Research

16 pages, 2188 KiB

Open AccessArticle

Drug Design, Synthesis and Biological Evaluation of Heterocyclic Molecules as Anti-Inflammatory Agents

by Jignasa Savjani, Bhavesh Variya, Snehal Patel, Suja Mulamkattil, Harsh Amin, Shital Butani, Ahmed Allam, Jamaan Ajarem and Harsh Shah

Molecules 2022, 27(4), 1262; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27041262 - 14 Feb 2022

Cited by 3 | Viewed by 2827

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are generally utilized for numerous inflammatory ailments. The long-term utilization of NSAIDs prompts adverse reactions such as gastrointestinal ulceration, renal dysfunction and hepatotoxicity; however, selective COX-2 inhibitors prevent these adverse events. Various scientific approaches have been employed to identify [...] Read more.

Non-steroidal anti-inflammatory drugs (NSAIDs) are generally utilized for numerous inflammatory ailments. The long-term utilization of NSAIDs prompts adverse reactions such as gastrointestinal ulceration, renal dysfunction and hepatotoxicity; however, selective COX-2 inhibitors prevent these adverse events. Various scientific approaches have been employed to identify safer COX-2 inhibitors, as in any case, a large portion of particular COX-2 inhibitors have been retracted from the market because of severe cardiovascular events. This study aimed to develop and synthesize a novel series of indomethacin analogues with potential anti-inflammatory properties and fewer side effects, wherein carboxylic acid moiety was substituted using DCC/DMAP coupling. This study incorporates the docking of various indomethacin analogues to detect the binding interactions with COX-2 protein (PDB ID: 3NT1). MD simulation was performed to measure the stability and flexibility of ligand–protein interactions at the atomic level, for which the top-scoring ligand–protein complex was selected. These compounds were evaluated in vitro for COX enzymes inhibition. Likewise, selected compounds were screened in vivo for anti-inflammatory potential using the carrageenan-induced rat paw oedema method and their ulcerogenic potential. The acute toxicity of compounds was also predicted using in silico tools. Most of the compounds exhibited the potent inhibition of both COX enzymes; however, 3e and 3c showed the most potent COX-2 inhibition having IC50 0.34 µM and 1.39 µM, respectively. These compounds also demonstrated potent anti-inflammatory potential without ulcerogenic liability. The biological evaluation revealed that the compound substituted with 4-nitrophenyl was most active. Full article

(This article belongs to the Special Issue Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III)

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12 pages, 12084 KiB

Open AccessArticle

Chrysin Derivative CM1 and Exhibited Anti-Inflammatory Action by Upregulating Toll-Interacting Protein Expression in Lipopolysaccharide-Stimulated RAW264.7 Macrophage Cells

by Eui-Baek Byun, Ha-Yeon Song, Woo Sik Kim, Jeong Moo Han, Ho Seong Seo, Woo Yong Park, Kwangwook Kim and Eui-Hong Byun

Molecules 2021, 26(6), 1532; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26061532 - 11 Mar 2021

Cited by 6 | Viewed by 2079

Abstract

Although our previous study revealed that gamma-irradiated chrysin enhanced anti-inflammatory activity compared to intact chrysin, it remains unclear whether the chrysin derivative, CM1, produced by gamma irradiation, negatively regulates toll-like receptor (TLR) signaling. In this study, we investigated the molecular basis for the [...] Read more.

Although our previous study revealed that gamma-irradiated chrysin enhanced anti-inflammatory activity compared to intact chrysin, it remains unclear whether the chrysin derivative, CM1, produced by gamma irradiation, negatively regulates toll-like receptor (TLR) signaling. In this study, we investigated the molecular basis for the downregulation of TLR4 signal transduction by CM1 in macrophages. We initially determined the appropriate concentration of CM1 and found no cellular toxicity below 2 μg/mL. Upon stimulation with lipopolysaccharide (LPS), CM1 modulated LPS-stimulated inflammatory action by suppressing the release of proinflammatory mediators (cytokines TNF-α and IL-6) and nitric oxide (NO) and downregulated the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, CM1 markedly elevated the expression of the TLR negative regulator toll-interacting protein (Tollip) in dose- and time-dependent manners. LPS-induced expression of cell surface molecules (CD80, CD86, and MHC class I/II), proinflammatory cytokines (TNF-α and IL-6), COX-2, and iNOS-mediated NO were inhibited by CM1; these effects were prevented by the knockdown of Tollip expression. Additionally, CM1 did not affect the downregulation of LPS-induced expression of MAPKs and NF-κB signaling in Tollip-downregulated cells. These findings provide insight into effective therapeutic intervention of inflammatory disease by increasing the understanding of the negative regulation of TLR signaling induced by CM1. Full article

(This article belongs to the Special Issue Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III)

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13 pages, 2584 KiB

Open AccessArticle

Suppressive Effect of Two Cucurbitane-Type Triterpenoids from Momordica charantia on Cutibacterium acnes-Induced Inflammatory Responses in Human THP-1 Monocytic Cell and Mouse Models

by Lu-Te Chuang, Wen-Cheng Huang, Yu-Chen Hou, Jong-Ho Chyuan, Hsiang Chang, Chi-I Chang, Tsung-Hsien Tsai and Po-Jung Tsai

Molecules 2021, 26(3), 579; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26030579 - 22 Jan 2021

Cited by 8 | Viewed by 2986

Abstract

Cutibacterium acnes (formerly Propionibacterium acnes) is one of the major bacterial species responsible for acne vulgaris. Numerous bioactive compounds from Momordica charantia Linn. var. abbreviata Ser. have been isolated and examined for many years. In this study, we evaluated the suppressive effect [...] Read more.

Cutibacterium acnes (formerly Propionibacterium acnes) is one of the major bacterial species responsible for acne vulgaris. Numerous bioactive compounds from Momordica charantia Linn. var. abbreviata Ser. have been isolated and examined for many years. In this study, we evaluated the suppressive effect of two cucurbitane-type triterpenoids, 5β,19-epoxycucurbita-6,23-dien-3β,19,25-triol (Kuguacin R; KR) and 3β,7β,25-trihydroxycucurbita-5,23-dien-19-al (TCD) on live C. acnes-stimulated in vitro and in vivo inflammatory responses. Using human THP-1 monocytes, KR or TCD suppressed C. acnes-induced production of interleukin (IL)-1β, IL-6 and IL-8 at least above 56% or 45%, as well as gene expression of these three pro-inflammatory cytokines. However, a significantly strong inhibitory effect on production and expression of tumor necrosis factor (TNF)-α was not observed. Both cucurbitanes inhibited C. acnes-induced activation of the myeloid differentiation primary response 88 (MyD88) (up to 62%) and mitogen-activated protein kinases (MAPK) (at least 36%). Furthermore, TCD suppressed the expression of pro-caspase-1 and cleaved caspase-1 (p10). In a separate study, KR or TCD decreased C. acnes-stimulated mouse ear edema by ear thickness (20% or 14%), and reduced IL-1β-expressing leukocytes and neutrophils in mouse ears. We demonstrated that KR and TCD are potential anti-inflammatory agents for modulating C. acnes-induced inflammation in vitro and in vivo. Full article

(This article belongs to the Special Issue Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III)

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13 pages, 958 KiB

Open AccessFeature PaperArticle

The Systemic Inflammation Index on Admission Predicts In-Hospital Mortality in COVID-19 Patients

by Alessandro G. Fois, Panagiotis Paliogiannis, Valentina Scano, Stefania Cau, Sergio Babudieri, Roberto Perra, Giulia Ruzzittu, Elisabetta Zinellu, Pietro Pirina, Ciriaco Carru, Luigi B. Arru, Alessandro Fancellu, Michele Mondoni, Arduino A. Mangoni and Angelo Zinellu

Molecules 2020, 25(23), 5725; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25235725 - 04 Dec 2020

Cited by 163 | Viewed by 6077

Abstract

Background. The rapid onset of a systemic pro-inflammatory state followed by acute respiratory distress syndrome is the leading cause of mortality in patients with COVID-19. We performed a retrospective observational study to explore the capacity of different complete blood cell count (CBC)-derived inflammation [...] Read more.

Background. The rapid onset of a systemic pro-inflammatory state followed by acute respiratory distress syndrome is the leading cause of mortality in patients with COVID-19. We performed a retrospective observational study to explore the capacity of different complete blood cell count (CBC)-derived inflammation indexes to predict in-hospital mortality in this group. Methods. The neutrophil to lymphocyte ratio (NLR), derived NLR (dNLR), platelet to lymphocyte ratio (PLR), mean platelet volume to platelet ratio (MPR), neutrophil to lymphocyte × platelet ratio (NLPR), monocyte to lymphocyte ratio (MLR), systemic inflammation response index (SIRI), systemic inflammation index (SII), and the aggregate index of systemic inflammation (AISI) were calculated on hospital admission in 119 patients with laboratory confirmed COVID-19. Results. Non-survivors had significantly higher AISI, dNLR, NLPR, NLR, SII, and SIRI values when compared to survivors. Similarly, Kaplan–Meier survival curves showed significantly lower survival in patients with higher AISI, dNLR, MLR, NLPR, NLR, SII, and SIRI. However, after adjusting for confounders, only the SII remained significantly associated with survival (HR = 1.0001; 95% CI, 1.0000–1.0001, p = 0.029) in multivariate Cox regression analysis. Conclusions. The SII on admission independently predicts in-hospital mortality in COVID-19 patients and may assist with early risk stratification in this group. Full article

(This article belongs to the Special Issue Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III)

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11 pages, 246 KiB

Open AccessArticle

Oxidative Stress Biomarkers and Peripheral Endothelial Dysfunction in Rheumatoid Arthritis: A Monocentric Cross-Sectional Case-Control Study

by Stefania Bassu, Angelo Zinellu, Salvatore Sotgia, Arduino Aleksander Mangoni, Alberto Floris, Giuseppina Farina, Giuseppe Passiu, Ciriaco Carru and Gian Luca Erre

Molecules 2020, 25(17), 3855; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25173855 - 25 Aug 2020

Cited by 13 | Viewed by 2397

Abstract

Previous studies have suggested that oxidative stress may heighten atherosclerotic burden in rheumatoid arthritis (RA), but direct evidence is lacking. Objective: To evaluate the relationship between established plasma oxidative stress biomarkers and peripheral endothelial dysfunction (ED), a marker of early atherosclerosis, in RA. [...] Read more.

Previous studies have suggested that oxidative stress may heighten atherosclerotic burden in rheumatoid arthritis (RA), but direct evidence is lacking. Objective: To evaluate the relationship between established plasma oxidative stress biomarkers and peripheral endothelial dysfunction (ED), a marker of early atherosclerosis, in RA. Methods: Paroxonase-1 (PON-1), protein-SH (PSH), and malondialdehyde (MDA) were measured in 164 RA patient s and 100 age- and sex-matched healthy controls without previous cardiovascular events. Peripheral ED, evaluated by flow-mediated pulse amplitude tonometry, was defined by log-transformed reactive hyperemia index (Ln-RHI) values < 0.51. Results: PON-1 activity and PSH concentrations were significantly reduced in RA patients compared to controls. In regression analysis, increased plasma MDA levels were significantly associated with reduced Ln-RHI [B coefficient (95% CI) = −0.003 (−0.005 to −0.0008), p = 0.008] and the presence of peripheral ED (OR (95% CI) = 1.75 (1.06–2.88), p = 0.028). Contrary to our expectations, increased PON-1 activity was significantly associated, albeit weakly, with the presence of ED (OR (95% CI) = 1.00 (1.00–1.01), p = 0.017). Conclusions: In this first evidence of a link between oxidative stress and markers of atherosclerosis, MDA and PON-1 showed opposite associations with peripheral vasodilatory capacity and the presence of ED in RA. Further studies are needed to determine whether this association predicts atherosclerotic events in the RA population. Full article

(This article belongs to the Special Issue Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III)

9 pages, 3015 KiB

Open AccessArticle

Anti-Inflammatory Effect of Simonsinol on Lipopolysaccharide Stimulated RAW264.7 Cells through Inactivation of NF-κB Signaling Pathway

by Lian-Chun Li, Zheng-Hong Pan, De-Sheng Ning and Yu-Xia Fu

Molecules 2020, 25(16), 3573; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25163573 - 06 Aug 2020

Cited by 8 | Viewed by 3104

Abstract

Simonsinol is a natural sesqui-neolignan firstly isolated from the bark of Illicium simonsii. In this study, the anti-inflammatory activity of simonsinol was investigated with a lipopolysaccharide (LPS)-stimulated murine macrophages RAW264.7 cells model. The results demonstrated that simonsinol could antagonize the effect of [...] Read more.

Simonsinol is a natural sesqui-neolignan firstly isolated from the bark of Illicium simonsii. In this study, the anti-inflammatory activity of simonsinol was investigated with a lipopolysaccharide (LPS)-stimulated murine macrophages RAW264.7 cells model. The results demonstrated that simonsinol could antagonize the effect of LPS on morphological changes of RAW264.7 cells, and decrease the production of nitric oxide (NO), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in LPS-stimulated RAW264.7 cells, as determined by Griess assay and enzyme-linked immunosorbent assay (ELISA). Furthermore, simonsinol could downregulate transcription of inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 as measured by reverse transcription polymerase chain reaction (RT-PCR), and inhibit phosphorylation of the alpha inhibitor of NF-κB (IκBα) as assayed by Western blot. In conclusion, these data demonstrate that simonsinol could inhibit inflammation response in LPS-stimulated RAW264.7 cells through the inactivation of the nuclear transcription factor kappa-B (NF-κB) signaling pathway. Full article

(This article belongs to the Special Issue Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III)

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Review

Jump to: Research, Other

16 pages, 2926 KiB

Open AccessReview

Inhibitory Role of Berberine, an Isoquinoline Alkaloid, on NLRP3 Inflammasome Activation for the Treatment of Inflammatory Diseases

by Paromita Sarbadhikary, Blassan P. George and Heidi Abrahamse

Molecules 2021, 26(20), 6238; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26206238 - 15 Oct 2021

Cited by 10 | Viewed by 2860

Abstract

The pyrin domain-containing multiprotein complex NLRP3 inflammasome, consisting of the NLRP3 protein, ASC adaptor, and procaspase-1, plays a vital role in the pathophysiology of several inflammatory disorders, including neurological and metabolic disorders, chronic inflammatory diseases, and cancer. Several phytochemicals act as promising anti-inflammatory [...] Read more.

The pyrin domain-containing multiprotein complex NLRP3 inflammasome, consisting of the NLRP3 protein, ASC adaptor, and procaspase-1, plays a vital role in the pathophysiology of several inflammatory disorders, including neurological and metabolic disorders, chronic inflammatory diseases, and cancer. Several phytochemicals act as promising anti-inflammatory agents and are usually regarded to have potential applications as complementary or alternative therapeutic agents against chronic inflammatory disorders. Various in vitro and in vivo studies have reported the anti-inflammatory role of berberine (BRB), an organic heteropentacyclic phytochemical and natural isoquinoline, in inhibiting NLRP3 inflammasome-dependent inflammation against many disorders. This review summarizes the mechanism and regulation of NLRP3 inflammasome activation and its involvement in inflammatory diseases, and discusses the current scientific evidence on the repressive role of BRB on NLRP3 inflammasome pathways along with the possible mechanism(s) and their potential in counteracting various inflammatory diseases. Full article

(This article belongs to the Special Issue Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III)

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10 pages, 1048 KiB

Open AccessReview

Therapeutic Potential of Resveratrol in COVID-19-Associated Hemostatic Disorders

by Roberta Giordo, Angelo Zinellu, Ali Hussein Eid and Gianfranco Pintus

Molecules 2021, 26(4), 856; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26040856 - 06 Feb 2021

Cited by 49 | Viewed by 6591

Abstract

Coagulation disorders, endotheliopathy and inflammation are the most common hallmarks in SARS-CoV-2 infection, largely determining COVID-19’s outcome and severity. Dysfunctions of endothelial cells and platelets are tightly linked in contributing to the systemic inflammatory response that appears to be both a cause and [...] Read more.

Coagulation disorders, endotheliopathy and inflammation are the most common hallmarks in SARS-CoV-2 infection, largely determining COVID-19’s outcome and severity. Dysfunctions of endothelial cells and platelets are tightly linked in contributing to the systemic inflammatory response that appears to be both a cause and a consequence of COVID-19-associated coagulation disorders and thrombotic events. Indeed, elevated levels of circulating inflammatory cytokines are often associated with abnormal coagulation parameters in COVID-19 patients. Although treatments with low molecular weight heparin (LMWH) have shown beneficial effects in decreasing patient mortality with severe COVID-19, additional therapeutic strategies are urgently needed. Utilizing the anti-inflammatory and anti-thrombotic properties of natural compounds may provide alternative therapeutic approaches to prevent or reduce the risk factors associated with pre-existing conditions and comorbidities that can worsen COVID-19 patients’ outcomes. In this regard, resveratrol, a natural compound found in several plants and fruits such as grapes, blueberries and cranberries, may represent a promising coadjuvant for the prevention and treatment of COVID-19. By virtue of its anti-thrombotic and anti-inflammatory properties, resveratrol would be expected to lower COVID-19-associated mortality, which is well known to be increased by thrombosis and inflammation. This review analyzes and discusses resveratrol’s ability to modulate vascular hemostasis at different levels targeting both primary hemostasis (interfering with platelet activation and aggregation) and secondary hemostasis (modulating factors involved in coagulation cascade). Full article

(This article belongs to the Special Issue Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III)

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Other

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11 pages, 504 KiB

Open AccessBrief Report

Iloprost Attenuates Oxidative Stress-Dependent Activation of Collagen Synthesis Induced by Sera from Scleroderma Patients in Human Pulmonary Microvascular Endothelial Cells

by Roberta Giordo, Duong Thi Bich Thuan, Anna Maria Posadino, Annalisa Cossu, Angelo Zinellu, Gian Luca Erre and Gianfranco Pintus

Molecules 2021, 26(16), 4729; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26164729 - 05 Aug 2021

Cited by 8 | Viewed by 2071

Abstract

Endothelial cell injury is an early event in systemic sclerosis (SSc) pathogenesis and several studies indicate oxidative stress as the trigger of SSc-associated vasculopathy. Here, we show that circulating factors present in sera of SSc patients increased reactive oxygen species (ROS) production and [...] Read more.

Endothelial cell injury is an early event in systemic sclerosis (SSc) pathogenesis and several studies indicate oxidative stress as the trigger of SSc-associated vasculopathy. Here, we show that circulating factors present in sera of SSc patients increased reactive oxygen species (ROS) production and collagen synthesis in human pulmonary microvascular endothelial cells (HPMECs). In addition, the possibility that iloprost, a drug commonly used in SSc therapy, might modulate the above-mentioned biological phenomena has been also investigated. In this regard, as compared to sera of SSc patients, sera of iloprost-treated SSc patients failed to increased ROS levels and collagen synthesis in HPMEC, suggesting a potential antioxidant mechanism of this drug. Full article

(This article belongs to the Special Issue Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry-III)

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