High-altitude hypoxia induces disorders of the brain- endocrine-immune network through activation of corticotropin-releasing factor and its type- 1 receptors

High-altitude hypoxia can induce physiological dysfunction and mountain sickness,but the underlying mechanism is not fully understood.Corticotrophin-releasing factor(CRF) and CRF type-1 receptors(CRFR1) are members of the CRF family and the essential controllers of the physiological activity of the hypothalamo-pituitary-adrenal(HPA) axis and modulators of endocrine and behavioral activity in response to various stressors.We have previously found that high-altitude hypoxia induces disorders of the brain-endocrine-immune network through activation of CRF and CRFR1 in the brain and periphery that include activation of the HPA axis in a time-and dose-dependent manner,impaired or improved learning and memory,and anxiety-like behavioral change.Meanwhile,hypoxia induces dysfunctions of the hypothalamo-pituitary-endocrine and immune systems,including suppression of growth and development,as well as inhibition of reproductive,metabolic and immune functions.In contrast,the small mammals that live on the Qinghai-Tibet Plateau alpine meadow display low responsiveness to extreme high-altitudehypoxia challenge,suggesting well-acclimatized genes and a physiological strategy that developed during evolution through interactions between the genes and environment.All the findings provide evidence for understanding the neuroendocrine mechanisms of hypoxia-induced physiological dysfunction.This review extends these findings.

Relationships among magnetic resonance imaging, histological findings, and IGF-I in steroid-induced osteonecrosis of the femoral head in rabbits

Objective: To study the relationships among magnetic resonance imaging (MRI), histological findings, and insu- lin-like growth factor-I (IGF-I) in steroid-induced osteonecrosis of the femoral head in rabbits. Methods: Thirty rabbits were randomly divided into experimental Group A (n=15) and control Group B (n=15). The 7.5 mg/kg (2 ml) of dexamethasone (DEX) and physiological saline (2 ml) were injected into the right gluteus medius muscle twice at one-week intervals in animals of Groups A and B, respectively. At 4, 8 and 16 weeks after obtaining an MRI, the rabbits were sacrificed and the femoral head from one side was removed for histological study of lacunae empty of osteocytes, subchondral vessels, and size of fat cells under microscopy, and the femoral head from the other side was removed for enzyme-linked immunoadsorbent assay (ELISA) for IGF-I. Results: At 4, 8 and 16 weeks after treatment, no necrotic lesions were detected in Group B, while they were detected in Group A. Light microscopy revealed that the fat cells of the marrow cavity were enlarged, subchondral vessels were evidently decreased, and empty bone lacunae were clearly increased. The IGF-I levels in Group A were significantly higher than those in Group B. At 8 weeks after the DEX injection, the MRI of all 20 femora showed an inhomogeneous, low signal intensity area in the femoral head, and at 16 weeks, the findings of all 10 femora showed a specific "line-like sign". The MRI findings of all femora in Group B were normal. Conclusion: MRI is a highly sensitive means of diagnosing early experimental osteonecrosis of the femoral head. However, the abnormal marrow tissues appeared later than 4 weeks when the expression of IGF-I increased. This reparative factor has an early and important role in response to steroid-induced osteonecrosis of the femoral head, and provides a theoretical foundation for understanding the pathology and designing new therapies.

Translational Neurobiology. Current Challenges and Opportunities

（中文介绍）转化神经生物学是整合从神经生物学的基础研究到优化人类神经系统疾病病人的护理和预防战略，从实验室到临床的研究。在过去10年药物的发现已经有了革命性的变化。然而，新药品审批的数量仍然停滞不前，药物市场的成本比以往任何时候都高。这也提出现有药物开发的模式，已不适应变化的科学和公众对制药公司的期待。

S1B-2 Therapeutics and Biomarker Development in Huntington’Disease

Most neurodegenerative diseases,including Alzheimer’s,Parkinson’s,and Huntington’s disease(HD),have converging pathogenesis,such as formation of abnormal protein aggregates and mitochondrial dysfunction.Unfortunately,despite tremendous efforts by many scientists and increasing knowledge about disease mechanisms,we still lack disease-modifying treatments for any of these diseases.Drug discovery has been revolutionized in the past decade.Despite technological advances as a result of substantial investment,the number of new drug approvals remains stagnant and the cost of bringing a drug to market is higher than ever.This highlights the persistence of a model of drug development that has not adapted to changes in science and public perception of drug companies.While these diseases affect different areas of the brain and are distinct at the cellular and molecular levels,they share many underlying similarities.Thus,development of treatment for any of these diseases may provide clues to accelerate the path to the treatment for other neurodegenerative diseases.Research into potential therapies for HD is particularly attractive because it is a genetically homogeneous disease for which well-established models exist.The HD gene encodes the protein huntingtin(Htt),whose polyglutamine expansion is believed to mediate the cytotoxic effects of HD.Therefore,HD also serves a model for polyglutamine diseases.HD is a monogenic neurodegenerative disorder caused by mutation of the gene Huntingtin.Htt lowering(gene silencing)strategies,including antisense oligonucleotides,shRNA,miRNA et al,have shown great preclinical promise,and the first HTT lowering clinical trial is underway.The key to success of these trials will be to know where and when to intervene,since these reagents do not penetrate the blood-brain-barrier,and must be delivered directly to the CNS.HD is notable for preferential atrophy of the striatum but also involves degeneration in cortex,subcortical white matter,and specific subcortical grey matter regions.It has been shown regional spread of pathology in the HD brain using neuroimaging.In addition,neurodegeneration in HD is mainly caused by toxic effects of the abnormal Htt protein,and there is increasing evidence that mutant Htt can spread,like prions.A better understanding of HD pathology at a cellular level and in the network context would be important for determining the optimal timing and brain regional location of therapeutic interventions.HD mouse models provide unique values to answer these questions,as brain samples can be collected at a temporal manner from different disease stages(before disease onset,at the onset,after the onset)in a relatively short period.Knowledge of HD pathogenesis is bearing fruit in experimental treatments,using agents to decrease production of the huntingtin message RNA and protein.An understanding of how pathology of HD may spread throughout the brain can be guided by an understanding of the cortico-basal-ganglionic circuitry.Selective pathology within the basal ganglia circuit may contribute to features of HD phenotype.

Targeting α-synuclein by PD03 AFFITOPE■ and Anle 138b rescues neurodegenerative pathology in a model of multiple system atrophy:clinical relevance

Background:Misfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of a-synucleinopathies including Parkinson's disease and multiple system atrophy,and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta.Here we aimed to analyze the therapeutic efficacy of PD03,a new AFFITOPE■ immunotherapy approach,either alone or in combination with Anle138b,in a PLP-α-syn mouse model.Methods:The PLP-α-syn mice were treated with PD03 immunotherapy,Anle138b,or a combination of two.Five months after study initiation,the mice underwent behavioral testing and were sacrificed for neuropathological analysis.The treatment groups were compared to the vehicle group with regard to motor performance,nigral neuronal loss,microglial activation and α-synuclein pathology.Results:The PLP-α-syn mice receiving the PD03 or Anle138b single therapy showed improvement of gait deficits and preservation of nigral dopaminergic neurons associated with the reduced α-synuclein oligomer levels and decreased microglial activation.The combined therapy with Anle138b and PD03 resulted in lower lgG binding in the brain as compared to the single immunotherapy with PD03.Conclusions:PD03 and Anle138b can selectively target oligomeric α-synuclein,resulting in attenuation of neurodegeneration in the PLP-α-syn mice.Both approaches are potential therapies that should be developed further for disease modification in α-synucleinopathies.

Microglial senescence in neurodegeneration:Insights,implications,and therapeutic opportunities

The existing literature on neurodegenerative diseases(NDDs)reveals a common pathological feature:the accumulation of misfolded proteins.However,the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs.Dementia,a hallmark symptom across various NDDs,serves as a multifaceted denominator,contributing to the clinical manifestations of these disorders.There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression.Recent research has linked disease-associated microglia to their transition into a senescent state—characterized by irreversible cell cycle arrest—in aging populations and NDDs.Although senescent microglia are consistently observed in NDDs,few studies have utilized animal models to explore their role in disease pathology.Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence,indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets.This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs,including Alzheimer's disease,Parkinson's disease,Huntington's disease,and amyotrophic lateral sclerosis.Additionally,it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.

Shining more light on G protein signalling modules:a novel optogenetic tool for Gq activation

The use of optogenetic and chemogenetic approaches to control cellular activities with high temporal,spatial and cell-type specific resolution has profoundly transformed the field of neuroscience.In addition to enabling the manipulation of neuronal excitability,there is a great need for targeting intracellular signalling proteins and secondary messengers precisely。

NADPH oxidase and reactive oxygen species as signaling molecules in carcinogenesis

Reactive oxygen species(ROS)are small molecule metabolites of oxygen that are prone to participate in redox reactions via their high reactivity.Intracellular ROS could be generated in reduced nicotina-mide-adenine dinucleotidephosphate(NADPH)oxidase-dependent and/or NADPH oxidase-independent manners.Physiologically,ROS are involved in many signaling cascades that contribute to normal processes.One classical example is that ROS derived from the NADPH oxidase and released in neurotrophils are able to digest invading bacteria.Excessive ROS,however,contribute to patho-genesis of various human diseases including cancer,aging,dimentia and hypertension.As signaling messengers,ROS are able to oxidize many targets such as DNA,proteins and lipids,which may be linked with tumor growth,invasion or metastasis.The present review summarizes recent advances in our comprehensive understanding of ROS-linked signaling pathways in regulation of tumor growth,invasion and metastasis,and focuses on the role of the NADPH oxidase-derived ROS in cancer pathogenesis.