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Molecular Targets for Anti-inflammatory Therapy

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 19529

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Dr. Simona Dedoni

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Guest Editor

Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, University of Cagliari, 09042 Monserrato, Italy
Interests: cell signaling; apoptosis; neurotrophins; cytokines; neuroscience
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There is increasing evidence that an inflammatory state negatively impacts myriad health outcomes. Effects on cognitive function and depression have also been reported and linked to inflammation. The brain's immune system primarily comprises cells called microglia, which are important for brain function. Alterations in the mechanisms that regulate the promotion of inflammatory conditions may be involved in the progression of inflammation and, particularly, neuropsychiatric disorders. In this Special Issue, we aim to promote original research and reviews that explore inflammatory biomarkers and new therapeutic molecules (of natural origin or synthetic), elucidating the molecular mechanisms involved in the anti-inflammatory response. The aim is to improve knowledge for reducing inflammation and inflammatory pathologies significantly linked to brain cells and cell bodies.

Dr. Simona Dedoni
Guest Editor

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Keywords

inflammation
cytokines
apoptosis
cell signaling
survival
nutraceutics

Published Papers (6 papers)

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19 pages, 6620 KiB

Open AccessArticle

Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives

by Lin-Hao Zhang, Ming-Yue Li, Da-Yuan Wang, Xue-Jun Jin, Fen-Er Chen and Hu-Ri Piao

Molecules 2022, 27(22), 7925; https://doi.org/10.3390/molecules27227925 - 16 Nov 2022

Cited by 1 | Viewed by 1173

Abstract

(1) Background: Nuclear factor κB (NF-κB) is an important transcriptional regulator that regulates the inflammatory pathway and plays a key role in cellular inflammatory and immune responses. The presence of a high concentration of NF-κB is positively correlated with the severity of inflammation. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation; (2) Methods: we designed and synthesized 23 mollugin derivatives and evaluated their inhibitory activity against NF-κB transcription; (3) Results: Compound 6d exhibited the most promising inhibitory activity (IC₅₀ = 3.81 µM) and did not show any significant cytotoxicity against the tested cell lines. Investigation of the mechanism of action indicated that 6d down-regulated NF-κB expression, possibly by suppressing TNF-α-induced expression of the p65 protein. Most of the compounds exhibited potent anti-inflammatory activity. Compound 4f was the most potent compound with 83.08% inhibition of inflammation after intraperitoneal administration, which was more potent than mollugin and the reference drugs (ibuprofen and mesalazine). ADMET prediction analysis indicated that compounds 6d and 4f had good pharmacokinetics and drug-like behavior; (4) Conclusions: Several series of mollugin derivatives were designed, synthesized, and evaluated for NF-κB inhibitory activity and toxicity. These results provide an initial basis for the development of 4f and 6d as potential anti-inflammatory agents. Full article

(This article belongs to the Special Issue Molecular Targets for Anti-inflammatory Therapy)

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25 pages, 466 KiB

Open AccessReview

Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases

by Abdur Rauf, Himani Badoni, Tareq Abu-Izneid, Ahmed Olatunde, Md. Mominur Rahman, Sakshi Painuli, Prabhakar Semwal, Polrat Wilairatana and Mohammad S. Mubarak

Molecules 2022, 27(10), 3194; https://doi.org/10.3390/molecules27103194 - 17 May 2022

Cited by 80 | Viewed by 8415

Abstract

Neuroinflammation, a protective response of the central nervous system (CNS), is associated with the pathogenesis of neurodegenerative diseases. The CNS is composed of neurons and glial cells consisting of microglia, oligodendrocytes, and astrocytes. Entry of any foreign pathogen activates the glial cells (astrocytes and microglia) and overactivation of these cells triggers the release of various neuroinflammatory markers (NMs), such as the tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-1β (IL-10), nitric oxide (NO), and cyclooxygenase-2 (COX-2), among others. Various studies have shown the role of neuroinflammatory markers in the occurrence, diagnosis, and treatment of neurodegenerative diseases. These markers also trigger the formation of various other factors responsible for causing several neuronal diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), ischemia, and several others. This comprehensive review aims to reveal the mechanism of neuroinflammatory markers (NMs), which could cause different neurodegenerative disorders. Important NMs may represent pathophysiologic processes leading to the generation of neurodegenerative diseases. In addition, various molecular alterations related to neurodegenerative diseases are discussed. Identifying these NMs may assist in the early diagnosis and detection of therapeutic targets for treating various neurodegenerative diseases. Full article

(This article belongs to the Special Issue Molecular Targets for Anti-inflammatory Therapy)

14 pages, 896 KiB

Open AccessReview

K18- and CAG-hACE2 Transgenic Mouse Models and SARS-CoV-2: Implications for Neurodegeneration Research

by Simona Dedoni, Valeria Avdoshina, Chiara Camoglio, Carlotta Siddi, Walter Fratta, Maria Scherma and Paola Fadda

Molecules 2022, 27(13), 4142; https://doi.org/10.3390/molecules27134142 - 28 Jun 2022

Cited by 9 | Viewed by 3696

Abstract

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that might lead to very serious consequences. Notably, mental status change, brain confusion, and smell and taste disorders along with neurological complaints have been reported in patients infected with SARS-CoV-2. Furthermore, human brain tissue autopsies from COVID-19 patients show the presence of SARS-CoV-2 neuroinvasion, which correlates with the manifestation of meningitis, encephalitis, leukocyte infiltration, and neuronal damage. The olfactory mucosa has been suggested as a way of entry into the brain. SARS-CoV-2 infection is also known to provoke a hyper-inflammatory reaction with an exponential increase in the production of pro-inflammatory cytokines leading to systemic responses, even in the absence of direct infection of brain cells. Angiotensin-converting enzyme 2 (ACE2), the entry receptor of SARS-CoV-2, has been extensively demonstrated to be present in the periphery, neurons, and glial cells in different brain regions. To dissect the details of neurological complications and develop therapies helping COVID-19 survivors regain pre-infection quality of life, the development of robust clinical models is highly warranted. Several human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models have been developed and used for antiviral drug screening and vaccine development, as well as for better understanding of the molecular pathogenetic mechanisms of SARS-CoV-2 infection. In this review, we summarize recent results from the studies involving two such mouse models, namely K18- and CAG-hACE2 transgenics, to evaluate the direct and indirect impact of SARS-CoV-2 infection on the central nervous system. Full article

(This article belongs to the Special Issue Molecular Targets for Anti-inflammatory Therapy)

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16 pages, 1829 KiB

Open AccessArticle

The Effect of Progestins on Cytokine Production in the Peripheral Blood Mononuclear Cells of Menopausal Women and Their Luminol-Dependent Chemiluminescence

by Tatiana I. Pavlik, Nikolay L. Shimanovsky, Olga A. Zemlyanaya and Tatiana A. Fedotcheva

Molecules 2023, 28(11), 4354; https://doi.org/10.3390/molecules28114354 - 26 May 2023

Cited by 1 | Viewed by 1618

Abstract

Steroid hormones are the key regulators of inflammatory and autoimmune processes. The role of steroid hormones is mostly inhibitory in these processes. The expression of IL-6, TNFα, and IL-1β, as markers of inflammation, and TGFβ, as a marker of fibrosis, could be useful tools to predict the response of an individual’s immune system to the different progestins suitable for the treatment of menopausal inflammatory disorders, including endometriosis. In this study, the progestins P4 and MPA, as well as the novel progestin gestobutanoyl (GB), which possess potent anti-inflammatory properties towards endometriosis, were studied at a fixed concentration of 10 µM. Their influence on the production of the above cytokines in PHA-stimulated peripheral blood mononuclear cells (PBMCs) during 24 h incubation was evaluated by ELISA. It was found that synthetic progestins stimulated the production of IL-1β, IL-6, and TNFα and inhibited TGFβ production, while P4 inhibited IL-6 (33% inhibition) and did not influence TGFβ production. In the MTT-viability test, P4 also decreased PHA-stimulated PBMC viability by 28% during 24 h incubation, but MPA and GB did not have any inhibitory or stimulatory effects. The luminol-dependent chemiluminescence (LDC) assay revealed the anti-inflammatory and antioxidant properties of all the tested progestins, as well as some other steroid hormones and their antagonists: cortisol, dexamethasone, testosterone, estradiol, cyproterone, and tamoxifen. Of these, tamoxifen showed the most pronounced effect on the oxidation capacity of PBMC but not on that of dexamethasone, as was expected. Collectively, these data demonstrate that PBMCs from menopausal women respond differently to P4 and synthetic progestins, most likely due to distinct actions via various steroid receptors. It is not only the progestin affinity to nuclear progesterone receptors (PR), androgen receptors, glucocorticoid receptors, or estrogen receptors that is important for the immune response, but also the membrane PR or other nongenomic structures in immune cells. Full article

(This article belongs to the Special Issue Molecular Targets for Anti-inflammatory Therapy)

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11 pages, 3459 KiB

Open AccessArticle

Benzoylaconitine Alleviates Progression of Psoriasis via Suppressing STAT3 Phosphorylation in Keratinocytes

by Yuanbo Li, Dandan Guo, Qianqian Wang, Aifang Li, Sugai Yin, Shuxuan Li, Yalan Li, Baiyan Wang, Tao Guo and Shuying Feng

Molecules 2023, 28(11), 4473; https://doi.org/10.3390/molecules28114473 - 31 May 2023

Cited by 2 | Viewed by 1305

Abstract

Psoriasis is a chronic and multifactorial skin disease which is caused by inflammatory infiltrates, keratinocyte hyperproliferation, and accumulation of immune cells. As part of the Aconitum species, Benzoylaconitine (BAC) shows potential antiviral, anti-tumor, and anti-inflammatory effects. In this study, we investigated the effects and mechanisms of BAC on tumor necrosis factor-alpha (TNF-α)/LPS-induced HaCaT keratinocytes in a imiquimod(IMQ)-induced mice model. The results showed that BAC could relieve the symptoms of psoriasis by inhibiting cell proliferation, the release of inflammatory factors, and the accumulation of Th17 cells, while no obvious effect on cell viability and safety was observed both in vitro and in vivo. Additionally, BAC can markedly inhibit the protein and mRNA levels of inflammatory cytokines in TNF-α/LPS-induced HaCaT keratinocytes by inhibiting the phosphorylation of STAT3. In brief, our data indicated that BAC could alleviate the progression of psoriasis and may be a potential therapeutic agent for treating psoriasis in clinical practice. Full article

(This article belongs to the Special Issue Molecular Targets for Anti-inflammatory Therapy)

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14 pages, 2781 KiB

Open AccessArticle

Plant-Derived Molecule 4-Methylumbelliferone Suppresses FcεRI-Mediated Mast Cell Activation and Allergic Inflammation

by Hui-Na Wang, Qiu-An Xiang, Hao-Hui Lin, Jie-Ning Chen, Wen-Jie Guo, Wan-Meng Guo, Xiang-Ning Yue, Zhen-Fu Zhao, Kunmei Ji and Jia-Jie Chen

Molecules 2022, 27(5), 1577; https://doi.org/10.3390/molecules27051577 - 27 Feb 2022

Cited by 3 | Viewed by 2452

Abstract

Mast cells (MCs) are an important treatment target for high-affinity IgE Fc receptor (FcεRI)-mediated allergic diseases. The plant-derived molecule 4-methylumbelliferone (4-MU) has beneficial effects in animal models of inflammation and autoimmunity diseases. The aim of this study was to examine 4-MU effects on MC activation and probe the underlying molecular mechanism(s). We sensitized rat basophilic leukemia cells (RBLs) and mouse bone marrow-derived mast cells (BMMCs) with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated them with exposure to DNP-human serum albumin (HSA), and then treated stimulated cells with 4-MU. Signaling-protein expression was determined by immunoblotting. In vivo allergic responses were examined in IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) mouse models. 4-MU inhibited β-hexosaminidase activity and histamine release dose-dependently in FcεRI-activated RBLs and BMMCs. Additionally, 4-MU reduced cytomorphological elongation and F-actin reorganization while down-regulating IgE/Ag-induced phosphorylation of SYK, NF-κB p65, ERK1/2, p38, and JNK. Moreover, 4-MU attenuated the PCA allergic reaction (i.e., less ear thickening and dye extravasation). Similarly, we found that 4-MU decreased body temperature, serum histamine, and IL4 secretion in OVA-challenged ASA model mice. In conclusion, 4-MU had a suppressing effect on MC activation both in vitro and in vivo and thus may represent a new strategy for treating IgE-mediated allergic conditions. Full article

(This article belongs to the Special Issue Molecular Targets for Anti-inflammatory Therapy)

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