New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

Inflammatory myopathies are chronic, immune-mediated diseases characterized with progressive proximal muscle weakness. They encompass a variety of syndromes with protean manifestations. The aims of therapy are to increase muscle strength, prevent the development of contractures, and to manage the systemic manifestations of the disease. This is a complex treatment which requires routine and wide knowledge. The most important task is to recognize the disease and guide the patient to immunologic center. Although the first line of therapy continues to include corticosteroids, there are a multitude of agents available for treating patients with myositis. There are several different immunosuppressive agents which may be applied alone or in combination with each other, as well as an increasing number of novel and exciting biologic agents targeting molecules participating in the pathogenesis of inflammatory myopathy. Physiotherapy and rehabilitation in the remission period may significantly improve the functional outcome of patients with these disorders. Orv. Hetil., 2011, 152, 1552–1559.

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New Aspects of the Epigenetics of Pancreatic Carcinogenesis

Epigenomes ◽

10.3390/epigenomes4030018 ◽

2020 ◽

Vol 4 (3) ◽

pp. 18

Author(s):

Murat Toruner ◽

Martin E. Fernandez-Zapico ◽

Christopher L. Pin

Keyword(s):

Pancreatic Cancer ◽

Dna Methylation ◽

Survival Rate ◽

Epigenetic Mechanisms ◽

Therapeutic Approaches ◽

Cancer Epigenetics ◽

Pancreatic Carcinogenesis ◽

New Therapeutic Approaches ◽

Environmental Events ◽

Underlying Pathogenesis

Pancreatic cancer remains among the deadliest forms of cancer with a 5 year survival rate less than 10%. With increasing numbers being observed, there is an urgent need to elucidate the pathogenesis of pancreatic cancer. While both contribute to disease progression, neither genetic nor environmental factors completely explain susceptibility or pathogenesis. Defining the links between genetic and environmental events represents an opportunity to understand the pathogenesis of pancreatic cancer. Epigenetics, the study of mitotically heritable changes in genome function without a change in nucleotide sequence, is an emerging field of research in pancreatic cancer. The main epigenetic mechanisms include DNA methylation, histone modifications and RNA interference, all of which are altered by changes to the environment. Epigenetic mechanisms are being investigated to clarify the underlying pathogenesis of pancreatic cancer including an increasing number of studies examining the role as possible diagnostic and prognostic biomarkers. These mechanisms also provide targets for promising new therapeutic approaches for this devastating malignancy.

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A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

Immuno ◽

10.3390/immuno1030011 ◽

2021 ◽

Vol 1 (3) ◽

pp. 174-193

Author(s):

Jenny Valentina Garmendia ◽

Juan Bautista De Sanctis

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Embryo Implantation ◽

Inflammatory Cells ◽

Cell Physiology ◽

Therapeutic Approaches ◽

Pharmacological Modulation ◽

New Therapeutic Approaches ◽

Pharmacologic Modulation ◽

Inflammatory Burden

NK cells are lymphocytes involved in the innate and adaptative immune response. These cells are located in peripheral blood and tissues with ample functions, from immune vigilant to tolerogenic reactions. In the endometrium, NK cell populations vary depending on age, hormones, and inflammation. When pregnancy occurs, tissue-resident NK cells and conventional NK cells are recruited to protect the fetus, a tolerogenic response. On the contrary, in the inflamed endometrium, various inflammatory cells down-regulate NK tolerance and impair embryo implantation. Therefore, NK cells’ pharmacological modulation is difficult to achieve. Several strategies have been used, from progesterone, lipid emulsions to steroids; the success has not been as expected. However, new therapeutic approaches have been proposed to decrease the endometrial inflammatory burden and increase pregnancy success based on understanding NK cell physiology.

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The Effect of a Polyester Nanofibrous Membrane with a Fibrin-Platelet Lysate Coating on Keratinocytes and Endothelial Cells in a Co-Culture System

Nanomaterials ◽

10.3390/nano11020457 ◽

2021 ◽

Vol 11 (2) ◽

pp. 457

Author(s):

Andreu Blanquer ◽

Jana Musilkova ◽

Elena Filova ◽

Johanka Taborska ◽

Eduard Brynda ◽

...

Keyword(s):

Wound Healing ◽

Endothelial Cells ◽

Chronic Wounds ◽

Human Keratinocytes ◽

Skin Wound ◽

Platelet Lysate ◽

Therapeutic Approaches ◽

Skin Wound Healing ◽

New Therapeutic Approaches ◽

Proliferation And Differentiation

Chronic wounds affect millions of patients worldwide, and it is estimated that this number will increase steadily in the future due to population ageing. The research of new therapeutic approaches to wound healing includes the development of nanofibrous meshes and the use of platelet lysate (PL) to stimulate skin regeneration. This study considers a combination of a degradable electrospun nanofibrous blend of poly(L-lactide-co-ε-caprolactone) and poly(ε-caprolactone) (PLCL/PCL) membranes (NF) and fibrin loaded with various concentrations of PL aimed at the development of bioactive skin wound healing dressings. The cytocompatibility of the NF membranes, as well as the effect of PL, was evaluated in both monocultures and co-cultures of human keratinocytes and human endothelial cells. We determined that the keratinocytes were able to adhere on all the membranes, and their increased proliferation and differentiation was observed on the membranes that contained fibrin with at least 50% of PL (Fbg + PL) after 14 days. With respect to the co-culture experiments, the membranes with fibrin with 20% of PL were observed to enhance the metabolic activity of endothelial cells and their migration, and the proliferation and differentiation of keratinocytes. The results suggest that the newly developed NF combined with fibrin and PL, described in the study, provides a promising dressing for chronic wound healing purposes.

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Regulation of Eosinophilia in Asthma—New Therapeutic Approaches for Asthma Treatment

Cells ◽

10.3390/cells10040817 ◽

2021 ◽

Vol 10 (4) ◽

pp. 817

Author(s):

Ruth P. Cusack ◽

Christiane E. Whetstone ◽

Yanqing Xie ◽

Maral Ranjbar ◽

Gail M. Gauvreau

Keyword(s):

Drug Targets ◽

Airflow Obstruction ◽

Chronic Inflammatory Disease ◽

Therapeutic Approaches ◽

Eosinophilic Asthma ◽

Airway Eosinophilia ◽

Gm Csf ◽

New Therapeutic Approaches ◽

Cellular Apoptosis ◽

Reversible Airflow Obstruction

Asthma is a complex and chronic inflammatory disease of the airways, characterized by variable and recurring symptoms, reversible airflow obstruction, bronchospasm, and airway eosinophilia. As the pathophysiology of asthma is becoming clearer, the identification of new valuable drug targets is emerging. IL-5 is one of these such targets because it is the major cytokine supporting eosinophilia and is responsible for terminal differentiation of human eosinophils, regulating eosinophil proliferation, differentiation, maturation, migration, and prevention of cellular apoptosis. Blockade of the IL-5 pathway has been shown to be efficacious for the treatment of eosinophilic asthma. However, several other inflammatory pathways have been shown to support eosinophilia, including IL-13, the alarmin cytokines TSLP and IL-33, and the IL-3/5/GM-CSF axis. These and other alternate pathways leading to airway eosinophilia will be described, and the efficacy of therapeutics that have been developed to block these pathways will be evaluated.

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Parkin regulates drug-taking behavior in rat model of methamphetamine use disorder

Translational Psychiatry ◽

10.1038/s41398-021-01387-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Akhil Sharma ◽

Arman Harutyunyan ◽

Bernard L. Schneider ◽

Anna Moszczynska

Keyword(s):

Neural Substrates ◽

Genetically Engineered ◽

Wild Type ◽

Therapeutic Approaches ◽

Self Administration ◽

Methamphetamine Use ◽

New Therapeutic Approaches ◽

Extended Access ◽

High Doses ◽

Methamphetamine Use Disorder

AbstractThere is no FDA-approved medication for methamphetamine (METH) use disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH use disorder. PARKIN knockout, PARKIN-overexpressing, and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. Reinforcing/rewarding properties of METH were assessed by quantifying drug-taking behavior and time spent in a METH-paired environment. PARKIN knockout rats self-administered more METH and spent more time in the METH-paired environment than wild-type rats. Wild-type rats overexpressing PARKIN self-administered less METH and spent less time in the METH-paired environment. PARKIN knockout rats overexpressing PARKIN self-administered less METH during the first half of drug self-administration days than PARKIN-deficient rats. The results indicate that rats with PARKIN excess or PARKIN deficit are useful models for studying neural substrates underlying “resilience” or vulnerability to METH use disorder and identify PARKIN as a novel potential drug target to treat heavy use of METH.

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The emerging role of mechanical and topographical factors in the development and treatment of nervous system disorders: dark and light sides of the force

Pharmacological Reports ◽

10.1007/s43440-021-00315-2 ◽

2021 ◽

Author(s):

Natalia Bryniarska-Kubiak ◽

Andrzej Kubiak ◽

Małgorzata Lekka ◽

Agnieszka Basta-Kaim

Keyword(s):

Nervous System ◽

Physical Factors ◽

Nervous System Diseases ◽

Therapeutic Approaches ◽

System Disease ◽

New Therapeutic Approaches ◽

The Subject ◽

Topographical Factors ◽

New Treatment

AbstractNervous system diseases are the subject of intensive research due to their association with high mortality rates and their potential to cause irreversible disability. Most studies focus on targeting the biological factors related to disease pathogenesis, e.g. use of recombinant activator of plasminogen in the treatment of stroke. Nevertheless, multiple diseases such as Parkinson’s disease and Alzheimer’s disease still lack successful treatment. Recently, evidence has indicated that physical factors such as the mechanical properties of cells and tissue and topography play a crucial role in homeostasis as well as disease progression. This review aims to depict these factors’ roles in the progression of nervous system diseases and consequently discusses the possibility of new therapeutic approaches. The literature is reviewed to provide a deeper understanding of the roles played by physical factors in nervous system disease development to aid in the design of promising new treatment approaches. Graphic abstract

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337 Metabolic Foundations of Microbiota-Host Interactions

Journal of Animal Science ◽

10.1093/jas/skaa278.126 ◽

2020 ◽

Vol 98 (Supplement_4) ◽

pp. 69-69

Author(s):

Dylan Dodd

Keyword(s):

Gastrointestinal Tract ◽

Gut Microbiota ◽

Small Molecules ◽

Recent Work ◽

Mechanistic Studies ◽

Therapeutic Approaches ◽

Dense Population ◽

Metabolic Potential ◽

Host Interactions ◽

New Therapeutic Approaches

Abstract The gastrointestinal tract of mammals is home to a dense population of microbes which influence host physiology and health. One of the most concrete ways that the gut microbiota impacts host biology is through the production of hundreds of chemically diverse small molecules. These molecules are absorbed into the bloodstream, where they reach concentrations similar to those achieved by pharmaceuticals and bind host receptors leading to changes in cellular and organ physiology. Here I will summarize recent work from our group and others that show how microbially sourced metabolites alter health and physiology of the host. I will also discuss how mechanistic studies of small molecules from the microbiota are enabling new therapeutic approaches to harness the metabolic potential of the gut microbiota.

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Lipid Related Genes Altered in NASH Connect Inflammation in Liver Pathogenesis Progression to HCC: A Canonical Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms20225594 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5594 ◽

Cited By ~ 2

Author(s):

Desterke ◽

Chiappini

Keyword(s):

Molecular Basis ◽

Public Health Problem ◽

Gene Expression Omnibus ◽

Canonical Pathway ◽

Therapeutic Approaches ◽

Database Querying ◽

New Therapeutic Approaches ◽

Data Mining Approach ◽

Pubmed Database ◽

Genome Alteration

Nonalcoholic steatohepatitis (NASH) is becoming a public health problem worldwide. While the number of research studies on NASH progression rises every year, sometime their findings are controversial. To identify the most important and commonly described findings related to NASH progression, we used an original bioinformatics, integrative, text-mining approach that combines PubMed database querying and available gene expression omnibus dataset. We have identified a signature of 25 genes that are commonly found to be dysregulated during steatosis progression to NASH and cancer. These genes are implicated in lipid metabolism, insulin resistance, inflammation, and cancer. They are functionally connected, forming the basis necessary for steatosis progression to NASH and further progression to hepatocellular carcinoma (HCC). We also show that five of the identified genes have genome alterations present in HCC patients. The patients with these genes associated to genome alteration are associated with a poor prognosis. In conclusion, using an integrative literature- and data-mining approach, we have identified and described a canonical pathway underlying progression of NASH. Other parameters (e.g. polymorphisms) can be added to this pathway that also contribute to the progression of the disease to cancer. This work improved our understanding of the molecular basis of NASH progression and will help to develop new therapeutic approaches.

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