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Cell Aug 2023The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases...
The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.
Topics: Animals; Humans; Mice; Bone Marrow; Brain; Carrier Proteins; Nervous System Diseases; Positron-Emission Tomography; Receptors, GABA; Skull
PubMed: 37562402
DOI: 10.1016/j.cell.2023.07.009 -
Annals of Indian Academy of Neurology 2023Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of anterior horn cells with a dismal prognosis. Over a century since its description, we still do not...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of anterior horn cells with a dismal prognosis. Over a century since its description, we still do not have a cure for this disorder. Edaravone, Riluzole, and combination of phenylbutyrate and taurursodiol are a handful of FDA-approved drugs that only delay the progression of the disease by a few months. Tofersen, an antisense oligonucleotide, in SOD1 related ALS, has joined the bandwagon of FDA-approved drugs for ALS recently. It is a gene therapy that has been found to lower SOD1 concentrations and neurofilament light chain concentrations in blood and CSF, a known biomarker of ALS, leading to the accelerated approval of the drug. Although it did not show any statistically significant clinical improvement. In this article, we discuss the development and approval process of the first gene-based therapy, Tofersen, for ALS.
PubMed: 38022476
DOI: 10.4103/aian.aian_734_23 -
Annals of Clinical and Translational... Dec 2023Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo-controlled and open-label extension phases. On intent-to-treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6-month double-blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo-to-active crossover, we performed a post hoc survival analysis comparing PB and TURSO-randomized participants from CENTAUR and a propensity score-matched, PB and TURSO-naïve external control cohort from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.
METHODS
Clinical trial control participants from the PRO-ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO-randomized CENTAUR participants using prognostically significant covariates in ALS.
RESULTS
Baseline characteristics including propensity score-matched covariates were generally well balanced between CENTAUR PB and TURSO (n = 89) and PRO-ACT external control (n = 85) groups. Estimated median (IQR) OS was 23.54 (14.56-39.32) months in the CENTAUR PB and TURSO group and 13.15 (9.83-19.20) months in the PRO-ACT external control group; hazard of death was 52% lower in the former group (hazard ratio, 0.48; 95% CI, 0.31-0.72; p = 0.00048).
INTERPRETATION
This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo-to-active crossover than seen on ITT analysis in CENTAUR. Analyses using well-matched external controls may provide additional context for evaluating survival effects in future ALS trials.
Topics: Humans; Amyotrophic Lateral Sclerosis; Phenylbutyrates; Survival Analysis; Proportional Hazards Models
PubMed: 37807839
DOI: 10.1002/acn3.51915 -
Neural Regeneration Research Apr 2024The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex, basal ganglia,... (Review)
Review
The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex, basal ganglia, brainstem, and spinal cord, and commonly involves the muscles of the upper and/or lower extremities, and the muscles of the bulbar and/or respiratory regions. However, as the disease progresses, it affects the adjacent body regions, leading to generalized muscle weakness, occasionally along with memory, cognitive, behavioral, and language impairments; respiratory dysfunction occurs at the final stage of the disease. The disease has a complicated pathophysiology and currently, only riluzole, edaravone, and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries. The TAR DNA-binding protein 43 inclusions are observed in 97% of those diagnosed with amyotrophic lateral sclerosis. This review provides a preliminary overview of the potential effects of TAR DNA-binding protein 43 in the pathogenesis of amyotrophic lateral sclerosis, including the abnormalities in nucleoplasmic transport, RNA function, post-translational modification, liquid-liquid phase separation, stress granules, mitochondrial dysfunction, oxidative stress, axonal transport, protein quality control system, and non-cellular autonomous functions (e.g., glial cell functions and prion-like propagation).
PubMed: 37843214
DOI: 10.4103/1673-5374.382233 -
Clinical Drug Investigation Dec 2023Phase II studies on tauro-urso-deoxycholic acid (TUDCA) raised the promise of safety and efficacy in patients with amyotrophic lateral sclerosis, a currently incurable... (Review)
Review
Phase II studies on tauro-urso-deoxycholic acid (TUDCA) raised the promise of safety and efficacy in patients with amyotrophic lateral sclerosis, a currently incurable and devastating disease. We review the available evidence on the efficacy and safety of TUDCA, administered alone or in combination, by analyzing and comparing published and ongoing studies on amyotrophic lateral sclerosis. Two independent phase II studies (using TUDCA solo or combined with sodium phenylbutyrate) showed similar efficacy in slowing disease progression measured by functional scales. One open-label follow-up TUDCA+sodium phenylbutyrate study suggested a benefit on survival. Two subsequent phase III studies with TUDCA (solo or combined with sodium phenylbutyrate) have been initiated and are currently ongoing. Their completion is expected by the end of 2023 and beginning of 2024. Evidence collected by phase II studies indicates that there are no safety concerns in patients with amyotrophic lateral sclerosis. The efficacy shown in phase II studies was considered sufficient to grant approval in some countries but not in others, owing to discrepant views on the strength of evidence. It will be necessary to wait for the results of ongoing phase III studies to attain a full appreciation of these data.
Topics: Humans; Amyotrophic Lateral Sclerosis; Phenylbutyrates; Taurochenodeoxycholic Acid
PubMed: 37973672
DOI: 10.1007/s40261-023-01324-0 -
International Journal of Molecular... Dec 2023Artificial insemination (AI) with liquid-stored semen is the most prevalent and efficient assisted reproduction technique in the modern pork industry. Pyruvate...
Artificial insemination (AI) with liquid-stored semen is the most prevalent and efficient assisted reproduction technique in the modern pork industry. Pyruvate dehydrogenase complex component X (PDHX) was demonstrated to be associated with sperm metabolism and affected the boar sperm viability, motility, and fertility. Pyruvate Dehydrogenase Kinases (PDKs) are the key metabolic enzymes that regulate pyruvate dehydrogenase complex (PDHC) activity and also the conversion from glycolysis to oxidative phosphorylation. In the present study, two PDK inhibitors, Dichloroacetate (DCA) and Phenylbutyrate (4-PBA), were added to an extender and investigated to determine their regulatory roles in liquid-stored boar sperm at 17 °C. The results indicated that PDK1 and PDK3 were predominantly located at the head and flagella of the boar sperm. The addition of 2 mM DCA and 0.5 mM 4-PBA significantly enhanced the sperm motility, plasma membrane integrity (PMI), mitochondrial membrane potential (MMP), and ATP content. In addition, DCA and 4-PBA exerted their effects by inhibiting PDK1 and PDK3, respectively. In conclusion, DCA and 4-PBA were found to regulate the boar sperm metabolic activities via PDK1 and PDK3. These both can improve the quality parameters of liquid-stored boar sperm, which will help to improve and optimize liquid-stored boar semen after their addition in the extender.
Topics: Swine; Male; Animals; Semen; Phenylbutyrates; Semen Preservation; Sperm Motility; Spermatozoa; Semen Analysis; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Pyruvate Dehydrogenase Complex
PubMed: 38069413
DOI: 10.3390/ijms242317091 -
Journal of Neurology, Neurosurgery, and... Dec 2023An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis...
Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: results from the CENTAUR trial.
BACKGROUND
An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS. We performed analyses of neuroinflammatory biomarkers associated with ALS in the literature, including YKL-40 (also known as chitinase-3-like protein 1), chitinase 1 (CHIT1) and C reactive protein (CRP), in plasma samples collected in CENTAUR.
METHODS
Log10-transformed plasma biomarker measurements were analysed using a linear mixed-effects model. Correlation between paired biomarker concentrations and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores was assessed via Pearson correlation coefficients.
RESULTS
By week 24, geometric least squares mean YKL-40 plasma concentration decreased by approximately 20% (p=0.008) and CRP by 30% (p=0.048) in the PB and TURSO versus placebo group. YKL-40 (r of -0.21; p<0.0001) and CRP (r of -0.19; p=0.0002) concentration correlated with ALSFRS-R total score. CHIT1 levels were not significantly different between groups.
CONCLUSIONS
YKL-40 and CRP plasma levels were significantly reduced in participants with ALS receiving PB and TURSO in CENTAUR and correlated with disease progression. These findings suggest YKL-40 and CRP could be treatment-sensitive biomarkers in ALS, pending further confirmatory studies.
TRIAL REGISTRATION NUMBER
https://clinicaltrials.gov/study/NCT03127514.
PubMed: 38050066
DOI: 10.1136/jnnp-2023-332106 -
BioRxiv : the Preprint Server For... Oct 2023Inflammation drives many age-related, especially neurological, diseases, and likely mediates age-related proteotoxicity. For example, dementia due to Alzheimer's Disease...
Novel small molecules inhibit proteotoxicity and inflammation: Mechanistic and therapeutic implications for Alzheimer's Disease, healthspan and lifespan- Aging as a consequence of glycolysis.
Inflammation drives many age-related, especially neurological, diseases, and likely mediates age-related proteotoxicity. For example, dementia due to Alzheimer's Disease (AD), cerebral vascular disease, many other neurodegenerative conditions is increasingly among the most devastating burdens on the American (and world) health system and threatens to bankrupt the American health system as the population ages unless effective treatments are developed. Dementia due to either AD or cerebral vascular disease, and plausibly many other neurodegenerative and even psychiatric conditions, is driven by increased age-related inflammation, which in turn appears to mediate Abeta and related proteotoxic processes. The functional significance of inflammation during aging is also supported by the fact that Humira, which is simply an antibody to the pro-inflammatory cytokine TNF-a, is the best-selling drug in the world by revenue. These observations led us to develop parallel high-throughput screens to discover small molecules which inhibit age-related Abeta proteotoxicity in a model of AD AND LPS-induced microglial TNF-a. In the initial screen of 2560 compounds (Microsource Spectrum library) to delay Abeta proteotoxicity, the most protective compounds were, in order, phenylbutyrate, methicillin, and quetiapine, which belong to drug classes (HDAC inhibitors, beta lactam antibiotics, and tricyclic antipsychotics, respectably) already robustly implicated as promising to protect in neurodegenerative diseases, especially AD. RNAi and chemical screens indicated that the protective effects of HDAC inhibitors to reduce Abeta proteotoxicity are mediated by inhibition of HDAC2, also implicated in human AD, dependent on the HAT Creb binding protein (Cbp), which is also required for the protective effects of both dietary restriction and the mutation (inactivation of IGF-1 signaling) during aging. In addition to methicillin, several other beta lactam antibiotics also delayed Abeta proteotoxicity and reduced microglial TNF-a. In addition to quetiapine, several other tricyclic antipsychotic drugs also delayed age-related Abeta proteotoxicity and increased microglial TNF-a, leading to the synthesis of a novel congener, GM310, which delays Abeta as well as Huntingtin proteotoxicity, inhibits LPS-induced mouse and human microglial and monocyte TNF-a, is highly concentrated in brain after oral delivery with no apparent toxicity, increases lifespan, and produces molecular responses highly similar to those produced by dietary restriction, including induction of Cbp inhibition of inhibitors of Cbp, and genes promoting a shift away from glycolysis and toward metabolism of alternate (e.g., lipid) substrates. GM310, as well as FDA-approved tricyclic congeners, prevented functional impairments and associated increase in TNF-a in a mouse model of stroke. Robust reduction of glycolysis by GM310 was functionally corroborated by flux analysis, and the glycolytic inhibitor 2-DG inhibited microglial TNF-a and other markers of inflammation, delayed Abeta proteotoxicity, and increased lifespan. These results support the value of phenotypic screens to discover drugs to treat age-related, especially neurological and even psychiatric diseases, including AD and stroke, and to clarify novel mechanisms driving neurodegeneration (e.g., increased microglial glycolysis drives neuroinflammation and subsequent neurotoxicity) suggesting novel treatments (selective inhibitors of microglial glycolysis).
PubMed: 37398396
DOI: 10.1101/2023.06.12.544352 -
Hypertension (Dallas, Tex. : 1979) Aug 2023Notch3 (neurogenic locus notch homolog protein 3) is implicated in vascular diseases, including pulmonary hypertension (PH)/pulmonary arterial hypertension. However,...
BACKGROUND
Notch3 (neurogenic locus notch homolog protein 3) is implicated in vascular diseases, including pulmonary hypertension (PH)/pulmonary arterial hypertension. However, molecular mechanisms remain elusive. We hypothesized increased Notch3 activation induces oxidative and endoplasmic reticulum (ER) stress and downstream redox signaling, associated with procontractile pulmonary artery state, pulmonary vascular dysfunction, and PH development.
METHODS
Studies were performed in TgNotch3 mice (harboring gain-of-function [GOF] Notch3 mutation) exposed to chronic hypoxia to induce PH, and examined by hemodynamics. Molecular and cellular studies were performed in pulmonary artery smooth muscle cells from pulmonary arterial hypertension patients and in mouse lung. Notch3-regulated genes/proteins, ER stress, ROCK (Rho-associated kinase) expression/activity, Ca transients and generation of reactive oxygen species, and nitric oxide were measured. Pulmonary vascular reactivity was assessed in the presence of fasudil (ROCK inhibitor) and 4-phenylbutyric acid (ER stress inhibitor).
RESULTS
Hypoxia induced a more severe PH phenotype in TgNotch3 mice versus controls. TgNotch3 mice exhibited enhanced Notch3 activation and expression of Notch3 targets Hes Family BHLH Transcription Factor 5 (Hes5), with increased vascular contraction and impaired vasorelaxation that improved with fasudil/4-phenylbutyric acid. Notch3 mutation was associated with increased pulmonary vessel Ca transients, ROCK activation, ER stress, and increased reactive oxygen species generation, with reduced NO generation and blunted sGC (soluble guanylyl cyclase)/cGMP signaling. These effects were ameliorated by N-acetylcysteine. pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension recapitulated Notch3/Hes5 signaling, ER stress and redox changes observed in PH mice.
CONCLUSIONS
Notch3 GOF amplifies vascular dysfunction in hypoxic PH. This involves oxidative and ER stress, and ROCK. We highlight a novel role for Notch3/Hes5-redox signaling and important interplay between ER and oxidative stress in PH.
Topics: Animals; Mice; Basic Helix-Loop-Helix Transcription Factors; Hypertension; Hypertension, Pulmonary; Hypoxia; Myocytes, Smooth Muscle; Oxidation-Reduction; Pulmonary Arterial Hypertension; Pulmonary Artery; Reactive Oxygen Species; Receptor, Notch3; Repressor Proteins; Humans
PubMed: 37254738
DOI: 10.1161/HYPERTENSIONAHA.122.20449