Author response: Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

The nicotinic acetylcholine receptor (nAChR) is a major target of autoantibodies in myasthenia gravis (MG), an autoimmune disease that causes neuromuscular transmission dysfunction. Despite decades of research, the molecular mechanisms underlying MG have not been fully elucidated. Here, we present the crystal structure of the nAChR α1 subunit bound by the Fab fragment of mAb35, a reference monoclonal antibody that causes experimental MG and competes with ~65% of antibodies from MG patients. Our structures reveal for the first time the detailed molecular interactions between MG antibodies and a core region on nAChR α1. These structures suggest a major nAChR-binding mechanism shared by a large number of MG antibodies and the possibility to treat MG by blocking this binding mechanism. Structure-based modeling also provides insights into antibody-mediated nAChR cross-linking known to cause receptor degradation. Our studies establish a structural basis for further mechanistic studies and therapeutic development of MG.

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Decision letter: Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

10.7554/elife.23043.021 ◽

2017 ◽

Keyword(s):

Myasthenia Gravis ◽

Molecular Mechanisms ◽

Therapeutic Implications ◽

Structural Insights

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Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽

10.3390/cells10061548 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1548

Author(s):

Mustafa N. Mithaiwala ◽

Danielle Santana-Coelho ◽

Grace A. Porter ◽

Jason C. O’Connor

Keyword(s):

Molecular Mechanisms ◽

Treatment Options ◽

Treatment Strategies ◽

Kynurenine Pathway ◽

Economic Problem ◽

Cns Disease ◽

Therapeutic Implications ◽

Efficacious Treatment ◽

The Central Nervous System ◽

Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

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Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00454-7 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Yuefei Jin ◽

Wangquan Ji ◽

Haiyan Yang ◽

Shuaiyin Chen ◽

Weiguo Zhang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Endothelial Activation ◽

World Health ◽

Therapeutic Approaches ◽

Inflammatory Reactions ◽

Angiotensin Converting Enzyme 2 ◽

Therapeutic Implications ◽

Endothelial Inflammation ◽

The World ◽

Health Organization

AbstractOn 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization. As of 4 August 2020, more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some patients develop respiratory failure which is the leading cause of death among COVID-19 patients. Endothelial cells with high levels of angiotensin-converting enzyme 2 expression are major participants and regulators of inflammatory reactions and coagulation. Accumulating evidence suggests that endothelial activation and dysfunction participate in COVID-19 pathogenesis by altering the integrity of vessel barrier, promoting pro-coagulative state, inducing endothelial inflammation, and even mediating leukocyte infiltration. This review describes the proposed cellular and molecular mechanisms of endothelial activation and dysfunction during COVID-19 emphasizing the principal mediators and therapeutic implications.

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Neurodegeneration in the Pathogenesis of Diabetic Retinopathy: Molecular Mechanisms and Therapeutic Implications

Current Medicinal Chemistry ◽

10.2174/09298673113209990027 ◽

2013 ◽

Vol 20 (26) ◽

pp. 3241-3250 ◽

Cited By ~ 76

Author(s):

Maxwell Stem ◽

Thomas Gardner

Keyword(s):

Diabetic Retinopathy ◽

Molecular Mechanisms ◽

Therapeutic Implications

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Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

Cancers ◽

10.3390/cancers13184550 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4550

Author(s):

Laura Gramantieri ◽

Catia Giovannini ◽

Fabrizia Suzzi ◽

Ilaria Leoni ◽

Francesca Fornari

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Anticancer Agents ◽

Tumor Heterogeneity ◽

Molecular Mechanisms ◽

Driving Forces ◽

Predictive Biomarkers ◽

Molecular Classification ◽

Circulating Biomarkers ◽

Therapeutic Implications

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. HCC is associated with multiple risk factors and is characterized by a marked tumor heterogeneity that makes its molecular classification difficult to apply in the clinics. The lack of circulating biomarkers for the diagnosis, prognosis, and prediction of response to treatments further undermines the possibility of developing personalized therapies. Accumulating evidence affirms the involvement of cancer stem cells (CSCs) in tumor heterogeneity, recurrence, and drug resistance. Owing to the contribution of CSCs to treatment failure, there is an urgent need to develop novel therapeutic strategies targeting, not only the tumor bulk, but also the CSC subpopulation. Clarification of the molecular mechanisms influencing CSC properties, and the identification of their functional roles in tumor progression, may facilitate the discovery of novel CSC-based therapeutic targets to be used alone, or in combination with current anticancer agents, for the treatment of HCC. Here, we review the driving forces behind the regulation of liver CSCs and their therapeutic implications. Additionally, we provide data on their possible exploitation as prognostic and predictive biomarkers in patients with HCC.

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Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

eLife ◽

10.7554/elife.68039 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jenny I Aguilar ◽

Mary Hongying Cheng ◽

Josep Font ◽

Alexandra C Schwartz ◽

Kaitlyn Ledwitch ◽

...

Keyword(s):

High Speed ◽

Molecular Mechanisms ◽

Motor Coordination ◽

Neurodegenerative Disorder ◽

Expression System ◽

Distinct Type ◽

Underlying Disease ◽

Deficiency Syndrome ◽

Motor Deficits ◽

Therapeutic Implications

Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD.

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Molecular mechanisms and therapeutic implications of the carbon monoxide/hmox1 and the hydrogen sulfide/CSE pathways in the prevention of pre-eclampsia and fetal growth restriction

Pregnancy Hypertension ◽

10.1016/j.preghy.2014.04.013 ◽

2014 ◽

Vol 4 (3) ◽

pp. 243-244 ◽

Cited By ~ 12

Author(s):

Asif Ahmed

Keyword(s):

Carbon Monoxide ◽

Hydrogen Sulfide ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Molecular Mechanisms ◽

Growth Restriction ◽

Therapeutic Implications

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Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Medicines ◽

10.3390/medicines6030082 ◽

2019 ◽

Vol 6 (3) ◽

pp. 82 ◽

Cited By ~ 12

Author(s):

Ugo Testa ◽

Germana Castelli ◽

Elvira Pelosi

Keyword(s):

Prostate Cancer ◽

Molecular Mechanisms ◽

Intraepithelial Neoplasia ◽

Cancer Development ◽

Initial Development ◽

Therapeutic Implications ◽

Cancer Pathways ◽

Signaling Axis ◽

Prostate Cancer Development ◽

Prostate Cancers

Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

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Angiogenic Abnormalities in Diabetes Mellitus: Mechanistic and Clinical Aspects

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00980 ◽

2019 ◽

Vol 104 (11) ◽

pp. 5431-5444 ◽

Cited By ~ 9

Author(s):

Gian Paolo Fadini ◽

Mattia Albiero ◽

Benedetta Maria Bonora ◽

Angelo Avogaro

Keyword(s):

English Language ◽

Molecular Mechanisms ◽

Evidence Synthesis ◽

Clinical Manifestations ◽

Vascular Complications ◽

Peripheral Circulation ◽

Clinical Aspects ◽

Therapeutic Implications ◽

Diabetes Onset ◽

Increased Risk

Abstract Context Diabetes causes severe pathological changes to the microvasculature in many organs and tissues and is at the same time associated with an increased risk of coronary and peripheral macrovascular events. We herein review alterations in angiogenesis observed in human and experimental diabetes and how they contribute to diabetes onset and development of vascular complications. Evidence Acquisition The English language medical literature was searched for articles reporting on angiogenesis/vasculogenesis abnormalities in diabetes and their clinical manifestations, mechanistic aspects, and possible therapeutic implications. Evidence Synthesis Angiogenesis is a complex process, driven by a multiplicity of molecular mechanisms and involved in several physiological and pathological conditions. Incompetent angiogenesis is pervasive in diabetic vascular complications, with both excessive and defective angiogenesis observed in various tissues. A striking different angiogenic response typically occurs in the retina vs the myocardium and peripheral circulation, but some commonalities in abnormal angiogenesis can explain the well-known association between microangiopathy and macroangiopathy. Impaired angiogenesis can also affect endocrine islet and adipose tissue function, providing a link to diabetes onset. Exposure to high glucose itself directly affects angiogenic/vasculogenic processes, and the mechanisms include defective responses to hypoxia and proangiogenic factors, impaired nitric oxide bioavailability, shortage of proangiogenic cells, and loss of pericytes. Conclusions Dissecting the molecular drivers of tissue-specific alterations of angiogenesis/vasculogenesis is an important challenge to devise new therapeutic approaches. Angiogenesis-modulating therapies should be carefully evaluated in view of their potential off-target effects. At present, glycemic control remains the most reasonable therapeutic strategy to normalize angiogenesis in diabetes.

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