acetylcysteine was investigated.Administered concomitantly with acetaminophen,the combination significantly reduced the severity of liver injury.Delayed administration of the combination of drugs,2 h or 6 h after acetaminophen,also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone.In addition,administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine.CONCLUSION We demonstrate that,compared to N-acetylcysteine alone,co-administration of glycyrrhizin decreases the liver necrosis score and improves survival in a murine model of acetaminophen-induced liver injury.Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity.

Retinoid receptor-related orphan receptor alpha： a key gene setting brain circuits

The retinoid receptor-related orphan receptor alpha（RORα） is thought to act as a constitutive activator of transcription by binding to the ROR response element（RORE） of target genes. Several mouse models in which RORα is defective have revealed the decisive roles of RORα on the development, maturation and neuroprotection of various cerebral regions including the cerebellar and somatosensory systems. We have recently shown that RORα is needed for accurate thalamic sensory system organization and somatosensory cortex development. The phenotype of various RORα deficient mice models（staggerer mutant or mouse lacking RORα in specific somatosensory regions） is, in part, reminiscent of what has been described in mice lacking thyroid hormone triiodothyronine（T3）. As in in vitro studies or in other models, our studies strongly suggest that the T3/RORα-pathway, among others, is in part responsible for the staggerer phenotype. We have indeed identified some genes that were both regulated by T3 and RORα and that are known to be implicated in the cerebellar or somatosensory system development. Moreover, several groups have shown that RORα is at the crossroad of many biological processes and pathologies, including psychiatric and degenerative disorders. In particular, defective RORα-signalling has been demonstrated in humans to be associated with the emergence of autistic-like disorders. We believe that determining the appropriate amount of RORα activity could be crucial in detecting and preventing the emergence of specific brain diseases.

Lithium-related neurotoxicity despite serum concentrations in the therapeutic range:risk factors and diagnosis

We would like to comment on the interesting case report of lithium intoxication reported by Jing Peng.[1]An 18-year old female with mania developed confusion,trembling extremities,slurred speech,increased muscle tension,and hyperactive tendon reflexes 20 days after initiating treatment with routine dosages of lithium bicarbonate.When admitted to the hospital due to her acute neurological condition,her serum lithium concentration was in the therapeutic range(0.57 mmol/L).Most of her symptoms spontaneously reversed one

Sorafenib Acts through VEGFR-2 Inhibition in a Metastatic Clear-Cell Sarcoma of the Kidney

We report here the case of a young patient with metastatic clear-cell sarcoma of the kidney resistant to standard chemotherapy, and with complete response under sorafenib treatment. The remarkable response of her tumor to sorafenib led us to study sorafenib molecular targets in the metastatic tissue. Background: Biomarkers predicting response to anti-angiogenic tyrosine kinase inhibitors remain to be identified. Methods and Findings: In this paper, we studied the molecular targets of sorafenib in the lung metastasis of a kidney clear-cell sarcoma. In a patient with complete response under sorafenib treatment, we showed high VEGFR2 expression by tumor endothelial cells from the lung metastasis. Conclusion: The original mechanistic results that we obtained using immunostainings and quantitative RT-PCR on laser-microdissected tumor endothelial cells have a direct application in daily clinical practice: metastatic tumors with a large angiogenic component should be tested for VEGFRs expression to consider anti-angiogenic tyrosine kinase inhibitor treatments.

Heart‘omicsin’AGEing (HOMAGE):design,research objectives and characteristics of the common database

Heart failure is common in older people and its prevalence is increasing.The Heart ＇omics＇ in AGEing（HOMAGE） project aims to provide a biomarker approach that will improve the early diagnosis of heart failure.A large clinical database,based on（1） prospective population studies or（2） cross-sectional,prospective studies or randomized controlled trials（RCTs） of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising ＇omics＇-based biomarkers to identify the risk of developing heart failure and/or comorbidities.Population studies,patient cohorts and RCTs are eligible for inclusion in the common database,if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors.Currently,the HOMAGE database includes 43,065 subjects,from 20 studies in eight European countries,including healthy subjects from three population studies in France,Belgium and Italy（n = 7,124）,patients with heart failure（n = 4,312） from four cohorts in the UK,Spain and Switzerland and patients at high risk for cardiovascular disease（n = 31,629） in 13 cohorts.It is anticipated that more partners will join the consortium and enlarge the pooled data.This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.

Simulation study on cosmic ray background at large zenith angle based on GRANDProto35 coincidence array experiment

Neutrino detection in the 100 PeV energy region is the ultimate means of studying the origin of ultra-highenergy cosmic rays,in which the large radio detection array giant radio array for neutrino detection(GRAND)project aims to use to decipher this century-old problem.The GRANDProto35 compact array is a microform of 35 radio prototype detectors for the GRAND experiment,which verifies the reliability of GRAND performance through operation,and data analysis of the prototype detectors.As radio detectors are a novel development in recent years,and their indexes need to be verified by traditional detectors,the GRAND Cooperation Group designed and constructed the GRANDProto35 coincidence array composed of radio detectors and scintillation detectors.This study simulated the changes in detection efficiency,effective area,and event rate of cosmic rays with zenith angle based on this coincidence array.The study found that the 1017 eV energy region is sensitive to GRANDProto35 detection.When the energy exceeded 1017 eV,the array detection efficiency could reach more than 95%and the effective area was up to*29106 m2.A simulation study on cosmic ray events with large zenith angles showed that the event rate detected by the array decreased significantly with increasing zenith angle,and the event rate of cosmic rays was approximately 0.1 per day for a zenith angle of 75.This serves as the background pollution rate for neutrino observation caused by largeangle cosmic-ray events,providing an important reference for further experiments.The study results will be verified after the joint operation of the coincidence array.

Integrative rodent models for assessing male reproductive toxicity of environmental endocrine active substances

In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance （EAS） exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action （MOA） of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool （together with the epidemiological approach） for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction.

Extrahepatic hepcidin production:The intriguing outcomes of recent years

Hepcidin is the hyposideremic hormone regulating iron metabolism.It is a defensin-like disulfide-bonded peptide with antimicrobial activity.The main site of hepcidin production is the liver where its synthesis is modulated by iron,inflammation and erythropoietic signaling.However,hepcidin locally produced in several peripheral organs seems to be an important actor for the maintenance of iron homeostasis in these organs.This review highlights the presence of peripheral hepcidin and its potential functions.Understanding the role of extrahepatic hepcidin could be of great physiological and therapeutic importance for several specific pathologies.

Diet Composition of the Salamander Lyciasalamandra luschani basoglui on the Greek Island of Kastellorizo in the Southeast Aegean Sea

The diet composition of the Lycian salamander Lyciasalamandra luschani basoglui across both age and sex groups was studied. Specimens were collected from a small island in the Southeast Aegean Sea. The dominant prey group of juveniles consisted of Collembola, while Coleoptera dominated the diet of males and females. The number and size of prey items consumed by males and females of L. luschani basoglui were quite similar, while juveniles ate fewer items of much smaller size. The numerical abundance along with the four measures of the size of prey permitted discrimination among males, females and juveniles. Although discrimination between adults and juveniles is expected due to dissimilarity in body size, discrimination between males and females remains inexplicable despite their similarity in body size. Future studies should be focused on understanding how and why prey choice differs between sexes in L. luschani basoglui.

Nerves and hydrogen peroxide： how old enemies become new friends

ROS and nerves play together during the regeneration process： For many years, the role of reactive oxygen species （ROS） in neurobiology has mainly focused on its pathological implications in neurodegenerative diseases. Contrasting with this view, ROS were recently put forward as key positive signals for axon growth and repair, highlighting beneficial functions of ROS signalling in the vertebrate adult brain （Borquez et al., 2016）.

Age-related modifications of macrophages influenced by “inflammageing”in graft vs. host disease

Most studies focus on the adaptive immune cells in the GVHD pathogenesis,while little is known about innate immune cells in GVHD occurrence and development,especially macrophages.Meanwhile,a higher incidence of graft versus host disease(GVHD)is also found in the elderly patients.Though advances have been made in the modification of macrophages influenced by the inflamm-ageing,there is still no review on the role of macrophages in GVHD and the association between GVHD and the altered macrophages by inflamm-ageing.In this review,we focus on the potential age-related modifications of macrophage in GVHD,which contributes to the change of morbidity and mortality of GVHD.Via literature review,we found that the infiltration of macrophages is associated with GVHD and macrophages are modified in inflamm-ageing state,including the proliferation,migration,phagocytosis,antigen presentation,interaction with other immune cells,and pro-fibrosis.We suppose that altered macrophage functions in inflamm-ageing state contribute to GVHD in elderly patients.

Combined effect of <i>CYP2C9</i>and <i>VKORC1</i>polymorphisms on warfarin maintenance dose in Omani patients

Excepting host genetic factors, other influences on the pharmacokinetic and pharmacodynamic behavior of warfarin are subject to variations during the treatment despite attempts to stabilize the INR. In 214 Omani patients on warfarin therapy, we evaluated the extent of influence of known genetic predictors of warfarin dose variability, namely CYP2C9, CYP4F2 and VKORC1 gene polymorphisms in a genetically heterogeneous patient population. When patients were stratified according to their daily warfarin maintenance dose (to maintain INR between 2 and 3) into “low dose” (sensitive), “medium dose” (intermediate) and “high dose” (resistance) groups, overall, seven patients with three or four mutant alleles fell in the sensitive group and consequently 25% (7 out of 28) of at risk patients for over anticoagulation can be recognized by prospective pharmacogenetic testing in this patient population. Pre-prescription genotyping of these loci prior to therapy initiation will therefore benefit a small fraction of this population.

Effect of SOD1 Overexpression on the 20S Proteasome during Aging

Metabolism of oxygen derivatives has been shown to be altered in Down syndrome (DS) due to the overexpression of the Cu/Zn superoxide dismutase gene ( SOD-1) on chromosome 21. Transgenic mice for the human SOD1 gene (h SOD1) exhibit some features of the syndrome. Oxidation of proteins and oxidative stress are involved in normal and pathological aging. The proteasome is an adaptative system to eliminate the modified proteins which can be deleterious. As SOD1 overexpression has been shown to be either deleterious or protective according to tissues and paradigms, we have measured in function of age the 20S proteasome activities in neural tissues (cerebral hemisphere, cerebellum and cortex) and in the thymus and the heart from control and transgenic mice. Indeed, although SOD1 overexpression is very deleterious in thymus and heart, it has little effect in cerebral hemisphere and cortex depending on the proteolytic activity measured. Conversely in the cerebellum the three proteolytic activities decrease dramatically in transgenic old mice while it was not modified in control mice during aging. The results of this study suggest that some phenotypes of DS present in thymus, heart and neural tissues of h SOD1 transgenic mice might be partially due to the modulation of the 20S proteasome expression during aging.

Multi-Decadal Trends of Global Surface Temperature:A Broken Line with Alternating~30 yr Linear Segments?

We investigate global temperature data produced by the Climate Research Unit at the University of East Anglia (CRU) and the Berkeley Earth Surface Temperature consortium (BEST). We first fit the 1850-2010 data with polynomials of degrees 1 to 9. A significant ~60-yr oscillation is accounted for as soon as degree 4 is reached. This oscillation is even better modeled as a broken line, more precisely a series of ~30-yr long linear segments, with slope breaks (singularities) in ~1904, ~1940, and ~1974 (±3 yr), and a possible recent occurrence at the turn of the 20th century. Oceanic indices PDO (Pacific Decadal Oscillation) and AMO (Atlantic Multidecadal Oscillation) have undergone major changes (respectively of sign and slope) roughly at the same times as the temperature slope breaks. This can be interpreted with a system of oceanic non-linear coupled oscillators with abrupt mode shifts. Thus, the Earth’s climate may have entered a new mode (a new ~30-yr episode) near the turn of the 20th century: no further temperature increase, a dominantly negative PDO index and a decreasing AMO index might be expected for the next decade or two.

Analysis of single nucleotide polymorphisms in the region of CLDN2-MORC4 in relation to inflammatory bowel disease

AIM:To investigate a possible genetic influence of claudin(CLDN)1,CLDN2 and CLDN4 in the etiology of inflammatory bowel disease.METHODS:Allelic association between genetic regions of CLDN1,CLDN2 or CLDN4 and patients with inflammatory bowel disease,Crohn's disease(CD)or ulcerative colitis were investigated using both a casecontrol study approach(one case randomly selected from each of 191 Swedish inflammatory bowel disease families and 333 controls)and a family-based study(463 non-Swedish European inflammatory bowel disease-families).A nonsynonymous coding single nucleotide polymorphism in MORC4,located on the same linkage block as CLDN2,was investigated for association,as were two novel CLDN2 single nucleotide polymorphism markers,identified by resequencing.RESULTS:A single nucleotide polymorphism marker(rs12014762)located in the genetic region of CLDN2 was significantly associated to CD(case-control allelic OR = 1.98,95%CI:1.17-3.35,P = 0.007).MORC4 was present on the same linkage block as this CD marker.Using the case-control approach,a significant association(case control allelic OR = 1.61,95%CI:1.08-2.41,P = 0.018)was found between CD and a nonsynonymous coding single nucleotide polymorphism(rs6622126)in MORC4.The association between the CLDN2 marker and CD was not replicated in the familybased study.Ulcerative colitis was not associated to any of the single nucleotide polymorphism markers.CONCLUSION:These findings suggest that a variant of the CLDN2-MORC4 region predisposes to CD in a Swedish population.

Factors associated with DAA virological treatment failure and resistance-associated substitutions description in HIV/HCV coinfected patients

AIM To describe factors associated with treatment failure and frequency of resistance-associated substitutions(RAS).METHODS Human immunodeficiency virus(HIV)/hepatitis C virus(HCV) coinfected patients starting a first direct-acting antiviral(DAA) regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defined as:(1) non-response [HCV-RNA remained detectable during treatment, at end of treatment(EOT)]; and(2) relapse(HCVRNA suppressed at EOT but detectable thereafter). Sequencing analysis was performed to describe prevalence of drug class-specific RAS. Factors associated with failure were determined using logistic regression models.RESULTS Among 559 patients, 77% had suppressed plasma HIV-RNA < 50 copies/mL at DAA treatment initiation, 41% were cirrhotic, and 68% were HCV treatmentexperienced. Virological treatment failures occurred in 22 patients and were mainly relapses(17, 77%) then undefined failures(3, 14%) and non-responses(2, 9%). Mean treatment duration was 16 wk overall. Posttreatment NS3, NS5 A or NS5 B RAS were detected in 10/14 patients with samples available for sequencing analysis. After adjustment for age, sex, ribavirin use, HCV genotype and treatment duration, low platelet count was the only factor significantly associated with a higher risk of failure(OR: 6.5; 95%CI: 1.8-22.6). CONCLUSION Only 3.9% HIV-HCV coinfected patients failed DAA regimens and RAS were found in 70% of those failing. Low platelet count was independently associated with virological failure.