scholarly journals Nanoengineered DNA origami with repurposed TOP1 inhibitors targeting myeloid cells for the mitigation of neuroinflammation

2021 ◽  
Author(s):  
Keying Zhu ◽  
Yang Wang ◽  
Heela Sarlus ◽  
Keyi Geng ◽  
Erik Nutma ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Targeted Delivery ◽  
Therapeutic Strategy ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Dna Origami ◽  
Future Research ◽  
Drug Candidate ◽  
Topoisomerase 1 ◽  
Transcriptional Phenotype

AbstractTargeting myeloid cells, especially microglia, for the treatment of neuroinflammatory diseases such as multiple sclerosis (MS), is underappreciated. Here, we screened a library of compounds and identified the topoisomerase 1 (TOP1) inhibitor camptothecin (CPT) as a promising drug candidate for microglial modulation. CPT and its FDA-approved analog topotecan (TPT) inhibited inflammatory responses in microglia and macrophages, and ameliorated neuroinflammation in mice. Transcriptomic analysis of sorted microglia revealed an altered transcriptional phenotype following TPT treatment, with Ikzf1 identified as a potential target. Importantly, TOP1 expression was found elevated in several neuroinflammatory conditions, including human MS brains. To achieve targeted delivery to myeloid cells we designed a nanosystem using DNA origami and loaded TPT into it (TopoGami). TopoGami also significantly suppressed the inflammatory response in microglia and mitigated disease progression in MS-like mice. Our findings suggest that TOP1 inhibition represents a therapeutic strategy for neuroinflammatory diseases, and the proposed nanosystem may foster future research and drug development with a demand to target myeloid cells.

scholarly journals Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1181
Author(s):  
Alessandro Maglione ◽  
Miriam Zuccalà ◽  
Martina Tosi ◽  
Marinella Clerico ◽  
Simona Rolla
Keyword(s):  
Multiple Sclerosis ◽  
Environmental Factors ◽  
Lupus Erythematosus ◽  
Gut Microbiome ◽  
Complex Disease ◽  
Current Knowledge ◽  
Association Studies ◽  
Future Research ◽  
Genome Wide Association Studies ◽  
Host Genetics

As a complex disease, Multiple Sclerosis (MS)’s etiology is determined by both genetic and environmental factors. In the last decade, the gut microbiome has emerged as an important environmental factor, but its interaction with host genetics is still unknown. In this review, we focus on these dual aspects of MS pathogenesis: we describe the current knowledge on genetic factors related to MS, based on genome-wide association studies, and then illustrate the interactions between the immune system, gut microbiome and central nervous system in MS, summarizing the evidence available from Experimental Autoimmune Encephalomyelitis mouse models and studies in patients. Finally, as the understanding of influence of host genetics on the gut microbiome composition in MS is in its infancy, we explore this issue based on the evidence currently available from other autoimmune diseases that share with MS the interplay of genetic with environmental factors (Inflammatory Bowel Disease, Rheumatoid Arthritis and Systemic Lupus Erythematosus), and discuss avenues for future research.

Triggering receptor expressed on myeloid cells-1 (TREM-1) contributes to Bordetella pertussis inflammatory pathology

2021 ◽  
Author(s):  
Danisha Gallop ◽  
Karen Scanlon ◽  
Jeremy Ardanuy ◽  
Alexander B. Sigalov ◽  
Nicholas H. Carbonetti ◽  
...  
Keyword(s):  
Bordetella Pertussis ◽  
Inflammatory Responses ◽  
Whooping Cough ◽  
Pulmonary Inflammation ◽  
Myeloid Cells ◽  
Cell Surface Receptor ◽  
Bacterial Burden ◽  
Emerging Pathogens ◽  
Pertussis Infection ◽  
Bacterial Control

Whooping cough (pertussis) is a severe pulmonary infectious disease caused by the bacteria Bordetella pertussis . Pertussis infects an estimated 24 million people annually, resulting in >150,000 deaths. The NIH placed pertussis on the list of emerging pathogens in 2015. Antibiotics are ineffective unless administered before the onset of the disease characteristic cough. Therefore, there is an urgent need for novel pertussis therapeutics. We have shown that sphingosine-1-phosphate receptor (S1PR) agonists reduce pertussis inflammation, without increasing bacterial burden. Transcriptomic studies were performed to identify this mechanism and allow for the development of pertussis therapeutics which specifically target problematic inflammation without sacrificing bacterial control. These data suggested a role for triggering receptor expressed on myeloid cells-1 (TREM-1). TREM-1 cell surface receptor functions as an amplifier of inflammatory responses. Expression of TREM-1 is increased in response to bacterial infection of mucosal surfaces. In mice, B. pertussis infection results in TLR9-dependent increased expression of TREM-1 and its associated cytokines. Interestingly, S1PR agonists dampen pulmonary inflammation and TREM-1 expression. Mice challenged intranasally with B. pertussis and treated with ligand-dependent (LP17) and ligand-independent (GF9) TREM-1 inhibitors showed no differences in bacterial burden and significantly reduced TNF-α and CCL-2 expression compared to controls. Mice receiving TREM-1 inhibitors showed reduced pulmonary inflammation compared to controls indicating that TREM-1 promotes inflammatory pathology, but not bacterial control, during pertussis infection. This implicates TREM-1 as a potential therapeutic target for the treatment of pertussis.

Extended dosing of monoclonal antibodies in multiple sclerosis

2021 ◽  
pp. 135245852110657
Author(s):  
Zoé LE van Kempen ◽  
Alyssa A Toorop ◽  
Finn Sellebjerg ◽  
Gavin Giovannoni ◽  
Joep Killestein
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibodies ◽  
Treatment Options ◽  
Future Research ◽  
Therapeutic Drug ◽  
Therapeutic Landscape ◽  
Anti Cd20 ◽  
Dosing Intervals ◽  
Care Costs ◽  
Review Current

Over the past two decades, treatment options for patients with multiple sclerosis (MS) have increased exponentially. In the current therapeutic landscape, “no evidence of MS disease activity” is within reach in many of our patients. Minimizing risks of complications, improving treatment convenience, and decreasing health care costs are goals that are yet to be reached. One way to optimize MS therapy is to implement personalized or extended interval dosing. Monoclonal antibodies are suitable candidates for personalized dosing (by therapeutic drug monitoring) or extended interval dosing. An increasing number of studies are performed and underway reporting on altered dosing intervals of anti-α4β1-integrin treatment (natalizumab) and anti-CD20 treatment (ocrelizumab, rituximab, and ofatumumab) in MS. In this review, current available evidence regarding personalized and extended interval dosing of monoclonal antibodies in MS is discussed with recommendations for future research and clinical practice.

N-Acetyl Galactosamine Targeting: Paving the Way for Clinical Application of Nucleotide Medicines in Cardiovascular Diseases

2021 ◽  
Author(s):  
Erik A.L. Biessen ◽  
Theo J.C. Van Berkel
Keyword(s):  
Immune Responses ◽  
Targeted Delivery ◽  
Antisense Oligonucleotides ◽  
Sugar Metabolism ◽  
Innate Immune ◽  
Future Research ◽  
Clinical Use ◽  
Innate Immune Responses ◽  
Chemically Modified ◽  
Intrinsic Capacity

While the promise of oligonucleotide therapeutics, such as (chemically modified) ASO (antisense oligonucleotides) and short interfering RNAs, is undisputed from their introduction onwards, their unfavorable pharmacokinetics and intrinsic capacity to mobilize innate immune responses, were limiting widespread clinical use. However, these major setbacks have been tackled by breakthroughs in chemistry, stability and delivery. When aiming an intervention hepatic targets, such as lipid and sugar metabolism, coagulation, not to mention cancer and virus infection, introduction of N-acetylgalactosamine aided targeting technology has advanced the field profoundly and by now a dozen of N-acetylgalactosamine therapeutics for these indications have been approved for clinical use or have progressed to clinical trial stage 2 to 3 testing. This technology, in combination with major advances in oligonucleotide stability allows safe and durable intervention in targets that were previously deemed undruggable, such as Lp(a) and PCSK9, at high efficacy and specificity, often with as little as 2 doses per year. Their successful use even the most visionary would not have predicted 2 decades ago. Here, we will review the evolution of N-acetylgalactosamine technology. We shall outline their fundamental design principles and merits, and their application for the delivery of oligonucleotide therapeutics to the liver. Finally, we will discuss the perspectives of N-acetylgalactosamine technology and propose directions for future research in receptor targeted delivery of these gene medicines.

The protective effects of 1,3-butanediol acetoacetate diester on decompression sickness in rats

2021 ◽  
Author(s):  
Kun Zhang ◽  
Haidong Zhang ◽  
Hongjie Yi ◽  
Guoyang Huang ◽  
Xupeng Zhao ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Decompression Sickness ◽  
Bubble Formation ◽  
Antioxidant Properties ◽  
Oxygen Toxicity ◽  
Causative Factor ◽  
Male Rats ◽  
Drug Candidate ◽  
Pharmacokinetic Analysis ◽  
Protective Effects

Inert gas bubbles are widely accepted as the causative factor of decompression sickness (DCS), resulting in gas embolism and systemic inflammatory responses. The anticonvulsive ketone ester 1,3-butanediol acetoacetate diester (BD-AcAc2) was reported to have the characteristics of increasing blood oxygen partial pressure and anti-inflammation, and was thought to have the potential to reduce bubble formation and alleviate the pathological process of DCS. This study aims to investigate the potential protection of BD-AcAc2 against DCS in a rat model. A single dose of BD-AcAc2 was administered orally to adult male rats (5 g/kg body weight), followed by pharmacokinetic analysis or simulated air dives. After decompression, signs of DCS were monitored, and blood was sampled for biochemical measurements. Blood ketosis peaked at 2 h and lasted for more than 4 h.The incidence of DCS was decreased and postponed significantly in rats treated with BD-AcAc2 compared with those treated with saline (P<0.05). Though BD-AcAc2 failed to reduce bubble load (P>0.05), it showed an obvious decreasing trend. BD-AcAc2 significantly increased blood ppO2 and ameliorated oxidative and inflammatory responses, representing by increased plasma MDA, IL-1, IL-6 and TNF-α and decreased glutathione thiol (P<0.05), while blood pH remained unchanged (P>0.05). These results suggest that BD-AcAc2 exerted beneficial effects on DCS rats mainly related to increasing ppO2, anti-inflammatory and antioxidant properties. Together with its capacity for delaying CNS oxygen toxicity seizures, BD-AcAc2 might be an ideal drug candidate for DCS prevention and treatment.

Cerebellar Dysfunction in Multiple Sclerosis: Considerations for Research and Rehabilitation Therapy

2021 ◽  
pp. 154596832110654
Author(s):  
Erin M. Edwards ◽  
Nora E. Fritz ◽  
Amanda S. Therrien
Keyword(s):  
Multiple Sclerosis ◽  
Motor Control ◽  
Motor Impairment ◽  
Future Research ◽  
Disability Progression ◽  
Cerebellar Dysfunction ◽  
Motor Disability ◽  
Rehabilitation Outcomes ◽  
Critical Knowledge ◽  
The Impact

Introduction. Cerebellar pathology is common among persons with multiple sclerosis (PwMS). The cerebellum is well recognized for its role in motor control and motor learning and cerebellar pathology in multiple sclerosis is associated with enhanced motor impairment and disability progression. The Problem. To mitigate motor disability progression, PwMS are commonly prescribed exercise and task-specific rehabilitation training. Yet, whether cerebellar dysfunction differentially affects rehabilitation outcomes in this population remains unknown. Furthermore, we lack rehabilitation interventions targeting cerebellar dysfunction. The Solution. Here, we summarize the current understanding of the impact of cerebellar dysfunction on motor control, motor training, and rehabilitation in persons with multiple sclerosis. Recommendations. Additionally, we highlight critical knowledge gaps and propose that these guide future research studying cerebellar dysfunction in persons with multiple sclerosis.

An overview of the α4β1 integrin and the potential therapeutic role of its antagonists

2021 ◽  
Vol 28 ◽  
Author(s):  
Elenilze F. B. Ferreira ◽  
Luciane B. Silva ◽  
Josiane V. Cruz ◽  
Pedro H. F. Araújo ◽  
Njogu M. Kimani ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibody ◽  
Extracellular Matrix ◽  
Inflammatory Responses ◽  
Cellular Responses ◽  
Tumour Invasion ◽  
Potential Therapeutic Role ◽  
Integrin Antagonists ◽  
Inside Out

: This article presents a simplified view of integrins with emphasis on the α4 (α4β1/VLA-4) integrin. Integrins are heterodimeric proteins expressed on the cell surface of leukocytes that participate in a wide variety of functions, such as survival, growth, differentiation, migration, inflammatory responses, tumour invasion, among others. When the extracellular matrix is degraded or deformed, cells are forced to undergo responsive changes that influence remodelling during physiological and pathological events. Integrins recognize these changes and trigger a series of cellular responses, forming a physical connection between the interior and the outside of the cell. The communication of integrins through the plasma membrane occurs in both directions, from the extracellular to the intracellular (outside-in) and from the intracellular to the extracellular (inside-out). Integrins are valid targets for antibodies and small molecule antagonists. One example is the monoclonal antibody natalizumab, marketed under the name of TYSABRI®, used in the treatment of recurrent multiple sclerosis, which inhibits the adhesion of α4 integrin to its counter-receptor. α4β1 Integrin antagonists are summarized here and their utility as therapeutics discussed.

scholarly journals Can We Target Endogenous Anti-inflammatory Responses as a Therapeutic Strategy for Inflammatory Bowel Disease?

2018 ◽  
Vol 24 (10) ◽  
pp. 2123-2134 ◽  
Author(s):  
Ross John Porter ◽  
Caroline Andrews ◽  
Daniel Paul Brice ◽  
Scott Kenneth Durum ◽  
Mairi Hall McLean
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Therapeutic Strategy ◽  
Inflammatory Responses ◽  
Inflammatory Bowel ◽  
Anti Inflammatory

scholarly journals Gut Microbiota, Fusobacteria, and Colorectal Cancer

Diseases ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 109 ◽  
Author(s):  
Dervla Kelly ◽  
Liying Yang ◽  
Zhiheng Pei
Keyword(s):  
Colorectal Cancer ◽  
Gut Microbiota ◽  
Inflammatory Responses ◽  
Tumor Development ◽  
Host Responses ◽  
Future Research ◽  
Bacterial Microbiota ◽  
Promote Tumor Growth ◽  
Tumor Environment ◽  
Protective Strategies

The gut microbiota has emerged as an environmental contributor to colorectal cancer (CRC) in both animal models and human studies. It is now generally accepted that bacteria are ubiquitous colonizers of all exposed human body surfaces, including the entire alimentary tract (5). Recently, the concept that a normal bacterial microbiota is essential for the development of inflammation-induced carcinoma has emerged from studies of well-known colonic bacterial microbiota. This review explores the evidence for a role of fusobacteria, an anaerobic gram-negative bacterium that has repeatedly been detected at colorectal tumor sites in higher abundance than surrounding histologically normal tissue. Mechanistic studies provide insight on the interplay between fusobacteria, other gut microbiota, barrier functions, and host responses. Studies have shown that fusobacteria activate host inflammatory responses designed to protect against pathogens that promote tumor growth. We discuss how future research identifying the pathophysiology underlying fusobacteria colon colonization during colorectal cancer may lead to new therapeutic targets for cancer. Furthermore, disease-protective strategies suppressing tumor development by targeting the local tumor environment via bacteria represent another exciting avenue for researchers and are highlighted in this review.

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