Hydrogen sulfide signalling in neurodegenerative diseases.

The gaseous neurotransmitter hydrogen sulfide (H S) exerts neuroprotective efficacy in the brain via post-translational modification of cysteine residues by sulfhydration, also known as persulfidation. This process is comparable in biological impact to phosphorylation and mediates a variety of signalling events. Unlike conventional neurotransmitters, H S cannot be stored in vesicles due to its gaseous nature.

Inflammation Progresses to Normal Tissue in Patients with Anthracosis after Discontinuation of Exposure to Fossil Fuel.

Background: Exposure to toxic materials predisposes the lungs to infectious agents and inflammatory responses. The present study was performed on patients with anthracosis caused by exposure to fossil fuels in previous years, and histopathological features of airways' normal-appearing tissue were compared with histopathological features of anthracotic plaques in these patients.

Methods: Bronchoscopic evaluations were performed on bakery workers who were directly in contact with fossil fuels.

Protective Roles of Hydrogen Sulfide in Alzheimer's Disease and Traumatic Brain Injury.

The gaseous signaling molecule hydrogen sulfide (HS) critically modulates a plethora of physiological processes across evolutionary boundaries. These include responses to stress and other neuromodulatory effects that are typically dysregulated in aging, disease, and injury. HS has a particularly prominent role in modulating neuronal health and survival under both normal and pathologic conditions.

Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury.

Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood.

Comparison of the Nitric Oxide Synthase Interactomes and S-Nitroso-Proteomes: Furthering the Case for Enzymatic S-Nitrosylation.

S-nitrosylation of proteins is the main mechanism through which nitric oxide (NO) regulates cellular function and likely represents the archetype redox-based signaling system across aerobic and anaerobic organisms. How NO generated by different nitric oxide synthase (NOS) isoforms leads to specificity of S-nitrosylation remains incompletely understood. This study aimed to identify proteins interacting with, and whose S-nitrosylation is mediated by, human NOS isoforms in the same cellular system, thereby illuminating the contribution of individual NOSs to specificity.

Identification of a Selective SCoR2 Inhibitor That Protects Against Acute Kidney Injury.

Acute kidney injury (AKI) is associated with high morbidity and mortality, and no drugs are available clinically. Metabolic reprogramming resulting from the deletion of S-nitroso-coenzyme A reductase 2 (SCoR2; AKR1A1) protects mice against AKI, identifying SCoR2 as a potential drug target. Of the few known inhibitors of SCoR2, none are selective versus the related oxidoreductase AKR1B1, limiting therapeutic utility.

Control of tissue oxygenation by S-nitrosohemoglobin in human subjects.

S-Nitrosohemoglobin (SNO-Hb) is unique among vasodilators in coupling blood flow to tissue oxygen requirements, thus fulfilling an essential function of the microcirculation. However, this essential physiology has not been tested clinically. Reactive hyperemia following limb ischemia/occlusion is a standard clinical test of microcirculatory function, which has been ascribed to endothelial nitric oxide (NO).

Anti-inflammatory Therapy Protects Spiral Ganglion Neurons After Aminoglycoside Antibiotic-Induced Hair Cell Loss.

Destruction of cochlear hair cells by aminoglycoside antibiotics leads to gradual death of the spiral ganglion neurons (SGNs) that relay auditory information to the brain, potentially limiting the efficacy of cochlear implants. Because the reasons for this cochlear neurodegeneration are unknown, there are no neuroprotective strategies for patients. To investigate this problem, we assessed transcriptomic changes in the rat spiral ganglion following aminoglycoside antibiotic (kanamycin)-induced hair cell destruction.

CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer's disease.

Background: Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer's disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects.

Interpretable deep learning translation of GWAS and multi-omics findings to identify pathobiology and drug repurposing in Alzheimer's disease.

Translating human genetic findings (genome-wide association studies [GWAS]) to pathobiology and therapeutic discovery remains a major challenge for Alzheimer's disease (AD). We present a network topology-based deep learning framework to identify disease-associated genes (NETTAG). We leverage non-coding GWAS loci effects on quantitative trait loci, enhancers and CpG islands, promoter regions, open chromatin, and promoter flanking regions under the protein-protein interactome.

Population-based discovery and Mendelian randomization analysis identify telmisartan as a candidate medicine for Alzheimer's disease in African Americans.

Introduction: African Americans (AAs) and European Americans (EAs) differ in Alzheimer's disease (AD) prevalence, risk factors, and symptomatic presentation and AAs are less likely to enroll in AD clinical trials.

Methods: We conducted race-conscious pharmacoepidemiologic studies of 5.62 million older individuals (age ≥60) to investigate the association of telmisartan exposure and AD outcome using Cox analysis, Kaplan-Meier analysis, and log-rank test.

A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis.

Accumulating evidence suggests that protein S-nitrosylation is enzymatically regulated and that specificity in S-nitrosylation derives from dedicated S-nitrosylases and denitrosylases that conjugate and remove S-nitrosothiols, respectively. Here, we report that mice deficient in the protein denitrosylase SCoR2 (S-nitroso-Coenzyme A Reductase 2; AKR1A1) exhibit marked reductions in serum cholesterol due to reduced secretion of the cholesterol-regulating protein PCSK9. SCoR2 associates with endoplasmic reticulum (ER) secretory machinery to control an S-nitrosylation cascade involving ER cargo-selection proteins SAR1 and SURF4, which moonlight as S-nitrosylases.

The Alzheimer's Cell Atlas (TACA): A single-cell molecular map for translational therapeutics accelerator in Alzheimer's disease.

Introduction: Recent advances in generating massive single-cell/nucleus transcriptomic data have shown great potential for facilitating the identification of cell type-specific Alzheimer's disease (AD) pathobiology and drug-target discovery for therapeutic development.

Methods: We developed The Alzheimer's Cell Atlas (TACA) by compiling an AD brain cell atlas consisting of over 1.1 million cells/nuclei across 26 data sets, covering major brain regions (hippocampus, cerebellum, prefrontal cortex, and so on) and cell types (astrocyte, microglia, neuron, oligodendrocytes, and so on).

X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women.

Although women experience significantly higher tau burden and increased risk for Alzheimer's disease (AD) than men, the underlying mechanism for this vulnerability has not been explained. Here, we demonstrate through in vitro and in vivo models, as well as human AD brain tissue, that X-linked ubiquitin specific peptidase 11 (USP11) augments pathological tau aggregation via tau deubiquitination initiated at lysine-281. Removal of ubiquitin provides access for enzymatic tau acetylation at lysines 281 and 274.

β-PIX cooperates with GIT1 to regulate endothelial nitric oxide synthase in sinusoidal endothelial cells.

Previous studies have demonstrated that G protein-coupled receptor kinase interacting-1 protein (GIT1) associates with endothelial nitric oxide synthase (eNOS) to regulate nitric oxide production in sinusoidal endothelial cells (SECs). Here, we hypothesized that GIT1's tightly associated binding partner, β-PIX (p21-activated kinase-interacting exchange factor β, ARHGEF7) is specifically important in the regulation of eNOS activity. We examined β-PIX expression in normal rat liver by immunohistochemistry and explored β-PIX protein-protein interactions using immunoprecipitation and immunoblotting.

S-nitrosylation is required for βAR desensitization and experimental asthma.

The β-adrenergic receptor (βAR), a prototypic G-protein-coupled receptor (GPCR), is a powerful driver of bronchorelaxation, but the effectiveness of β-agonist drugs in asthma is limited by desensitization and tachyphylaxis. We find that during activation, the βAR is modified by S-nitrosylation, which is essential for both classic desensitization by PKA as well as desensitization of NO-based signaling that mediates bronchorelaxation. Strikingly, S-nitrosylation alone can drive βAR internalization in the absence of traditional agonist.

Optimized S-nitrosohemoglobin Synthesis in Red Blood Cells to Preserve Hypoxic Vasodilation Via Cys93.

Classic physiology links tissue hypoxia to oxygen delivery through control of microvascular blood flow (autoregulation of blood flow). Hemoglobin (Hb) serves both as the source of oxygen and the mediator of microvascular blood flow through its ability to release vasodilatory S-nitrosothiol (SNO) in proportion to degree of hypoxia. -globin Cys93Ala (Cys93Ala) mutant mice deficient in S-nitrosohemoglobin (SNO-Hb) show profound deficits in microvascular blood flow and tissue oxygenation that recapitulate microcirculatory dysfunction in multiple clinical conditions.

Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility.

Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain.

S-Nitrosylated hemoglobin predicts organ yield in neurologically-deceased human donors.

Current human donor care protocols following death by neurologic criteria (DNC) can stabilize macro-hemodynamic parameters but have minimal ability to preserve systemic blood flow and microvascular oxygen delivery. S-nitrosylated hemoglobin (SNO-Hb) within red blood cells (RBCs) is the main regulator of tissue oxygenation (StO). Based on various pre-clinical studies, we hypothesized that brain death (BD) would decrease post-mortem SNO-Hb levels to negatively-impact StO and reduce organ yields.

Aging-related cell type-specific pathophysiologic immune responses that exacerbate disease severity in aged COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID-19 incidence and severity as a function of age. Our analysis leveraged age-specific COVID-19 mortality and laboratory testing from a large COVID-19 registry, along with epidemiological data of ~3.

Artificial intelligence framework identifies candidate targets for drug repurposing in Alzheimer's disease.

Background: Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer's disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful.

Methods: To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein-protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics.

Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation.

Systemic hypoxia is characterized by peripheral vasodilation and pulmonary vasoconstriction. However, the system-wide mechanism for signaling hypoxia remains unknown. Accumulating evidence suggests that hemoglobin (Hb) in RBCs may serve as an O2 sensor and O2-responsive NO signal transducer to regulate systemic and pulmonary vascular tone, but this remains unexamined at the integrated system level.

The enzymatic function of the honorary enzyme: S-nitrosylation of hemoglobin in physiology and medicine.

The allosteric transition within tetrameric hemoglobin (Hb) that allows both full binding to four oxygen molecules in the lung and full release of four oxygens in hypoxic tissues would earn Hb the moniker of 'honorary enzyme'. However, the allosteric model for oxygen binding in hemoglobin overlooked the essential role of blood flow in tissue oxygenation that is essential for life (aka autoregulation of blood flow). That is, blood flow, not oxygen content of blood, is the principal determinant of oxygen delivery under most conditions.