scholarly journals Itaconate and its derivatives repress C2C12 myogenesis via succinate dehydrogenase inhibition

2021 ◽  
Author(s):  
Tae Seok Oh ◽  
Damian C. Hutchins ◽  
Rabina Mainali ◽  
Kevin Goslen ◽  
Joshua Hayes ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Krebs Cycle ◽  
Muscle Differentiation ◽  
Protein Markers ◽  
Dimethyl Malonate ◽  
Disease Treatment

AbstractA Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopies the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. More importantly, our findings suggest the therapeutic potential of itaconate and its derivatives could be limited due to deleterious effects on myogenesis.

scholarly journals Naringenin Nano-Delivery Systems and Their Therapeutic Applications

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 291
Author(s):  
Mohammed Bhia ◽  
Mahzad Motallebi ◽  
Banafshe Abadi ◽  
Atefeh Zarepour ◽  
Miguel Pereira-Silva ◽  
...  
Keyword(s):  
Skin Diseases ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Delivery Systems ◽  
In Vivo Models ◽  
Wide Range

Naringenin (NRG) is a polyphenolic phytochemical belonging to the class of flavanones and is widely distributed in citrus fruits and some other fruits such as bergamot, tomatoes, cocoa, and cherries. NRG presents several interesting pharmacological properties, such as anti-cancer, anti-oxidant, and anti-inflammatory activities. However, the therapeutic potential of NRG is hampered due to its hydrophobic nature, which leads to poor bioavailability. Here, we review a wide range of nanocarriers that have been used as delivery systems for NRG, including polymeric nanoparticles, micelles, liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanosuspensions, and nanoemulsions. These nanomedicine formulations of NRG have been applied as a potential treatment for several diseases, using a wide range of in vitro, ex vivo, and in vivo models and different routes of administration. From this review, it can be concluded that NRG is a potential therapeutic option for the treatment of various diseases such as cancer, neurological disorders, liver diseases, ocular disorders, inflammatory diseases, skin diseases, and diabetes when formulated in the appropriate nanocarriers.

Exploiting Anti-Inflammation Effects of Flavonoids in Chronic Inflammatory Diseases

2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cellular Level ◽  
Antiinflammatory Drugs ◽  
Suitable Alternative ◽  
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.

HMGB1 has sparked a lot of attention as a model DAMP molecule involved in inflammation, inflammatory diseases, and cancer.

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Sterile Inflammation ◽  
Clinical Testing ◽  
Specific Function ◽  
Redox States ◽  
Fundamental Knowledge

HMGB1, the second most prevalent protein inside the nucleus after histone, has sparked a lot of attention as a model DAMP molecule involved in inflammation, inflammatory diseases, and cancer. Building on the fundamental knowledge of HMGB1 as a cytokine/chemoattractant, several in vivo and in vitro studies have indicated therapeutic potential for targeting HMGB1 and lowering tissue damage once inflammation has gone awry. A few hurdles must be cleared before HMGB1 treatment may progress further into clinical trials. The exact mechanism by which HMGB1 travels from the nucleus to the cytoplasm and then to the ECM is unclear. Different HMGB1 redox states can generate in situ modulations, making it difficult to determine the specific function of HMGB1 isoforms. Furthermore, the investigation of HMGB1 and its antagonists in disease situations is complicated by various HMGB1 receptors with various degrees of cell selectivity for a certain HMGB1 isoform or HMGB1 cofactor complex. HMGB1 targeting has been found to be beneficial in the treatment of inflammation and inflammatory diseases, notably in sepsis, sterile inflammation, autoimmune diseases, and cancer, despite the difficulties. Continued HMGB1 research might help fill in the gaps in knowledge and push HMGB1 antagonists closer to the next step of clinical testing.

scholarly journals In Vitro and In Vivo Immunomodulator Activities of Allium sativum L.

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Mouna Moutia ◽  
Norddine Habti ◽  
Abdallah Badou
Keyword(s):  
Immune Cells ◽  
Allium Sativum ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Biological Activities ◽  
Antioxidant Properties ◽  
Allergic Airway Inflammation ◽  
Cytokine Gene Expression

Allium Sativum L. (garlic), which is a species of the onion family, Alliaceae, is one of the most used plants in traditional medicine worldwide. More than 200 chemicals with diverse properties have been found in garlic extracts. Several garlic compounds were suggested to be efficient in improving various pathologies including certain types of cancer. This paper is an overview of data about garlic biological activities in vitro and/or in vivo on immune cells, on the development of certain inflammatory diseases, and on different types of carcinomas and sarcomas. Garlic and its compounds were found to have notable antioxidant properties. Garlic therapeutic potential has also been studied in several inflammatory diseases such as allergic-airway inflammation, inflammatory bowel disease, arthritic rheumatism, and atherosclerosis. Furthermore, garlic was found to be able to maintain the immune system homeostasis and to exhibit beneficial effects on immune cells especially through regulation of proliferation and cytokine gene expression. Finally, we will show how major garlic components such as sulfur compounds and polyphenols might be responsible for the garlic biological activities revealed in different situations. If identified, specific compounds present in garlic could potentially be used in therapy.

scholarly journals KCNN4 Expression Is Elevated in Inflammatory Bowel Disease: This Might Be a Novel Marker and Therapeutic Option Targeting Potassium Channels

2020 ◽  
Vol 29 (4) ◽  
pp. 539-547
Author(s):  
Christoph Süss ◽  
Lucile Broncy ◽  
Kirstin Pollinger ◽  
Claudia Kunst ◽  
Karsten Gülow ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cell Monolayer ◽  
Secretory Diarrhea ◽  
K Channel ◽  
Epithelial Barrier ◽  
Mrna Levels ◽  
Inflammatory Bowel

Background and Aims: The K + channel KCNN4 is involved in many inflammatory diseases. Previous work has shown that this channel is involved in epithelial ion transport and intestinal restitution. In inflammatory bowel diseases (IBD) a defective epithelial barrier can lead to typical symptoms like secretory diarrhea and the formation of intestinal ulcers. We compared surgical samples from patients with IBD, diverticulitis and controls without inflammation to determine the potential role of KCNN4 as a diagnostic marker and/or therapeutic target. Methods: mRNA-levels of KCNN4 and a control K + channel were determined in intestinal epithelial cells (IEC) from patients with IBD, diverticulitis and controls. In addition, we performed a Western blot analysis of KCNN4 and a respective control K + channel in IEC from patients with IBD. Furthermore, we determined epithelial barrier integrity by measuring the flux of fluorescent-labeled dextran beads across a cell monolayer upon incubation with interferon-γ. Results: KCNN4 mRNA and protein levels were elevated in IEC from patients with Crohn`s disease (CD) and ulcerative colitis (UC). Of note, KCNN4 was not elevated in non-IBD intestinal inflammatory conditions e.g. diverticulitis. Of clinical relevance, pharmacological KCNN4 channel openers stabilized epithelial barrier function in vitro. Thus, KCNN4 may have a protective role in IBD and constitute a therapeutic target. Conclusions: Our data demonstrate elevated KCNN4 both at mRNA and protein level in IEC specifically from patients with IBD. Therefore, we conclude that KCNN4 could be used as a novel marker for IBD, especially for the establishment of initial diagnosis. Of therapeutic consequence, we show that pharmacological KCNN4 openers stabilize the epithelial barrier. Thus, KCNN4 might be a novel target to diagnose and treat IBD.

scholarly journals T-Type Calcium Channels: A Potential Novel Target in Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 391 ◽  
Author(s):  
Carla Barceló ◽  
Pol Sisó ◽  
Oscar Maiques ◽  
Inés de la Rosa ◽  
Rosa M. Martí ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Therapeutic Potential ◽  
Therapeutic Option ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Braf Inhibitors ◽  
Promising Therapeutic Approach ◽  
Novel Target ◽  
And Migration

T-type calcium channels (TTCCs) are overexpressed in several cancers. In this review, we summarize the recent advances and new insights into TTCC biology, tumor progression, and prognosis biomarker and therapeutic potential in the melanoma field. We describe a novel correlation between the Cav3.1 isoform and the increased basal autophagy in BRAFV600E-mutant melanomas and after acquired resistance to BRAF inhibitors. Indeed, TTCC blockers reduce melanoma cell viability and migration/invasion in vitro and tumor growth in mice xenografts in both BRAF-inhibitor-sensitive and -resistant scenarios. These studies open a new, promising therapeutic approach for disseminated melanoma and improved treatment in BRAFi relapsed melanomas, but further validation and clinical trials are needed for it to become a real therapeutic option.

scholarly journals Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2906
Author(s):  
Hiroyuki Ogasawara ◽  
Masato Noguchi
Keyword(s):  
Mast Cells ◽  
Immunoglobulin E ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Neuromuscular Blocking ◽  
Drug Induced ◽  
Functional Studies ◽  
Inflammatory Conditions ◽  
Functional Analyses

Mast cells (MCs) act as primary effectors in inflammatory and allergic reactions by releasing intracellularly-stored inflammatory mediators in diseases. The two major pathways for MC activation are known to be immunoglobulin E (IgE)-dependent and -independent. Although IgE-dependent signaling is the main pathway to MC activation, IgE-independent pathways have also been found to serve pivotal roles in the pathophysiology of various inflammatory conditions. Recent studies have shown that human and mouse MCs express several regulatory receptors such as toll-like receptors (TLRs), CD48, C300a, and GPCRs, including mas-related GPCR-X2 (MRGPRX2). MRGPRX2 has been reported as a novel GPCR that is expressed in MCs activated by basic secretagogues, neurokinin peptides, host defense antimicrobial peptides, and small molecule compounds (e.g., neuromuscular blocking agents) and leads to MC degranulation and eicosanoids release under in vitro experimental condition. Functional analyses of MRGPRX2 and Mrgprb2 (mouse ortholog) indicate that MRGPRX2 is involved in MC hypersensitivity reactions causing neuroinflammation such as postoperative pain, type 2 inflammation, non-histaminergic itch, and drug-induced anaphylactic-like reactions. In this review, we discuss the roles in innate immunity through functional studies on MRGPRX2-mediated IgE-independent MC activation and also the therapeutic potential of MRGPRX2 inhibitors on allergic and inflammatory diseases.

scholarly journals Naturally Available Flavonoid Aglycones as Potential Antiviral Drug Candidates against SARS-CoV-2

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6559
Author(s):  
Ahmed A. Al-Karmalawy ◽  
Mai M. Farid ◽  
Ahmed Mostafa ◽  
Alia Y. Ragheb ◽  
Sara H. Mahmoud ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Antiviral Drug ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Flavonoid Aglycones

Flavonoids are important secondary plant metabolites that have been studied for a long time for their therapeutic potential in inflammatory diseases because of their cytokine-modulatory effects. Five flavonoid aglycones were isolated and identified from the hydrolyzed aqueous methanol extracts of Anastatica hierochuntica L., Citrus reticulata Blanco, and Kickxia aegyptiaca (L.) Nabelek. They were identified as taxifolin (1), pectolinarigenin (2), tangeretin (3), gardenin B (4), and hispidulin (5). These structures were elucidated based on chromatographic and spectral analysis. In this study, molecular docking studies were carried out for the isolated and identified compounds against SARS-CoV-2 main protease (Mpro) compared to the co-crystallized inhibitor of SARS-CoV-2 Mpro (α-ketoamide inhibitor (KI), IC50 = 66.72 µg/mL) as a reference standard. Moreover, in vitro screening against SARS-CoV-2 was evaluated. Compounds 2 and 3 showed the highest virus inhibition with IC50 12.4 and 2.5 µg/mL, respectively. Our findings recommend further advanced in vitro and in vivo studies of the examined isolated flavonoids, especially pectolinarigenin (2), tangeretin (3), and gardenin B (4), either alone or in combination with each other to identify a promising lead to target SARS-CoV-2 effectively. This is the first report of the activity of these compounds against SARS-CoV-2.

scholarly journals Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action

2021 ◽  
Vol 12 ◽  
Author(s):  
Mahyar Ostadkarampour ◽  
Edward E. Putnins
Keyword(s):  
Monoamine Oxidase ◽  
Immune Cells ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Financial Burden ◽  
Mao Inhibitors ◽  
Mao Inhibitor ◽  
Anti Inflammatory

Chronic inflammatory diseases are debilitating, affect patients’ quality of life, and are a significant financial burden on health care. Inflammation is regulated by pro-inflammatory cytokines and chemokines that are expressed by immune and non-immune cells, and their expression is highly controlled, both spatially and temporally. Their dysregulation is a hallmark of chronic inflammatory and autoimmune diseases. Significant evidence supports that monoamine oxidase (MAO) inhibitor drugs have anti-inflammatory effects. MAO inhibitors are principally prescribed for the management of a variety of central nervous system (CNS)-associated diseases such as depression, Alzheimer’s, and Parkinson’s; however, they also have anti-inflammatory effects in the CNS and a variety of non-CNS tissues. To bolster support for their development as anti-inflammatories, it is critical to elucidate their mechanism(s) of action. MAO inhibitors decrease the generation of end products such as hydrogen peroxide, aldehyde, and ammonium. They also inhibit biogenic amine degradation, and this increases cellular and pericellular catecholamines in a variety of immune and some non-immune cells. This decrease in end product metabolites and increase in catecholamines can play a significant role in the anti-inflammatory effects of MAO inhibitors. This review examines MAO inhibitor effects on inflammation in a variety of in vitro and in vivo CNS and non-CNS disease models, as well as their anti-inflammatory mechanism(s) of action.

scholarly journals Leucosceptoside A from Devil’s Claw Modulates Psoriasis-like Inflammation via Suppression of the PI3K/AKT Signaling Pathway in Keratinocytes

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 7014
Author(s):  
Ivanka K. Koycheva ◽  
Liliya V. Mihaylova ◽  
Monika N. Todorova ◽  
Zhivka P. Balcheva-Sivenova ◽  
Kalina Alipieva ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Akt Signaling ◽  
Keratinocyte Differentiation ◽  
Hacat Cells ◽  
Keratinocyte Proliferation ◽  
Devil’S Claw ◽  
Ifn Γ ◽  
Inflammatory Skin

Psoriasis is a chronic inflammatory skin condition characterized by abnormal keratinocyte proliferation and differentiation that is accompanied with dysregulated immune response and abnormal vascularization. Devil’s claw (Harpagophytum procumbens (Burch.) DC. ex Meisn.) tubers extract has been used both systemically and topically for treatment of chronic inflammatory diseases such as arthritis, osteoporosis, inflammatory bowel disease, among others. However, its potential mechanisms of action against psoriasis remains poorly investigated. The human keratinocyte HaCaT cell line is a well-accepted in vitro model system for inflammatory skin disorders such as psoriasis. The present study involved an exploration of the effect of biotechnologically produced H. procumbens (HP) cell suspension extract and pure phenylethanoid glycosides verbascoside (VER) and leucosceptoside A (LEU) in interferon (IFN)-γ/interleukin (IL)-17A/IL-22-stimulated HaCaT cells as a model of psoriasis-like inflammation. Changes in key inflammatory signaling pathways related to psoriasis development were detected by reverse transcription polymerase chain reaction and western blotting. Treatment with LEU, but not VER and HP extract improved psoriasis-related inflammation via suppression of the PI3K/AKT signaling in IFN-γ/IL-17A/IL-22-stimulated HaCaT cells. Our results suggest that LEU may exhibit therapeutic potential against psoriasis by regulating keratinocyte differentiation through inhibition of the PI3K/AKT pathway.

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