Therapeutic Advantage of Tyk2 Inhibition for Treating Autoimmune and Chronic Inflammatory Diseases

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

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Lipid, fatty acid, carnitine- and choline derivative profiles in rheumatoid arthritis outpatients with different degrees of periodontal inflammation

Scientific Reports ◽

10.1038/s41598-021-84122-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kathrin Beyer ◽

Stein Atle Lie ◽

Bodil Bjørndal ◽

Rolf K. Berge ◽

Asbjørn Svardal ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Fatty Acid ◽

Mitochondrial Dysfunction ◽

Inflammatory Diseases ◽

Whole Body ◽

Cross Sectional ◽

Chronic Inflammatory Diseases ◽

Periodontal Inflammation ◽

Inflammatory Status ◽

Lipid Fatty Acid

AbstractRheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases with several pathogenic pathways in common. Evidence supports an association between the diseases, but the exact underlying mechanisms behind the connection are still under investigation. Lipid, fatty acid (FA) and metabolic profile alterations have been associated with several chronic inflammatory diseases, including RA and periodontitis. Mitochondria have a central role in regulating cellular bioenergetic and whole-body metabolic homeostasis, and mitochondrial dysfunction has been proposed as a possible link between the two disorders. The aim of this cross-sectional study was to explore whole-blood FA, serum lipid composition, and carnitine- and choline derivatives in 78 RA outpatients with different degrees of periodontal inflammation. The main findings were alterations in lipid, FA, and carnitine- and choline derivative profiles. More specifically, higher total FA and total cholesterol concentrations were found in active RA. Elevated phospholipid concentrations with concomitant lower choline, elevated medium-chain acylcarnitines (MC-AC), and decreased ratios of MC-AC and long-chain (LC)-AC were associated with prednisolone medication. This may indicate an altered mitochondrial function in relation to the increased inflammatory status in RA disease. Our findings may support the need for interdisciplinary collaboration within the field of medicine and dentistry in patient stratification to improve personalized treatment. Longitudinal studies should be conducted to further assess the potential impact of mitochondrial dysfunction on RA and periodontitis.

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Techniques to Study Inflammasome Activation and Inhibition by Small Molecules

Molecules ◽

10.3390/molecules26061704 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1704

Author(s):

Diego Angosto-Bazarra ◽

Cristina Molina-López ◽

Alejandro Peñín-Franch ◽

Laura Hurtado-Navarro ◽

Pablo Pelegrín

Keyword(s):

Inflammatory Response ◽

Small Molecules ◽

Mechanism Of Action ◽

Inflammatory Diseases ◽

Inflammasome Activation ◽

Chronic Inflammatory Diseases ◽

Anti Inflammatory ◽

Inhibitory Molecules ◽

Inflammasome Inhibitors

Inflammasomes are immune cytosolic oligomers involved in the initiation and progression of multiple pathologies and diseases. The tight regulation of these immune sensors is necessary to control an optimal inflammatory response and recover organism homeostasis. Prolonged activation of inflammasomes result in the development of chronic inflammatory diseases, and the use of small drug-like inhibitory molecules are emerging as promising anti-inflammatory therapies. Different aspects have to be taken in consideration when designing inflammasome inhibitors. This review summarizes the different techniques that can be used to study the mechanism of action of potential inflammasome inhibitory molecules.

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Impact of COVID-19 on initiation of biologic therapy prescriptions for chronic inflammatory diseases

Joint Bone Spine ◽

10.1016/j.jbspin.2021.105253 ◽

2021 ◽

pp. 105253

Author(s):

Pascal Richette ◽

Matthieu Allez ◽

Vincent Descamps ◽

Lucas Perray ◽

Simon Pilet ◽

...

Keyword(s):

Biologic Therapy ◽

Inflammatory Diseases ◽

Chronic Inflammatory Diseases

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The mercapturomic profile of health and non-communicable diseases

High-Throughput ◽

10.3390/ht8020010 ◽

2019 ◽

Vol 8 (2) ◽

pp. 10 ◽

Cited By ~ 4

Author(s):

Gonçalves-Dias ◽

Morello ◽

Semedo ◽

Correia ◽

Coelho ◽

...

Keyword(s):

Environmental Exposure ◽

Inflammatory Diseases ◽

Communicable Diseases ◽

Non Communicable Diseases ◽

Chronic Inflammatory Diseases ◽

Cardiometabolic Diseases ◽

Health And Disease ◽

Endogenous Metabolites

The mercapturate pathway is a unique metabolic circuitry that detoxifies electrophiles upon adducts formation with glutathione. Since its discovery over a century ago, most of the knowledge on the mercapturate pathway has been provided from biomonitoring studies on environmental exposure to toxicants. However, the mercapturate pathway-related metabolites that is formed in humans—the mercapturomic profile—in health and disease is yet to be established. In this paper, we put forward the hypothesis that these metabolites are key pathophysiologic factors behind the onset and development of non-communicable chronic inflammatory diseases. This review goes from the evidence in the formation of endogenous metabolites undergoing the mercapturate pathway to the methodologies for their assessment and their association with cancer and respiratory, neurologic and cardiometabolic diseases.

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Discovery of new polycyclic polyprenylated acylphloroglucinols with diverse architectures as potent cyclooxygenase-2 inhibitors

Organic Chemistry Frontiers ◽

10.1039/d0qo00259c ◽

2020 ◽

Vol 7 (11) ◽

pp. 1349-1357 ◽

Cited By ~ 2

Author(s):

Shuangshuang Xie ◽

Changxing Qi ◽

Yulin Duan ◽

Qianqian Xu ◽

Yaping Liu ◽

...

Keyword(s):

Therapeutic Target ◽

Inflammatory Diseases ◽

Cyclooxygenase 2 ◽

Chronic Inflammatory Diseases ◽

Cox 2 ◽

Cyclooxygenase 2 Inhibitors

Cyclooxygenase-2 (COX-2) is a significant therapeutic target of chronic inflammatory diseases.

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Intermittent rolling is a defect of the extravasation cascade caused by Myosin1e-deficiency in neutrophils

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1902502116 ◽

2019 ◽

Vol 116 (52) ◽

pp. 26752-26758 ◽

Cited By ~ 3

Author(s):

Eduardo Vadillo ◽

Sandra Chánez-Paredes ◽

Hilda Vargas-Robles ◽

Idaira María Guerrero-Fonseca ◽

Ramón Castellanos-Martínez ◽

...

Keyword(s):

Vascular Endothelium ◽

Actin Polymerization ◽

Inflammatory Diseases ◽

Chimeric Mice ◽

Rolling Velocity ◽

Chronic Inflammatory Diseases ◽

Neutrophil Extravasation ◽

Cytoskeletal Dynamics ◽

Adhesive Interactions ◽

Deficient Mice

Neutrophil extravasation is a migratory event in response to inflammation that depends on cytoskeletal dynamics regulated by myosins. Myosin-1e (Myo1e) is a long-tailed class-I myosin that has not yet been studied in the context of neutrophil–endothelial interactions and neutrophil extravasation. Intravital microscopy of TNFα-inflamed cremaster muscles in Myo1e-deficient mice revealed that Myo1e is required for efficient neutrophil extravasation. Specifically, Myo1e deficiency caused increased rolling velocity, decreased firm adhesion, aberrant crawling, and strongly reduced transmigration. Interestingly, we observed a striking discontinuous rolling behavior termed “intermittent rolling,” during which Myo1e-deficient neutrophils showed alternating rolling and jumping movements. Surprisingly, chimeric mice revealed that these effects were due to Myo1e deficiency in leukocytes. Vascular permeability was not significantly altered in Myo1e KO mice. Myo1e-deficient neutrophils showed diminished arrest, spreading, uropod formation, and chemotaxis due to defective actin polymerization and integrin activation. In conclusion, Myo1e critically regulates adhesive interactions of neutrophils with the vascular endothelium and neutrophil extravasation. Myo1e may therefore be an interesting target in chronic inflammatory diseases characterized by excessive neutrophil recruitment.

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