NLRP3/1-mediated pyroptosis:beneficial clues for the development of novel therapies for Alzheimer’s disease

The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis,which is a lytic,inflammatory form of cell death.There is accumulating evidence that nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3(NLRP3)inflammasome-mediated microglial pyroptosis and NLRP1 inflammasome-mediated neuronal pyroptosis in the brain are closely associated with the pathogenesis of Alzheimer’s disease.In this review,we summarize the possible pathogenic mechanisms of Alzheimer’s disease,focusing on neuroinflammation.We also describe the structures of NLRP3 and NLRP1 and the role their activation plays in Alzheimer’s disease.Finally,we examine the neuroprotective activity of small-molecule inhibitors,endogenous inhibitor proteins,microRNAs,and natural bioactive molecules that target NLRP3 and NLRP1,based on the rationale that inhibiting NLRP3 and NLRP1 inflammasome-mediated pyroptosis can be an effective therapeutic strategy for Alzheimer’s disease.

Rational and Continuous Measurement of Emotional-Fingerprint, Emotional-Quotient and Categorical vs Proportional Recognition of Facial Emotions with M.A.R.I.E., Second Half

Context: The advent of Artificial Intelligence (AI) requires modeling prior to its implementation in algorithms for most human skills. This observation requires us to have a detailed and precise understanding of the interfaces of verbal and emotional communications. The progress of AI is significant on the verbal level but modest in terms of the recognition of facial emotions even if this functionality is one of the oldest in humans and is omnipresent in our daily lives. Dysfunction in the ability for facial emotional expressions is present in many brain pathologies encountered by psychiatrists, neurologists, psychotherapists, mental health professionals including social workers. It cannot be objectively verified and measured due to a lack of reliable tools that are valid and consistently sensitive. Indeed, the articles in the scientific literature dealing with Visual-Facial-Emotions-Recognition (ViFaEmRe), suffer from the absence of 1) consensual and rational tools for continuous quantified measurement, 2) operational concepts. We have invented a software that can use computer-morphing attempting to respond to these two obstacles. It is identified as the Method of Analysis and Research of the Integration of Emotions (M.A.R.I.E.). Our primary goal is to use M.A.R.I.E. to understand the physiology of ViFaEmRe in normal healthy subjects by standardizing the measurements. Then, it will allow us to focus on subjects manifesting abnormalities in this ability. Our second goal is to make our contribution to the progress of AI hoping to add the dimension of recognition of facial emotional expressions. Objective: To study: 1) categorical vs dimensional aspects of recognition of ViFaEmRe, 2) universality vs idiosyncrasy, 3) immediate vs ambivalent Emotional-Decision-Making, 4) the Emotional-Fingerprint of a face and 5) creation of population references data. Methods: M.A.R.I.E. enables the rational, quantified measurement of Emotional Visual Acuity (EVA) in an individual observer and a population aged 20 to 70 years. Meanwhile, it can measure the range and intensity of expressed emotions through three Face- Tests, quantify the performance of a sample of 204 observers with hypernormal measures of cognition, “thymia” (defined elsewhere), and low levels of anxiety, and perform analysis of the six primary emotions. Results: We have individualized the following continuous parameters: 1) “Emotional-Visual- Acuity”, 2) “Visual-Emotional-Feeling”, 3) “Emotional-Quotient”, 4) “Emotional-Decision-Making”, 5) “Emotional-Decision-Making Graph” or “Individual-Gun-Trigger”, 6) “Emotional-Fingerprint” or “Key-graph”, 7) “Emotional-Fingerprint-Graph”, 8) detecting “misunderstanding” and 9) detecting “error”. This allowed us a taxonomy with coding of the face-emotion pair. Each face has specific measurements and graphics. The EVA improves from ages of 20 to 55 years, then decreases. It does not depend on the sex of the observer, nor the face studied. In addition, 1% of people endowed with normal intelligence do not recognize emotions. The categorical dimension is a variable for everyone. The range and intensity of ViFaEmRe is idiosyncratic and not universally uniform. The recognition of emotions is purely categorical for a single individual. It is dimensional for a population sample. Conclusions: Firstly, M.A.R.I.E. has made possible to bring out new concepts and new continuous measurements variables. The comparison between healthy and abnormal individuals makes it possible to take into consideration the significance of this line of study. From now on, these new functional parameters will allow us to identify and name “emotional” disorders or illnesses which can give additional dimension to behavioral disorders in all pathologies that affect the brain. Secondly, the ViFaEmRe is idiosyncratic, categorical, and a function of the identity of the observer and of the observed face. These findings stack up against Artificial Intelligence, which cannot have a globalist or regionalist algorithm that can be programmed into a robot, nor can AI compete with human abilities and judgment in this domain. *Here “Emotional disorders” refers to disorders of emotional expressions and recognition.

Rational and Continuous Measurement of the Emotional Decision Making in Visual Recognition of Facial Emotional Expressions with M.A.R.I.E.: First Half

Context: The advent of Artificial Intelligence (AI) requires modeling prior to its implementation in algorithms for most human skills. This observation requires us to have a detailed and precise understanding of the interfaces of verbal and emotional communications. The progress of AI is significant on the verbal level but modest in terms of the recognition of facial emotions even if this functionality is one of the oldest in humans and is omnipresent in our daily lives. Dysfunction in the ability for facial emotional expressions is present in many brain pathologies encountered by psychiatrists, neurologists, psychotherapists, mental health professionals including social workers. It cannot be objectively verified and measured due to a lack of reliable tools that are valid and consistently sensitive. Indeed, the articles in the scientific literature dealing with Visual-Facial-Emotions-Recognition (ViFaEmRe), suffer from the absence of 1) consensual and rational tools for continuous quantified measurement, 2) operational concepts. We have invented a software that can use computer-morphing attempting to respond to these two obstacles. It is identified as the Method of Analysis and Research of the Integration of Emotions (M.A.R.I.E.). Our primary goal is to use M.A.R.I.E. to understand the physiology of ViFaEmRe in normal healthy subjects by standardizing the measurements. Then, it will allow us to focus on subjects manifesting abnormalities in this ability. Our second goal is to make our contribution to the progress of AI hoping to add the dimension of recognition of facial emotional expressions. Objective: To study: 1) categorical vs dimensional aspects of recognition of ViFaEmRe, 2) universality vs idiosyncrasy, 3) immediate vs ambivalent Emotional-Decision-Making, 4) the Emotional-Fingerprint of a face and 5) creation of population references data. Methods: With M.A.R.I.E. enable a rational quantified measurement of Emotional-Visual-Acuity (EVA) of 1) a) an individual observer, b) in a population aged 20 to 70 years old, 2) measure the range and intensity of expressed emotions by 3 Face-Tests, 3) quantify the performance of a sample of 204 observers with hyper normal measures of cognition, “thymia,” (ibid. defined elsewhere) and low levels of anxiety 4) analysis of the 6 primary emotions. Results: We have individualized the following continuous parameters: 1) “Emotional-Visual-Acuity”, 2) “Visual-Emotional-Feeling”, 3) “Emotional-Quotient”, 4) “Emotional-Deci-sion-Making”, 5) “Emotional-Decision-Making Graph” or “Individual-Gun-Trigger”6) “Emotional-Fingerprint” or “Key-graph”, 7) “Emotional-Finger-print-Graph”, 8) detecting “misunderstanding” and 9) detecting “error”. This allowed us a taxonomy with coding of the face-emotion pair. Each face has specific measurements and graphics. The EVA improves from ages of 20 to 55 years, then decreases. It does not depend on the sex of the observer, nor the face studied. In addition, 1% of people endowed with normal intelligence do not recognize emotions. The categorical dimension is a variable for everyone. The range and intensity of ViFaEmRe is idiosyncratic and not universally uniform. The recognition of emotions is purely categorical for a single individual. It is dimensional for a population sample. Conclusions: Firstly, M.A.R.I.E. has made possible to bring out new concepts and new continuous measurements variables. The comparison between healthy and abnormal individuals makes it possible to take into consideration the significance of this line of study. From now on, these new functional parameters will allow us to identify and name “emotional” disorders or illnesses which can give additional dimension to behavioral disorders in all pathologies that affect the brain. Secondly, the ViFaEmRe is idiosyncratic, categorical, and a function of the identity of the observer and of the observed face. These findings stack up against Artificial Intelligence, which cannot have a globalist or regionalist algorithm that can be programmed into a robot, nor can AI compete with human abilities and judgment in this domain. *Here “Emotional disorders” refers to disorders of emotional expressions and recognition.

Aquaporin-4 in the formation of cerebral edema following severe burns What role do arginine vasopressin levels play?

BACKGROUND： Aquaporin-4 （AQP-4）, which is able to rapidly transport water within the brain, is highly expressed in brain tissue. It also plays an important role in the formation of cerebral edema following brain injury. However, the role of AQP-4 in the formation of cerebral edema following severe bums remains unknown. OBJECTIVE： To study changes in AQP-4 protein and mRNA expression during formation of cerebral edema following severe burns, and to explore the correlation between AQP-4 protein and mRNA expression with plasma levels of arginine vasopressin （AVP）. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Research Center of Neuroscience, Chongqing Medical University from 2007 to 2008. MATERIALS： Biotin-labeled goat anti-rabbit antibody was provided by Beijing Zhongshan Biotechnology, China; in situ hybridization kit was provided by Wuhan Boster Biotechnology, China; rabbit anti-AQP-4 polyclonal antibody and horseradish peroxidase-labeled goat anti-rabbit IgG were provided by Chemicon, USA; AVP radioimmunoassay kit was provided by the Research Department of Neurobiology, the Second Military Medical University of Shanghai, China. METHODS： A total of 180 adult, healthy, Wistar rats were randomly assigned to control and burn groups with 30 rats in each group. The burn group was observed at five different time points： 2, 6, 12, 24, and 48 hours after burn. Hair on the mouse back was removed to expose skin on the back. After 1 day, skin with the hair removed was dipped into 100℃ water for 15 seconds to induce grade III bum injury that measures 30% of total bum surface area. MAIN OUTCOME MEASURES： Brain water content was measured using the dry-wet weight method. AQP-4 protein and mRNA expressions were detected using immunohistochemistry, in situ hybridization, Western blot, and reverse transcription-polymerase chain reaction; dynamic changes in plasma AVP were detected using radioimmunoassay. RESULTS： Brain water content gradually increased following severe burn injury. AQP-4 protein and mRNA expressions were upregulated in the supraoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus, hippocampus, choroid plexus, and cerebral cortex. Plasma AVP levels increased following burn injury. AQP-4 protein and mRNA expressions positively correlated with brain water content and AVP levels during formation of cerebral edema （r= 0.870, 0.848, P 〈 0.01）. CONCLUSION： AQP-4 participated in the formation of cerebral edema following burn injury. Plasma AVP upregulated AQP-4 expression in brain tissue, thereby promoting formation of cerebral edema.

EFFECTS OF TOTAL SAPONINS OF PANAX NOTOGINSENG AND LIGUSTRAZINE ON THE PROLIFERATION OF CEREBRAL MICROVASCULAR ENDOTHELIAL CELLS OF RATS

Objective To investigate the effects of Total Saponins of Panax notoginseng(PNS) and Liguastrazine(LIT) on the proliferation of cultured cerebral microvascular endothelial cells. Methods The inverted microscope was used to observe endothelial cells and immunochemical methods was also used to detect FVIII-related antigens so as to observe endothelial cells. PNS or LIT in concentrations 0.5?g·L -1, 1.0?g·L -1 and 2.0?g·L -1 were used on the cultured cerebral endothelial cells of rats for 24 hours. MTT method was adopted to determine the outcome of endothelial proliferation. Results 1. Immunochemical methods was used to detect FVIII-related antigens. The brownish yellow showed positive, and the observation of the cultured endothelial cells under inverted microscope showed that the cells appeared to be in the morphological form of cobble-stones. 2. PNS in lower concentration (0.5?g·L -1) could facilitate the proliferation of the cells, while 1?g·L -1 and 2?g·L -1 of PNS could inhibit the proliferation of the cells. 0.5?g·L -1 of LIT could facilitate the proliferation of cellswhile LIT of 1?g·L -1 and 2?g·L -1 had no significant effect. Conclusion The two kind of TCM ingredients extracted in lower concentration could facilitate the proliferation of the cells. And, at the same concentration, the inhibition of PNS on the cells is stronger than that of LIT.

Evidence of impaired facial emotion recognition in mild Alzheimer’s disease: A mathematical approach and application

Objectives: The first objective of this paper is to show the improved binary outcomes resulting from using MARIE as a diagnostic instrument that allows valid and reliable visual recognition of facial emotional expressions (VRFEE) in an objective and quantitative manner. The second objective is to demonstrate mathematical modeling of binary responses that allow the measurement of categorical dimension, sensitivity, camber, equilibrium points, transition thresholds, etc. The final objective is to illustrate the use of this test for 1) testing a homogeneous sample of healthy young participants;and 2) applying this method to a sample of 12 participants with early Alz-heimer disease compared to a matched control sample of healthy elderly participants. Design: Transforming the binary outcomes of MARIE in mathematical variables (experiment 1), allowing verification of a disorder of VRFEE in early Alzheimer’s disease (experiment 2). Measures: Comparison of numerical variables and graphic representations of both samples. Results: The objective measurement of VRFEE is possible in a healthy population. The application of this methodology to a pathological population is also made possible. The results support the current literature. Conclusion: The combination of the mathematical method with the diagnostic instrument MARIE shows its power and ease of use in clinical practice and research. Its application in many clinical conditions and in clinical research can be useful for understanding brain function. This method improves 1) the inter-examiner comparison and standardizes the quantification of VRFEE for use by multiple researchers;2) the follow-up of a sample over time;3) the comparison of two or more samples. This method is already available in clinical work for refining the diagnosis of Alzheimer’s Disease (AD) in our department.

A Study of Visual Recognition of Facial Emotional Expressions in a Normal Aging Population in the Absence of Cognitive Disorders

Objective: To examine and measure the decision-making processes involved in Visual Recognition of Facial Emotional Expressions (VRFEE) and to study the effects of demographic factors on this process. Method: We evaluated a newly designed software application (M.A.R.I.E.) that permits computerized metric measurement of VRFEE. We administered it to 204 cognitively normal participants ranging in age from 20 to 70 years. Results: We established normative values for the recognition of anger, disgust, joy, fear, surprise and sadness expressed on the faces of three individuals. There was a significant difference in the: 1) measurement (F (8.189) = 3896, p = 0.0001);2) education level (x2(12) = 28.4, p = 0.005);3) face (F(2.195) = 10, p = 0.0001);4)series (F (8.189)=28, p = 0.0001);5) interaction between the identity and recognition of emotions (F (16, 181 =11, p = 0.0001). However, performance did not differ according to: 1) age (F (6.19669) = 1.35, p = 0.2) or 2) level of education (F (1, 1587) = 0.6, p = 0.4). Conclusions: In healthy participants, the VRFEE remains stable throughout the lifespan when cognitive functions remain optimal. Disgust, sadness, fear, and joy seem to be the four most easily recognized facial emotions, while anger and surprise are not easily recognized. Visual recognition of disgust and fear is independent of aging. The characteristics of a face have a significant influence on the ease with which people recognize expressed emotions (idiosyncrasy). Perception and recognition of emotions is categorical, even when the facial images are integrated in a spectrum of morphs reflecting two different emotions on either side.

Cell replacement with stem cell-derived retinal ganglion cells from different protocols

Glaucoma,characterized by a degenerative loss of retinal ganglion cells,is the second leading cause of blindness worldwide.There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury.Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases.In this review,we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture,including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes.Next,we discuss using 3D retinal organoids for retinal ganglion cell transplantation,comparing cell suspensions and clusters.This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation,with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies.

“PALPATION BY IMAGING”:MAGNETIC RESONANCE ELASTOGRAPHY

Elasticity is an important physical property of human tissues. There is a tremendous difference in elasticity between normal and pathological tissues. Noninvasive evaluation of the elasticity of human tissues would be valuable for clinical practice. Magnetic resonance elastography(MRE)is a recently developed noninvasive imaging technique that can directly visualize and quantitatively measure tissue elasticity. This article reviewed the MRE technique and its current status.

Mammalin cochlear supporting cells transdifferentiation into outer hair cells

Objective To study the recovery of the outer hair cells in the bat cochlea after gentamicin exposure. Methods Bats were injected with a daily dose of gentamicin for 15 consecutive days and bromodeoxyuridine (BrdU) was given from day 16 to day 40 of this recovery phase. Hearing was assessed by overt acoustic behavior and auditory brainstem responses analysis, which was performed one day prior to the first injection and a day after the last injection (day 16). On day 40 animals were sacrificed for detection of cells that could take up BrdU. Results After 15 days of gentamicin treatment, all of the animals were proved to be deafened with significant increases of ABR thresholds, compared with control group. The findings in immunocytochemical stained samples and scanning electron microscopy revealed that BrdU labeled nuclei were observed in the cochlea in all of the deafened animals most commonly in the regions of the first-row and second-row Deiter’s cells (DCs) and occasionally in the regions of the third-row DCs. Conclusion We suggest that, under sufficient drug and enough time, the bat cochlear supporting cells can directly transdifferentiate into the outer hair cells after aminoglycoside exposure. This transdifferentation process is essential for repair of outer hair cells and recovery of normal function after gentamicin exposure.

TRAIL and Celastrol Combinational Treatment Suppresses Proliferation, Migration, and Invasion of Human Glioblastoma Cells via Targeting Wnt/β-catenin Signaling Pathway

Objective To investigate the mechanistic basis for the anti-proliferation and anti-invasion effect of tumor necrosis factor-related apoptosis-induced ligand(TRAIL)and celastrol combination treatment(TCCT)in glioblastoma cells.Methods Cell counting kit-8 was used to detect the effects of different concentrations of celastrol(0-16µmol/L)and TRAIL(0-500 ng/mL)on the cell viability of glioblastoma cells.U87 cells were randomly divided into 4 groups,namely control,TRAIL(TRAIL 100 ng/mL),Cel(celastrol 0.5µmol/L)and TCCT(TRAIL 100 ng/mL+celastrol 0.5µmol/L).Cell proliferation,migration,and invasion were detected by colony formation,wound healing,and Transwell assays,respectively.Quantitative reverse transcription polymerase chain reaction and Western blotting were performed to assess the levels of epithelial-mesenchymal transition(EMT)markers(zona occludens,N-cadherin,vimentin,zinc finger E-box-binding homeobox,Slug,and β-catenin).Wnt pathway was activated by lithium chloride(LiCl,20 mol/L)and the mechanism for action of TCCT was explored.Results Celastrol and TRAIL synergistically inhibited the proliferation,migration,invasion,and EMT of U87 cells(P<0.01).TCCT up-regulated the expression of GSK-3β and down-regulated the expression of β-catenin and its associated proteins(P<0.05 or P<0.01),including c-Myc,Cyclin-D1,and matrix metalloproteinase(MMP)-2.In addition,LiCl,an activator of the Wnt signaling pathway,restored the inhibitory effects of TCCT on the expression of β-catenin and its downstream genes,as well as the migration and invasion of glioblastoma cells(P<0.05 or P<0.01).Conclusions Celastrol and TRAIL can synergistically suppress glioblastoma cell migration,invasion,and EMT,potentially through inhibition of Wnt/β-catenin pathway.This underlies a novel mechanism of action for TCCT as an effective therapy for glioblastoma.

Utility and Safety of Intrathecal Methotrexate Treatment in Severe Anti-N-methyI-D-aspartate Receptor Encephalitis： A Pilot Study

Background： Anti-N-methyl-D-aspartate receptor （anti-NMDAR） encephalitis is a treatable autoimmune neurologic syndrome that occurs with or without tumor association. However, some severe cases are refractory to systemic immunotherapy. This pilot study aimed to evaluate the utility and safety of intrathecal methotrexate injection for severe patients with anti-NMDAR encephalitis who did not respond to first-line immunotherapy. Methods： Intrathecal injections with methotrexate and dexamethasone were performed weekly in four legible patients within consecutive 4 weeks. Cerebrospinal fluid （CSF） was collected at baseline and each time of intrathecal injection lbr identification of anti-NMDAR antibody titers. Results： Significant clinical improvement was observed in three patients associated with a stepwise decrease of CSF anti-NMDAR antibody titers （maximum： 1/320 to minimum： 1/10）. After 2 months of follow-up, they were able to follow simple commands and had appropriate interactions with people （modified Rankin scale [mRS] of 0-2）. At 12 months of follow-up, they all had returned to most activities of daily life （.mRS of 0）, and no relapses were reported. One patient showed no clinical improvement and died of neurologic complications. Conclusions： lntrathecal treatment may be a potentially useful supplementary therapy in severely affected patients with anti-NMDAR encephalitis. Further large cohort study and animal experiment may help us elaborate the utility of intrathecal injection of methotrexate and its mechanism of action.

Human Recombinant PLD2 Can Repress p65 Activity of Guinea Pigs of Chronic Asthma in vivo

This article is to investigate the effect of human recombinant phospholipase D2 （rhPLD2） in vivo on the expression of nuclear transcription factor p65 in chronic asthma of guinea pigs. After treating the guinea pigs with chronic asthma by rhPLD2, the crude nuclear extraction was assayed with TransAM Transcription Factor Assay Kit for the activity of pulmo tissue nuclear transcription factor p65. Compared with the healthy guinea pigs, the activity of nuclear transcription factor p65 in guinea pigs of chronic asthma is much higher than that of control groups. Our results showed that rhPLD2 markedly depressed the activity of p65 when the guinea pigs were attacked by chronic asthma.

Research progress in traumatic brain penumbra

Objective Following traumatic brain injury （TBI）,brain tissue that surrounding the regional primary lesion is known as traumatic penumbra; this region may undergo secondary injury and is considered to have the potential to recover.This review aimed to reveal the existence and significance of traumatic penumbra by analyzing all relevant studies concerning basic pathologic changes and brain imaging after TBI.Data sources We collected all relevant studies about TBI and traumatic penumbra in Medline （1995 to June 2013） and ISI （1997 to March 2013）,evaluated their quality and relevance,then extracted and synthesized the information.Study selection We included all relevant studies concerning TBI and traumatic penumbra （there was no limitation of research design and article language） and excluded the duplicated articles.Results The crucial pathological changes after TBI include cerebral blood flow change,cerebral edema,blood-brain barrier damage,cell apoptosis and necrosis.Besides,traditional imaging method cannot characterize the consequences of CBF reduction at an early stage and provides limited insights into the underlying pathophysiology.While advanced imaging technique,such as diffusion tensor imaging （DTI） and positron emission tomography （PET）,may provide better characterization of such pathophysiology.Conclusions The future of traumatic brain lesions depends to a large extent on the evolution of the penumbra.Therefore,understanding the formation and pathophysiologic process of the traumatic penumbra and its imaging research progress is of great significant for early clinical determination and timely brain rescue.

Maltol as a Novel Agent Protecting SH-SY5Y Cells Against Hemin-induced Ferroptosis

Ferroptosis triggered by hemin is regarded as a primary factor accounting for neuronal death secondary to intracerebral hemorrhage.Thus,compounds with inhibitory effect on hemin-induced ferroptosis might be potential medicines to prevent neuronal death caused by intracerebral hemorrhage.Herein,we investigate whether maltol could alleviate hemin-induced SH-SY5Y cell ferroptosis and its potential mechanisms.It is found that maltol effectively prevents hemin-induced SH-SY5Y cell ferroptosis via three pathways.The first one is inhibiting intracellular iron increase via preventing upregulation of transferrin receptor,the second one is alleviating lipid peroxidation via attenuating H_(2)O_(2) generation by NOX4 and promoting H_(2)O_(2) clearance by catalase,and the third one is to reduce peroxidized lipids via maintaining GPX4/GSH pathway.Therefore,maltol is a novel agent preventing hemin-induced SH-SY5Y cell ferroptosis.