Jeremy Martin on the 6D Helmets Midweek Podcast

∙ Pulido, T.

About the Company

..., STARTS-2 Investigators STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension An open-label study to evaluate sildenafil for the treatment of lymphatic malformations Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations Subcomplexes of human ATP synthase mark mitochondrial biosynthesis disorders Kenvin, S. ∙ Torregrosa-Muñumer, R.

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∙ Reidelbach, M. ..

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Threshold of heteroplasmic truncating MT-ATP6 mutation in reprogramming, Notch hyperactivation and motor neuron metabolism MICOS assembly controls mitochondrial inner membrane remodeling and crista junction redistribution to mediate cristae formation Li, C. ∙ Enomoto, M. ∙ Rossi, A.M. .. Hoxa5: A Key Player in Development and Disease Sustained Hox5 gene activity is required for respiratory motor neuron development Dbx1 triggers crucial molecular programs required for midline crossing by midbrain commissural axons Eichholtz-Wirth, H.

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Mitochondrial disease in adults: a scale to monitor progression and treatment Natural History of Leigh Syndrome: A Study of Disease Burden and Progression Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8 Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington’s disease Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF Resurrection of sildenafil: potential for Huntington’s Disease, too? Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord Phosphodiesterase 5 inhibition as a therapeutic target for ischemic stroke: A systematic review of preclinical studies Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse Function of cGMP-dependent protein kinases in the nervous system Impairment of LTD and cerebellar learning by Purkinje cell-specific ablation of cGMP-dependent protein kinase I PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression The mitochondrial regulator PGC1alpha is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure cGMP-dependent protein kinase: linking foraging to energy homeostasis Paupardin-Tritsch, D. ∙ Hammond, C. ∙ Gerschenfeld, H.M. ..

Western blot analysis

cGMP-dependent protein kinase enhances Ca2+ current and potentiates the serotonin-induced Ca2+ current increase in snail neurones Distinct functions of a cGMP-dependent protein kinase in nerve terminal growth and synaptic vesicle cycling Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial Turning the Oxygen Dial: Balancing the Highs and Lows Cunnane, S.C. ∙ Trushina, E. ∙ Morland, C. .. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing Mitochondria at the crossroads of health and disease Mitochondria metabolism sets the species-specific tempo of neuronal development Feasibility and Safety sildenafil 130mg of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial Testing Higher Doses of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia: An Open-Label Dose-Finding Phase 1b Clinical Trial-Sildenafil Administration to Treat Neonatal Encephalopathy-Study 02 Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period Binding of tritiated sildenafil, tadalafil, or sildenafil 25 mg tablets vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences A reference human induced pluripotent stem cell line for large-scale collaborative studies A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells Genome-wide analysis of PDX1 target genes in human pancreatic progenitors Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis Prime-Editing of human ACTB in induced pluripotent stem cells to model human ACTB Loss-of-Function diseases and compensatory mechanisms Induced pluripotent stem cell lines derived from human somatic cells Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling Individual brain organoids reproducibly form cell diversity of the human cerebral cortex Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells A new mathematical model for relative quantification in real-time RT-PCR Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Dictionary learning for integrative, multimodal and scalable single-cell analysis Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression Modelling viral encephalitis caused by herpes simplex 20mg sildenafil virus 1 infection in cerebral organoids SCENIC: single-cell regulatory network inference and clustering The Molecular Signatures Database (MSigDB) hallmark gene set collection Protocol for the generation of cultured cortical brain organoid slices Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation Mitochondrial genomes gleaned from human whole-exome sequencing Rubino, F. ∙ Fritz, E. ∙ Wolz, L. Overexpression of the ‘silencer of death domain’, SODD/BAG-4, modulates both TNFR1- and CD95-dependent cell death pathways Lisowski, P. ∙ Lickfett, S. ∙ Rybak-Wolf, A... Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action Andrieu, G. ∙ Tran, A.H.

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∙ Strissel, K.J... BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling Bromodomain protein 4 mediates the roles of TGFβ1-induced Stat3 signaling in mouse liver fibrogenesis Neuregulin 1: an intriguing therapeutic target for neurodevelopmental disorders Sophocleous, R.A.

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∙ Sánchez-Vázquez, V.H. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB Waldeck-Weiermair, M. ∙ Deak, A.T. ∙ Groschner, L.N... Molecularly distinct routes of mitochondrial Ca2+ uptake are activated depending on the activity of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) Impact of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels in Sildenafil-Induced Cardioprotection in Rats Ca2+-activated K+ (KCa) channels are involved in the relaxations elicited by sildenafil in penile resistance arteries Checchetto, V.

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∙ Leanza, L. ∙ De Stefani, D. .. Mitochondrial K+ channels and their implications for disease mechanisms Loss of the large conductance calcium-activated potassium channel causes an increase in mitochondrial reactive oxygen species in glioblastoma cells High-content analysis of neuronal morphology in human iPSC-derived neurons Local and long-range reciprocal regulation of cAMP and cGMP in axon/dendrite formation Regulate axon branching by the cyclic GMP pathway via inhibition of glycogen synthase kinase 3 in dorsal root ganglion sensory neurons Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival in neural cells Modulation of synaptic function by cGMP and cGMP-gated cation channels Schmidt, H. ∙ Werner, M.

RV remained apparently normal by two-day LV pressure overload (TAC), with mild LV hypertrophy that was inhibited by sildenafil

∙ Heppenstall, P.A... cGMP-mediated signaling via cGKIalpha is required for the guidance and connectivity of sensory axons Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome Human iPSC-Derived Blood-Brain Barrier Models: Valuable Tools for Preclinical Drug Discovery and Development? A scale to monitor progression and treatment of mitochondrial disease in children Schaefer, A.M. ∙ Phoenix, C. ∙ Elson, J.L... ∙ Ooi, L.

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∙ Sluyter, R. The P2X4 Receptor: Cellular and Molecular Characteristics of a Promising Neuroinflammatory Target The SLC37 family of sugar-phosphate/phosphate exchangers Generation of Human Brain Organoids for Mitochondrial Disease Modeling Generation of human striatal organoids and cortico-striatal assembloids from human pluripotent stem cells WDR45, one gene associated with multiple neurodevelopmental disorders Klim, J.R.

Side Effect	Severity	Notes
Headache	Common	Usually mild
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∙ Williams, L.A. ∙ Limone, F. .. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair RGS6 interacts with SCG10 and promotes neuronal differentiation.

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∙ Pulido, T. ..., STARTS-2 Investigators STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension An open-label study to evaluate sildenafil for the treatment of lymphatic malformations Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations Subcomplexes of human ATP synthase mark mitochondrial biosynthesis disorders Kenvin, S. ∙ Torregrosa-Muñumer, R. ∙ Reidelbach, M. ..

RV revealed early hypertrophic molecular changes similar to LV during LV pressure-overload, and sildenafil inhibited these in both ventricles

Threshold of heteroplasmic truncating MT-ATP6 mutation in reprogramming, Notch hyperactivation and motor neuron metabolism MICOS assembly controls mitochondrial inner membrane remodeling and crista junction redistribution to mediate cristae formation Li, C. ∙ Enomoto, M. ∙ Rossi, A.M. .. Hoxa5: A Key Player in Development and Disease Sustained Hox5 gene activity is required for respiratory motor neuron development Dbx1 triggers crucial molecular programs required for midline crossing by midbrain commissural axons Eichholtz-Wirth, H.

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∙ Fritz, E. ∙ Wolz, L. Overexpression of the ‘silencer of death domain’, SODD/BAG-4, modulates both TNFR1- and CD95-dependent cell death pathways Lisowski, P. ∙ Lickfett, S. ∙ Rybak-Wolf, A... Role of the G gamma subunit-like (GGL) domain of RGS6 An integrated transcriptomic cell atlas of human neural organoids Petersilie, L.

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• Sildenafil can cause headaches, dizziness, or temporary vision changes.
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• Misuse or overdose increases the risk of serious health complications.

∙ Heiduschka, S. ∙ Nelson, J.S.E... Cortical brain organoid slices (cBOS) for the study of human neural cells in minimal networks Interplay Between Intracellular Ca(2+) Oscillations and Ca(2+)-stimulated Mitochondrial Metabolism Impaired mitochondrial function due to familial Alzheimer’s disease-causing presenilins mutants via Ca(2+) disruptions The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer’s disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore Intracellular Injection of Brain Extracts from Alzheimer’s Disease Patients Triggers Unregulated Ca2+ Release from Intracellular Stores That Hinders Cellular Bioenergetics D’Angelo, D. ∙ Sánchez-Vázquez, V.H. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB Waldeck-Weiermair, M. ∙ Deak, A.T.

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∙ Groschner, L.N... Molecularly distinct routes of mitochondrial Ca2+ uptake are activated depending on the activity of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) Impact of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels in Sildenafil-Induced Cardioprotection in Rats Ca2+-activated K+ (KCa) channels are involved in the relaxations elicited by sildenafil in penile resistance arteries Checchetto, V. ∙ Leanza, L. ∙ De Stefani, D.

• Sildenafil was first approved for erectile dysfunction treatment in the late 1990s.
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.. Mitochondrial K+ channels and their implications for disease mechanisms Loss of the large conductance calcium-activated potassium channel causes an increase in mitochondrial reactive oxygen species in glioblastoma cells High-content analysis of neuronal morphology in human iPSC-derived neurons Local and long-range reciprocal regulation of cAMP and cGMP in axon/dendrite formation Regulate axon branching by the cyclic GMP pathway via inhibition of glycogen synthase kinase 3 in dorsal root ganglion sensory neurons Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival in neural cells Modulation of synaptic function by cGMP and cGMP-gated cation channels Schmidt, H. ∙ Werner, M. ∙ Heppenstall, P.A... cGMP-mediated signaling via cGKIalpha is required for the guidance and connectivity of sensory axons Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome Human iPSC-Derived Blood-Brain Barrier Models: Valuable Tools for Preclinical Drug Discovery and Development? A scale to monitor progression and treatment of mitochondrial disease in children Schaefer, A.M. ∙ Phoenix, C. ∙ Elson, J.L... Mitochondrial disease in adults: a scale to monitor progression and treatment Natural History of Leigh Syndrome: A Study of Disease Burden and Progression Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8 Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington’s disease Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF Resurrection of sildenafil: potential for Huntington’s Disease, too? Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord Phosphodiesterase 5 inhibition as a therapeutic target for ischemic stroke: A systematic review of preclinical studies Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse Function of cGMP-dependent protein kinases in the nervous system Impairment of LTD and cerebellar learning by Purkinje cell-specific ablation of cGMP-dependent protein kinase I PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression The mitochondrial regulator PGC1alpha is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure cGMP-dependent protein kinase: linking foraging to energy homeostasis Paupardin-Tritsch, D.

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Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action Andrieu, G. ∙ Tran, A.H. ∙ Strissel, K.J... BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling Bromodomain protein 4 mediates the roles of TGFβ1-induced Stat3 signaling in mouse liver fibrogenesis Neuregulin 1: an intriguing therapeutic target for neurodevelopmental disorders Sophocleous, R.A. ∙ Ooi, L.

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∙ Sluyter, R. The P2X4 Receptor: Cellular and Molecular Characteristics of a Promising Neuroinflammatory Target The SLC37 family of sugar-phosphate/phosphate exchangers Generation of Human Brain Organoids for Mitochondrial Disease Modeling Generation of human striatal organoids and cortico-striatal assembloids from human pluripotent stem cells WDR45, one gene associated with multiple neurodevelopmental disorders Klim, J.R. ∙ Williams, L.A. ∙ Limone, F. ..

How does sildenafil work (mechanism of action)?

ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair RGS6 interacts with SCG10 and promotes neuronal differentiation. Role of the G gamma subunit-like (GGL) domain of RGS6 An integrated transcriptomic cell atlas of human neural organoids Petersilie, L. ∙ Heiduschka, S. ∙ Nelson, J.S.E... Cortical brain organoid slices (cBOS) for the study of human neural cells in minimal networks Interplay Between Intracellular Ca(2+) Oscillations and Ca(2+)-stimulated Mitochondrial Metabolism Impaired mitochondrial function due to familial Alzheimer’s disease-causing presenilins mutants via Ca(2+) disruptions The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer’s disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore Intracellular Injection of Brain Extracts from Alzheimer’s Disease Patients Triggers Unregulated Ca2+ Release from Intracellular Stores That Hinders Cellular Bioenergetics D’Angelo, D. ∙ Hammond, C. ∙ Gerschenfeld, H.M. .. cGMP-dependent protein kinase enhances Ca2+ current and potentiates the serotonin-induced Ca2+ current increase in snail neurones Distinct functions of a cGMP-dependent protein kinase in nerve terminal growth and synaptic vesicle cycling Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial Turning the Oxygen Dial: Balancing the Highs and Lows Cunnane, S.C. ∙ Trushina, E. ∙ Morland, C. .. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing Mitochondria at the crossroads of health and disease Mitochondria metabolism sets the species-specific tempo of neuronal development Feasibility and Safety sildenafil 130mg of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial Testing Higher Doses of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia: An Open-Label Dose-Finding Phase 1b Clinical Trial-Sildenafil Administration to Treat Neonatal Encephalopathy-Study 02 Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period Binding of tritiated sildenafil, tadalafil, or sildenafil 25 mg tablets vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences A reference human induced pluripotent stem cell line for large-scale collaborative studies A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells Genome-wide analysis of PDX1 target genes in human pancreatic progenitors Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis Prime-Editing of human ACTB in induced pluripotent stem cells to model human ACTB Loss-of-Function diseases and compensatory mechanisms Induced pluripotent stem cell lines derived from human somatic cells Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling Individual brain organoids reproducibly form cell diversity of the human cerebral cortex Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells A new mathematical model for relative quantification in real-time RT-PCR Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Dictionary learning for integrative, multimodal and scalable single-cell analysis Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression Modelling viral encephalitis caused by herpes simplex 20mg sildenafil virus 1 infection in cerebral organoids SCENIC: single-cell regulatory network inference and clustering The Molecular Signatures Database (MSigDB) hallmark gene set collection Protocol for the generation of cultured cortical brain organoid slices Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation Mitochondrial genomes gleaned from human whole-exome sequencing Rubino, F.