International Journal of Molecular Sciences

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17 pages, 5042 KiB

Open AccessArticle

Maytenus octogona Superoxide Scavenging and Anti-Inflammatory Caspase-1 Inhibition Study Using Cyclic Voltammetry and Computational Docking Techniques

by Francesco Caruso, Miriam Rossi, Eric Eberhardt, Molly Berinato, Raiyan Sakib, Felipe Surco-Laos and Haydee Chavez

Int. J. Mol. Sci. 2023, 24(13), 10750; https://doi.org/10.3390/ijms241310750 - 28 Jun 2023

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Abstract

The relationship between oxidative stress and inflammation is well known, and exogenous antioxidants, primarily phytochemical natural products, may assist the body’s endogenous defense systems in preventing diseases due to excessive inflammation. In this study, we evaluated the antioxidant properties of ethnomedicines from Peru [...] Read more.

The relationship between oxidative stress and inflammation is well known, and exogenous antioxidants, primarily phytochemical natural products, may assist the body’s endogenous defense systems in preventing diseases due to excessive inflammation. In this study, we evaluated the antioxidant properties of ethnomedicines from Peru that exhibit anti-inflammatory activity by measuring the superoxide scavenging activity of ethanol extracts of Maytenus octogona aerial parts using hydrodynamic voltammetry at a rotating ring-disk electrode (RRDE). The chemical compositions of these extracts are known and the interactions of three methide-quinone compounds found in Maytenus octogona with caspase-1 were analyzed using computational docking studies. Caspase-1 is a critical enzyme triggered during the activation of the inflammasome and its actions are associated with excessive release of cytokines. The most important amino acid involved in active site caspase-1 inhibition is Arg341 and, through docking calculations, we see that this amino acid is stabilized by interactions with the three potential methide-quinone Maytenus octogona inhibitors, hydroxytingenone, tingenone, and pristimerin. These findings were also confirmed after more rigorous molecular dynamics calculations. It is worth noting that, in these three compounds, the methide-quinone carbonyl oxygen is the preferred hydrogen bond acceptor site, although tingenone’s other carbonyl group also shows a similar binding energy preference. The results of these calculations and cyclovoltammetry studies support the effectiveness and use of anti-inflammatory ethnopharmacological ethanol extract of Maytenus octogona (L’Héritier) DC. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases)

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17 pages, 13840 KiB

Open AccessArticle

Lipid-Independent Regulation of PLIN5 via IL-6 through the JAK/STAT3 Axis in Hep3B Cells

by Marinela Krizanac, Paola Berenice Mass Sanchez, Sarah K. Schröder, Ralf Weiskirchen and Anastasia Asimakopoulos

Int. J. Mol. Sci. 2023, 24(8), 7219; https://doi.org/10.3390/ijms24087219 - 13 Apr 2023

Cited by 2 | Viewed by 2022

Abstract

Perilipin 5 (PLIN5) is a lipid droplet coat protein that is highly expressed in oxidative tissues such as those of muscles, the heart and the liver. PLIN5 expression is regulated by a family of peroxisome proliferator-activated receptors (PPARs) and modulated by the cellular [...] Read more.

Perilipin 5 (PLIN5) is a lipid droplet coat protein that is highly expressed in oxidative tissues such as those of muscles, the heart and the liver. PLIN5 expression is regulated by a family of peroxisome proliferator-activated receptors (PPARs) and modulated by the cellular lipid status. So far, research has focused on the role of PLIN5 in the context of non-alcoholic fatty liver disease (NAFLD) and specifically in lipid droplet formation and lipolysis, where PLIN5 serves as a regulator of lipid metabolism. In addition, there are only limited studies connecting PLIN5 to hepatocellular carcinoma (HCC), where PLIN5 expression is proven to be upregulated in hepatic tissue. Considering that HCC development is highly driven by cytokines present throughout NAFLD development and in the tumor microenvironment, we here explore the possible regulation of PLIN5 by cytokines known to be involved in HCC and NAFLD progression. We demonstrate that PLIN5 expression is strongly induced by interleukin-6 (IL-6) in a dose- and time-dependent manner in Hep3B cells. Moreover, IL-6-dependent PLIN5 upregulation is mediated by the JAK/STAT3 signaling pathway, which can be blocked by transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α). Furthermore, IL-6-mediated PLIN5 upregulation changes when IL-6 trans-signaling is stimulated through the addition of soluble IL-6R. In sum, this study sheds light on lipid-independent regulation of PLIN5 expression in the liver, making PLIN5 a crucial target for NAFLD-induced HCC. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases)

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18 pages, 4093 KiB

Open AccessArticle

Src-FAK Signaling Mediates Interleukin 6-Induced HCT116 Colorectal Cancer Epithelial–Mesenchymal Transition

by Yu-Han Huang, Han-Kun Chen, Ya-Fen Hsu, Hsiu-Chen Chen, Chin-Hui Chuang, Shiu-Wen Huang and Ming-Jen Hsu

Int. J. Mol. Sci. 2023, 24(7), 6650; https://doi.org/10.3390/ijms24076650 - 2 Apr 2023

Cited by 6 | Viewed by 1986

Abstract

Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival [...] Read more.

Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival outcomes. Although IL-6 is recognized as a potent inducer of colorectal cancer progression, the detail mechanisms underlying IL-6-induced colorectal cancer epithelial–mesenchymal transition (EMT), one of the major process of tumor metastasis, remain unclear. In the present study, we investigated the regulatory role of IL-6 signaling in colorectal cancer EMT using HCT116 human colorectal cancer cells. We noted that the expression of epithelial marker E-cadherin was reduced in HCT116 cells exposed to IL-6, along with the increase in a set of mesenchymal cell markers including vimentin and α-smooth muscle actin (α-SMA), as well as EMT transcription regulators—twist, snail and slug. The changes of EMT phenotype were related to the activation of Src, FAK, ERK1/2, p38 mitogen-activated protein kinase (p38MAPK), as well as transcription factors STAT3, κB and C/EBPβ. IL-6 treatment has promoted the recruitment of STAT3, κB and C/EBPβ toward the Twist promoter region. Furthermore, the Src-FAK signaling blockade resulted in the decline of IL-6 induced activation of ERK1/2, p38MAPK, κB, C/EBPβ and STAT3, as well as the decreasing mesenchymal state of HCT116 cells. These results suggested that IL-6 activates the Src-FAK-ERK/p38MAPK signaling cascade to cause the EMT of colorectal cancer cells. Pharmacological approaches targeting Src-FAK signaling may provide potential therapeutic strategies for rescuing colorectal cancer progression. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases)

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11 pages, 1943 KiB

Open AccessArticle

Asprosin Enhances Cytokine Production by a Co-Culture of Fully Differentiated Mature Adipocytes and Macrophages Leading to the Exacerbation of the Condition Typical of Obesity-Related Inflammation

by Agnieszka I. Mazur-Bialy

Int. J. Mol. Sci. 2023, 24(6), 5745; https://doi.org/10.3390/ijms24065745 - 17 Mar 2023

Cited by 4 | Viewed by 1423

Abstract

Asprosin, a fasting-induced, glucogenic, and orexigenic adipokine, has gained popularity in recent years as a potential target in the fight against obesity and its complications. However, the contribution of asprosin to the development of moderate obesity-related inflammation remains still unknown. The present study [...] Read more.

Asprosin, a fasting-induced, glucogenic, and orexigenic adipokine, has gained popularity in recent years as a potential target in the fight against obesity and its complications. However, the contribution of asprosin to the development of moderate obesity-related inflammation remains still unknown. The present study aimed to evaluate the effect of asprosin on the inflammatory activation of adipocyte–macrophage co-cultures at various stages of differentiation. The study was performed on co-cultures of the murine 3T3L1 adipocyte and the RAW264.7 macrophage cell lines treated with asprosin before, during, and after 3T3L1 cell differentiation, with or without lipopolysaccharide (LPS) stimulation. Cell viability, overall cell activity, and the expression and release of key inflammatory cytokines were analyzed. In the concentration range of 50–100 nM, asprosin increased the pro-inflammatory activity in the mature co-culture and enhanced the expression and release of tumor necrosis factor α (TNF-α), high-mobility group box protein 1 (HMGB1), and interleukin 6 (IL-6). Macrophage migration was also increased, which could be related to the upregulated expression and release of monocyte chemoattractant protein-1 (MCP-1) by the adipocytes. In summary, asprosin exerted a pro-inflammatory effect on the mature adipocyte–macrophage co-culture and may contribute to the spread of moderate obesity-associated inflammation. Nevertheless, further research is needed to fully elucidate this process. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases)

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9 pages, 596 KiB

Open AccessArticle

Can Baseline IL-6 Levels Predict Long COVID in Subjects Hospitalized for SARS-CoV-2 Disease?

by Lydia Giannitrapani, Luigi Mirarchi, Simona Amodeo, Anna Licata, Maurizio Soresi, Francesco Cavaleri, Salvatore Casalicchio, Gregorio Ciulla, Maria Elena Ciuppa, Melchiorre Cervello, Mario Barbagallo, Nicola Veronese and the COMEPA Group

Int. J. Mol. Sci. 2023, 24(2), 1731; https://doi.org/10.3390/ijms24021731 - 15 Jan 2023

Cited by 3 | Viewed by 2000

Abstract

The immune response to infection plays a crucial role in the pathogenesis of COVID-19, but several patients develop a wide range of persistent symptoms, which is becoming a major global health and economic burden. However, reliable indicators are not yet available to predict [...] Read more.

The immune response to infection plays a crucial role in the pathogenesis of COVID-19, but several patients develop a wide range of persistent symptoms, which is becoming a major global health and economic burden. However, reliable indicators are not yet available to predict the persistence of symptoms typical of the so-called long COVID. Our study aims to explore an eventual role of IL-6 levels as a marker of long COVID. Altogether, 184 patients admitted to the COVID Medicine Unit of the University Hospital in Palermo, Italy, from the 1st of September 2020, were analyzed. Patients were divided into two groups according to the IL-6 serum levels (normal or elevated), considering the serum IL-6 levels measured during the first four days of hospitalization. In our study, higher serum IL-6 levels were associated with a doubled higher risk of long COVID (OR = 2.05; 95% CI: 1.04–4.50) and, in particular, they were associated with a higher incidence of mobility decline (OR = 2.55; 95% CI: 1.08–9.40) and PTSD (OR = 2.38; 95% CI: 1.06–8.61). The analysis of our case series confirmed the prominent role of IL-6 levels in response to SARS-CoV-2 infection, as predictors not only of COVID-19 disease severity and unfavorable outcomes, but also long COVID development trends. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases)

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Review

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16 pages, 1666 KiB

Open AccessReview

Glycine: The Smallest Anti-Inflammatory Micronutrient

by Karla Aidee Aguayo-Cerón, Fausto Sánchez-Muñoz, Rocío Alejandra Gutierrez-Rojas, Lourdes Nallely Acevedo-Villavicencio, Aurora Vanessa Flores-Zarate, Fengyang Huang, Abraham Giacoman-Martinez, Santiago Villafaña and Rodrigo Romero-Nava

Int. J. Mol. Sci. 2023, 24(14), 11236; https://doi.org/10.3390/ijms241411236 - 8 Jul 2023

Cited by 2 | Viewed by 3969

Abstract

Glycine is a non-essential amino acid with many functions and effects. Glycine can bind to specific receptors and transporters that are expressed in many types of cells throughout an organism to exert its effects. There have been many studies focused on the anti-inflammatory [...] Read more.

Glycine is a non-essential amino acid with many functions and effects. Glycine can bind to specific receptors and transporters that are expressed in many types of cells throughout an organism to exert its effects. There have been many studies focused on the anti-inflammatory effects of glycine, including its abilities to decrease pro-inflammatory cytokines and the concentration of free fatty acids, to improve the insulin response, and to mediate other changes. However, the mechanism through which glycine acts is not clear. In this review, we emphasize that glycine exerts its anti-inflammatory effects throughout the modulation of the expression of nuclear factor kappa B (NF-κB) in many cells. Although glycine is a non-essential amino acid, we highlight how dietary glycine supplementation is important in avoiding the development of chronic inflammation. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases)

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23 pages, 1818 KiB

Open AccessReview

The Role of IL-23 in the Pathogenesis and Therapy of Inflammatory Bowel Disease

by Aleksandra Korta, Julia Kula and Krzysztof Gomułka

Int. J. Mol. Sci. 2023, 24(12), 10172; https://doi.org/10.3390/ijms241210172 - 15 Jun 2023

Cited by 5 | Viewed by 4363

Abstract

Interleukin-23 (IL-23) is a proinflammatory cytokine produced mainly by macrophages and antigen-presenting cells (APCs) after antigenic stimulation. IL-23 plays a significant role as a mediator of tissue damage. Indeed, the irregularities in IL-23 and its receptor signaling have been implicated in inflammatory bowel [...] Read more.

Interleukin-23 (IL-23) is a proinflammatory cytokine produced mainly by macrophages and antigen-presenting cells (APCs) after antigenic stimulation. IL-23 plays a significant role as a mediator of tissue damage. Indeed, the irregularities in IL-23 and its receptor signaling have been implicated in inflammatory bowel disease. IL-23 interacts with both the innate and adaptive immune systems, and IL-23/Th17 appears to be involved in the development of chronic intestinal inflammation. The IL-23/Th17 axis may be a critical driver of this chronic inflammation. This review summarizes the main aspects of IL-23’s biological function, cytokines that control cytokine production, effectors of the IL-23 response, and the molecular mechanisms associated with IBD pathogenesis. Although IL-23 modulates and impacts the development, course, and recurrence of the inflammatory response, the etiology and pathophysiology of IBD are not completely understood, but mechanism research shows huge potential for clinical applications as therapeutic targets in IBD treatment. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases)

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12 pages, 2114 KiB

Open AccessReview

Molecular Mechanisms Underlying IL-33-Mediated Inflammation in Inflammatory Bowel Disease

by Ioanna Aggeletopoulou, Efthymios P. Tsounis and Christos Triantos

Int. J. Mol. Sci. 2023, 24(1), 623; https://doi.org/10.3390/ijms24010623 - 30 Dec 2022

Cited by 8 | Viewed by 2324

Abstract

Interleukin-33 (IL-33) is a cytokine defined by its pleiotropic function, acting either as a typical extracellular cytokine or as a nuclear transcription factor. IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), interact with both innate and adaptive immunity and are considered critical [...] Read more.

Interleukin-33 (IL-33) is a cytokine defined by its pleiotropic function, acting either as a typical extracellular cytokine or as a nuclear transcription factor. IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), interact with both innate and adaptive immunity and are considered critical regulators of inflammatory disorders. The IL-33/ST2 axis is involved in the maintenance of intestinal homeostasis; on the basis of their role as pro- or anti-inflammatory mediators of first-line innate immunity, their expression is of great importance in regard to mucosal defenses. Mucosal immunity commonly presents an imbalance in inflammatory bowel disease (IBD). This review summarizes the main cellular and molecular aspects of IL-33 and ST2, mainly focusing on the current evidence of the pro- and anti-inflammatory effects of the IL-33/ST2 axis in the course of ulcerative colitis and Crohn’s disease, as well as the molecular mechanisms underlying the association of IL-33/ST2 signaling in IBD pathogenesis. Although IL-33 modulates and impacts the development, course, and recurrence of the inflammatory response, the exact role of this molecule is elusive, and it seems to be associated with the subtype of the disease or the disease stage. Unraveling of IL-33/ST2-mediated mechanisms involved in IBD pathology shows great potential for clinical application as therapeutic targets in IBD treatment. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases)

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