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15 pages, 3102 KiB

Open AccessArticle

Inhibitory Effect of Periodontitis through C/EBP and 11β-Hydroxysteroid Dehydrogenase Type 1 Regulation of Betulin Isolated from the Bark of Betula platyphylla

by Eun-Nam Kim and Gil-Saeng Jeong

Pharmaceutics 2022, 14(9), 1868; https://doi.org/10.3390/pharmaceutics14091868 - 5 Sep 2022

Cited by 1 | Viewed by 1757

Abstract

Periodontitis is an infectious inflammatory disease of the tissues around the tooth that destroys connective tissue and is characterized by loss of periodontal ligaments and alveolar bone. Currently, surgical methods for the treatment of periodontitis have limitations and new treatment strategies are needed. [...] Read more.

Periodontitis is an infectious inflammatory disease of the tissues around the tooth that destroys connective tissue and is characterized by loss of periodontal ligaments and alveolar bone. Currently, surgical methods for the treatment of periodontitis have limitations and new treatment strategies are needed. Therefore, this study evaluated the efficacy of the compound betulin isolated from bark of Betula platyphylla on the inhibition of periodontitis in vitro and in vivo periodontitis induction models. In the study, betulin inhibited pro-inflammatory mediators, such as tumor necrosis factor, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2, in human periodontal ligament cells stimulated with Porphyromonas gingivalis lipopolysaccharide (PG-LPS). In addition, it showed an anti-inflammatory effect by down-regulating 11β-hydroxysteroid dehydrogenase type 1 and transcription factor C/EBP β produced by PG-LPS. Moreover, PG-LPS inhibited the osteogenic induction of human periodontal ligament cells. The protein and mRNA levels of osteogenic markers, such as inhibited osteopontin (OPN) and runt-related transcription factor 2 (RUNX2), were regulated by betulin. In addition, the efficacy of betulin was demonstrated in a typical in vivo model of periodontitis induced by PG-LPS, and the results showed through hematoxylin & eosin staining and micro-computed tomography that the administration of betulin alleviated alveolar bone loss and periodontal inflammation caused by PG-LPS. Therefore, this study proved the efficacy of the compound betulin isolated from B. platyphylla in the inhibition of periodontitis and alveolar bone loss, two important strategies for the treatment of periodontitis, suggesting the potential as a new treatment for periodontitis. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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15 pages, 2667 KiB

Open AccessArticle

Lung-Targeted Delivery of Cepharanthine by an Erythrocyte-Anchoring Strategy for the Treatment of Acute Lung Injury

by Jinpeng Zheng, Caihong Lu, Meiyan Yang, Jiejie Sun, Jinbang Zhang, Yuanyuan Meng, Yuli Wang, Zhiping Li, Yang Yang, Wei Gong and Chunsheng Gao

Pharmaceutics 2022, 14(9), 1820; https://doi.org/10.3390/pharmaceutics14091820 - 29 Aug 2022

Cited by 6 | Viewed by 1904

Abstract

As one of the most frequent complications of critical illness, acute lung injury (ALI) carries a high risk of clinical morbidity and mortality. Cepharanthine (CPA) has significant anti-inflammatory activity, however, due to poor water solubility, low bioavailability, and short half-life, it fails to [...] Read more.

As one of the most frequent complications of critical illness, acute lung injury (ALI) carries a high risk of clinical morbidity and mortality. Cepharanthine (CPA) has significant anti-inflammatory activity, however, due to poor water solubility, low bioavailability, and short half-life, it fails to provide effective clinical management measures. Here, we explored the flexibility of an erythrocyte-anchoring strategy using CPA-encapsulated chitosan-coating nanoparticles (CPA-CNPs) anchored onto circulating erythrocytes for the treatment of ALI. CPA-CNPs adhered to erythrocytes successfully (E-CPA-CNPs) and exhibited high erythrocyte adhesion efficiency (>80%). Limited toxicity and favorable biocompatibility enabled further application of E-CPA-CNPs. Next, the reticuloendothelial system evasion features were analyzed in RAW264.7 macrophages and Sprague-Dawley rats. Compared with bare CPA-CNPs, erythrocyte-anchored CNPs significantly decreased cellular uptake in immune cells and prolonged circulation time in vivo. Notably, the erythrocyte-anchoring strategy enabled CNPs to be delivered and accumulated in the lungs (up to 6-fold). In the ALI mouse model, E-CPA-CNPs attenuated the progression of ALI by inhibiting inflammatory responses. Overall, our results demonstrate the outstanding advantages of erythrocyte-anchored CPA-CNPs in improving the pharmacokinetics and bioavailability of CPA, which offers great promise for a lung-targeted drug delivery system for the effective treatment of ALI. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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19 pages, 4094 KiB

Open AccessArticle

Cinnamic Acid Attenuates Peripheral and Hypothalamic Inflammation in High-Fat Diet-Induced Obese Mice

by Aden Geonhee Lee, Sora Kang, Suyeol Im and Youngmi Kim Pak

Pharmaceutics 2022, 14(8), 1675; https://doi.org/10.3390/pharmaceutics14081675 - 11 Aug 2022

Cited by 11 | Viewed by 3150

Abstract

Obesity is closely linked to chronic inflammation in peripheral organs and the hypothalamus. Chronic consumption of a high-fat diet (HFD) induces the differentiation of Ly6c^high monocytes into macrophages in adipose tissue, the liver, and the brain, as well as the secretion of [...] Read more.

Obesity is closely linked to chronic inflammation in peripheral organs and the hypothalamus. Chronic consumption of a high-fat diet (HFD) induces the differentiation of Ly6c^high monocytes into macrophages in adipose tissue, the liver, and the brain, as well as the secretion of pro-inflammatory cytokines. Although cinnamon improves obesity and related diseases, it is unclear which components of cinnamon can affect macrophages and inflammatory cytokines. We performed in silico analyses using ADME, drug-likeness, and molecular docking simulations to predict the active compounds of cinnamon. Among the 82 active compounds of cinnamon, cinnamic acid (CA) showed the highest score of ADME, blood–brain barrier permeability, drug-likeness, and cytokine binding. We then investigated whether CA modulates obesity-induced metabolic profiles and macrophage-related inflammatory responses in HFD-fed mice. While HFD feeding induced obesity, CA ameliorated obesity and related symptoms, such as epididymal fat gain, insulin resistance, glucose intolerance, and dyslipidemia, without hepatic and renal toxicity. CA also improved HFD-induced tumor necrosis factor-α, fat deposition, and macrophage infiltration in the liver and adipose tissue. CA decreased Ly6c^high monocytes, adipose tissue M1 macrophages, and hypothalamic microglial activation. These results suggest that CA attenuates the peripheral and hypothalamic inflammatory monocytes/macrophage system and treats obesity-related metabolic disorders. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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19 pages, 5341 KiB

Open AccessArticle

Evaluation of the Cytotoxic, Anti-Inflammatory, and Immunomodulatory Effects of Withaferin A (WA) against Lipopolysaccharide (LPS)-Induced Inflammation in Immune Cells Derived from BALB/c Mice

by Abdullah M. Alnuqaydan, Abdulmajeed Almutary, Gh Rasool Bhat, Tanveer Ahmad Mir, Shadil Ibrahim Wani, Mohd Younis Rather, Shabir Ahmad Mir, Bader Alshehri, Sulaiman Alnasser, Faten M. Ali Zainy and Bilal Rah

Pharmaceutics 2022, 14(6), 1256; https://doi.org/10.3390/pharmaceutics14061256 - 13 Jun 2022

Cited by 8 | Viewed by 3105

Abstract

(1) Background: Inflammation is one of the primary responses of the immune system and plays a key role in the pathophysiology of various diseases. Recent reports suggest that various phytochemicals exhibit promising anti-inflammatory and immunomodulation activities with relatively few undesirable effects, thus offering [...] Read more.

(1) Background: Inflammation is one of the primary responses of the immune system and plays a key role in the pathophysiology of various diseases. Recent reports suggest that various phytochemicals exhibit promising anti-inflammatory and immunomodulation activities with relatively few undesirable effects, thus offering a viable option to deal with inflammation and associated diseases. The current study evaluates the anti-inflammatory and immunomodulatory effects of withaferin A (WA) in immune cells extracted from BALB/c mice. (2) Methods: MTT assays were performed to assess the cell viability of splenocytes and anti-inflammatory doses of WA. Under aseptic conditions, the isolation of macrophages and splenocytes from BALB/c mice was performed to investigate the anti-inflammatory effects of WA. Analysis of the expression of proinflammatory cytokines and associated signaling mediators was performed using proinflammatory assay kits, real-time polymerase chain reaction (RT-PCR), and immunoblotting, while the quantification of B and T cells was performed by flow cytometry. (3) Results: Our results demonstrated that WA exhibits anti-inflammatory and immunomodulatory effects in LPS-stimulated macrophages and splenocytes derived from BALB/c mice, respectively. Mechanistically, we found that WA promotes an anti-inflammatory effect on LPS-stimulated macrophages by attenuating the secretion and expression of proinflammatory cytokines TNF-α, IL-1β, IL-6, and the inflammation modulator NO, both at the transcriptional and translational level, respectively. Further, WA inhibits LPS-stimulated inflammatory signaling by dephosphorylation of p-Akt-Ser473 and p-ERK1/2. This dephosphorylation does not allow IĸB-kinase activation to disrupt IĸB–NF-ĸB interaction. The consistent interaction of IĸB with NF-ĸB in WA-treated cells attenuates the activation of downstream inflammatory signaling mediators Cox-2 and iNOS expression, which play crucial roles in inflammatory signaling. Additionally, we observed significant immunomodulation of LPS-stimulated spleen-derived lymphocytes by suppression of B (CD19) and T (CD4⁺/CD8⁺) cell populations after treatment with WA. (4) Conclusion: WA exhibits anti-inflammatory and immunomodulatory activity by modulating Akt/ERK/NF-kB-mediated inflammatory signaling in macrophages and immunosuppression of B (CD19) and T cell (CD4⁺/CD8⁺) populations in splenocytes after LPS stimulation. These results suggest that WA could act as a potential anti-inflammatory/immunomodulatory molecule and support its use in the field of immunopharmacology to modulate immune system cells. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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26 pages, 4601 KiB

Open AccessArticle

Immunomodulatory Properties of Pomegranate Peel Extract in a Model of Human Peripheral Blood Mononuclear Cell Culture

by Miodrag Čolić, Marina Bekić, Sergej Tomić, Jelena Đokić, Dušan Radojević, Katarina Šavikin, Nataša Miljuš, Milan Marković and Ranko Škrbić

Pharmaceutics 2022, 14(6), 1140; https://doi.org/10.3390/pharmaceutics14061140 - 27 May 2022

Cited by 10 | Viewed by 2941

Abstract

Pomegranate peel extract (PoPEx) has been shown to have antioxidant and anti-inflammatory properties, but its effect on the adaptive immune system has not been sufficiently investigated. In this study, the treatment of human peripheral blood mononuclear cells (PBMC) with PoPEx (range 6.25–400 µg/mL) [...] Read more.

Pomegranate peel extract (PoPEx) has been shown to have antioxidant and anti-inflammatory properties, but its effect on the adaptive immune system has not been sufficiently investigated. In this study, the treatment of human peripheral blood mononuclear cells (PBMC) with PoPEx (range 6.25–400 µg/mL) resulted in cytotoxicity at concentrations of 100 µg/mL and higher, due to the induction of apoptosis and oxidative stress, whereas autophagy was reduced. At non-cytotoxic concentrations, the opposite effect on these processes was observed simultaneously with the inhibition of PHA-induced PBMC proliferation and a significant decrease in the expression of CD4. PoPEx differently modulated the expression of activation markers (CD69, CD25, ICOS) and PD1 (inhibitory marker), depending on the dose and T-cell subsets. PoPEx (starting from 12.5 µg/mL) suppressed the production of Th1 (IFN-γ), Th17 (IL-17A, IL-17F, and IL-22), Th9 (IL-9), and proinflammatory cytokines (TNF-α and IL-6) in culture supernatants. Lower concentrations upregulated Th2 (IL-5 and IL-13) and Treg (IL-10) responses as well as CD4+CD25hiFoxp3+ cell frequency. Higher concentrations of PoPEx increased the frequency of IL-10- and TGF-β-producing T-cells (much higher in the CD4+ subset). In conclusion, our study suggested for the first time complex immunoregulatory effects of PoPEx on T cells, which could assist in the suppression of chronic inflammatory and autoimmune diseases. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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11 pages, 1906 KiB

Open AccessArticle

Anti-Inflammatory Effect of Vanillin Protects the Stomach against Ulcer Formation

by Murilo Piologo Ciciliato, Matheus Chiaradia de Souza, Carolina Mendes Tarran, Ana Laura Tironi de Castilho, Ana Júlia Vieira and Ariane Leite Rozza

Pharmaceutics 2022, 14(4), 755; https://doi.org/10.3390/pharmaceutics14040755 - 30 Mar 2022

Cited by 22 | Viewed by 2985

Abstract

Gastric ulcer is one of the most frequent gastrointestinal disorders, and there is an increasing search for natural products that can heal ulcers and avoid their recurrence. We aimed to evaluate the gastroprotective activity of vanillin, including the investigation of anti-inflammatory activity and [...] Read more.

Gastric ulcer is one of the most frequent gastrointestinal disorders, and there is an increasing search for natural products that can heal ulcers and avoid their recurrence. We aimed to evaluate the gastroprotective activity of vanillin, including the investigation of anti-inflammatory activity and the modulation of gene expression. Wistar rats were orally treated with vehicle, carbenoxolone, or vanillin (25, 50, or 100 mg/kg) and orally received absolute ethanol to develop gastric ulcers. We analyzed the ulcer area, conducted histological analysis, and measured the levels of the inflammatory cytokines TNF-α, IL-6, IL-1β, and IFN-γ, and anti-inflammatory cytokine IL-10 by ELISA. We analyzed mRNA expression for NF-κB, TNF-α, and Il-10. We measured NOx levels using the Griess reaction. Our results showed similar gastroprotection for the three doses. Vanillin increased mucus production and preserved gastric mucosa integrity. The gastroprotective effect was linked to anti-inflammatory activity as a result of decreasing the levels of TNF-α, IL-6, IL-1β, and IFN-γ and increasing IL-10 levels. Vanillin downregulated the mRNA expression of NF-κB and TNF-α, upregulated the mRNA expression of Il-10, and increased NOx levels in the stomach. The gastroprotective activity of vanillin is related to the maintenance of gastric mucus and the local inflammatory response modulation. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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25 pages, 6489 KiB

Open AccessArticle

Relationship between Hormonal Modulation and Gastroprotective Activity of Malvidin and Cyanidin Chloride: In Vivo and In Silico Approach

by Melina Luzzi Zarricueta, Felipe Leonardo Fagundes, Quélita Cristina Pereira, Simone Queiroz Pantaleão and Raquel de Cássia dos Santos

Pharmaceutics 2022, 14(3), 565; https://doi.org/10.3390/pharmaceutics14030565 - 4 Mar 2022

Cited by 2 | Viewed by 2454

Abstract

Peptic ulcers are lesions that affect the gastrointestinal tract and that can be triggered by external factors such as alcohol use. This study investigated the gastroprotective role of two anthocyanidins, malvidin and cyanidin chloride, in an ethanol-induced gastric ulcer model in male and [...] Read more.

Peptic ulcers are lesions that affect the gastrointestinal tract and that can be triggered by external factors such as alcohol use. This study investigated the gastroprotective role of two anthocyanidins, malvidin and cyanidin chloride, in an ethanol-induced gastric ulcer model in male and female mice (ovariectomized and supplemented with 17β-estradiol or not) and aimed to evaluate the effectiveness of anthocyanidins in preventing the formation of lesions and to identify the underlying mechanisms, while considering hormonal differences. Moreover, in silico comparative analysis was performed to predict the properties and biological behaviors of the molecules. We observed that the hormonal status did not interfere with the gastroprotective action of malvidin, although antioxidant mechanisms were modulated differently depending on sex. On the other hand, cyanidin showed gastroprotective activity at different doses, demonstrating that, for the same experimental model, there is a need to adjust the effective dose depending on sex. In silico analysis showed that, despite being structurally similar, the interaction with receptors and target proteins in this study (myeloperoxidase, superoxide dismutase, catalase, and reduced glutathione) differed between the two molecules, which explains the difference observed in in vivo treatments. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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19 pages, 5096 KiB

Open AccessFeature PaperArticle

Exploring the Potential Effects and Mechanisms of Asarum sieboldii Radix Essential Oil for Treatment of Asthma

by Jae Min Han, Mi Hye Kim, La Yoon Choi, Gyeongsang Kim and Woong Mo Yang

Pharmaceutics 2022, 14(3), 558; https://doi.org/10.3390/pharmaceutics14030558 - 3 Mar 2022

Cited by 13 | Viewed by 2662

Abstract

Asthma, a common chronic pulmonary disorder characterized by airway remodeling, hyperresponsiveness and obstruction, can be aggravated by repeated exposure to particulate matter (PM). The potential effect and mechanisms of Asarum sieboldii Radix essential oil (AEO) against asthma were explored based on network pharmacology. [...] Read more.

Asthma, a common chronic pulmonary disorder characterized by airway remodeling, hyperresponsiveness and obstruction, can be aggravated by repeated exposure to particulate matter (PM). The potential effect and mechanisms of Asarum sieboldii Radix essential oil (AEO) against asthma were explored based on network pharmacology. AEO was pre-treated using a nebulizer for 3 weeks and the mice were sensitized to ovalbumin (OVA) and PM₁₀ with the co-treatment of AEO for 4 weeks. In addition, A549 lung epithelial cells were sensitized with PM₁₀ to investigate the underlying mechanisms of AEO regarding the lung-fibrosis-related mediators. The target genes of methyl eugenol, a main compound of AEO, were highly matched by 48% with the gene set of asthma. AEO markedly inhibited the increase in epithelial thickness through the accumulation of goblet cells in the airways. Collagen deposition in the lung tissues of OVA+PM₁₀-challenged asthmatic mice was significantly decreased by AEO. AEO also inhibited the influx of inflammatory cells in the bronchoalveolar lavage fluid, as well as the increases in serum IgE and IgG_2a and cytokines in the lung tissues. Furthermore, AEO regulated the expressions of fibrotic mediators, especially POSTN and TGF-β. In conclusion, we expect that AEO can be one of the effective alternative therapeutics to relieve asthma. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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11 pages, 2271 KiB

Open AccessCommunication

Gallic Acid as a Non-Selective Inhibitor of α/β-Hydrolase Fold Enzymes Involved in the Inflammatory Process: The Two Sides of the Same Coin

by Marcos Hikari Toyama, Airam Rogero, Laila Lucyane Ferreira de Moraes, Gustavo Antônio Fernandes, Caroline Ramos da Cruz Costa, Mariana Novo Belchor, Agatha Manzi De Carli and Marcos Antônio de Oliveira

Pharmaceutics 2022, 14(2), 368; https://doi.org/10.3390/pharmaceutics14020368 - 6 Feb 2022

Cited by 5 | Viewed by 2345

Abstract

(1) Background: Gallic acid (GA) has been characterized as an effective anti-inflammatory, antivenom, and promising drug for therapeutic use. (2/3) Methods and Results: GA was identified from ethanolic extract of fresh pitanga (Eugenia uniflora) leaves, which was identified using commercial GA. [...] Read more.

(1) Background: Gallic acid (GA) has been characterized as an effective anti-inflammatory, antivenom, and promising drug for therapeutic use. (2/3) Methods and Results: GA was identified from ethanolic extract of fresh pitanga (Eugenia uniflora) leaves, which was identified using commercial GA. Commercial GA neutralized the enzymatic activity of secretory PLA2 (sPLA2) by inhibiting the active site and inducing changes in the secondary structure of the enzyme. Pharmacological edema assays showed that GA strongly decreased edema when the compound was previously incubated with sPLA2. However, prior treatment of GA (30 min before) significantly increased the edema and myotoxicity induced by sPLA2. The molecular docking results of GA with platelet-acetylhydrolase (PAF-AH) and acetylcholinesterase reveal that this compound was able to interact with the active site of both molecules, inhibiting the hydrolysis of platelet-activating factor (PAF) and acetylcholine (ACh). (4) Conclusion: GA has a great potential application; however, our results show that this compound can also induce adverse effects in previously treated animals. Additionally, the increased edema and myotoxicity observed experimentally in GA-treated animals may be due to the inhibition of PAF-AH and Acetylcholinesterase. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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24 pages, 4572 KiB

Open AccessArticle

Quercetin Liposomal Nanoformulation for Ischemia and Reperfusion Injury Treatment

by Margarida Ferreira-Silva, Catarina Faria-Silva, Manuela C. Carvalheiro, Sandra Simões, H. Susana Marinho, Paulo Marcelino, Maria Celeste Campos, Josbert M. Metselaar, Eduarda Fernandes, Pedro V. Baptista, Alexandra R. Fernandes and Maria Luísa Corvo

Pharmaceutics 2022, 14(1), 104; https://doi.org/10.3390/pharmaceutics14010104 - 3 Jan 2022

Cited by 19 | Viewed by 3115

Abstract

Ischemia and reperfusion injury (IRI) is a common complication caused by inflammation and oxidative stress resulting from liver surgery. Current therapeutic strategies do not present the desirable efficacy, and severe side effects can occur. To overcome these drawbacks, new therapeutic alternatives are necessary. [...] Read more.

Ischemia and reperfusion injury (IRI) is a common complication caused by inflammation and oxidative stress resulting from liver surgery. Current therapeutic strategies do not present the desirable efficacy, and severe side effects can occur. To overcome these drawbacks, new therapeutic alternatives are necessary. Drug delivery nanosystems have been explored due to their capacity to improve the therapeutic index of conventional drugs. Within nanocarriers, liposomes are one of the most successful, with several formulations currently in the market. As improved therapeutic outcomes have been demonstrated by using liposomes as drug carriers, this nanosystem was used to deliver quercetin, a flavonoid with anti-inflammatory and antioxidant properties, in hepatic IRI treatment. In the present work, a stable quercetin liposomal formulation was developed and characterized. Additionally, an in vitro model of ischemia and reperfusion was developed with a hypoxia chamber, where the anti-inflammatory potential of liposomal quercetin was evaluated, revealing the downregulation of pro-inflammatory markers. The anti-inflammatory effect of quercetin liposomes was also assessed in vivo in a rat model of hepatic IRI, in which a decrease in inflammation markers and enhanced recovery were observed. These results demonstrate that quercetin liposomes may provide a significant tool for addressing the current bottlenecks in hepatic IRI treatment. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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12 pages, 3262 KiB

Open AccessArticle

The Use of Menthol in Skin Wound Healing—Anti-Inflammatory Potential, Antioxidant Defense System Stimulation and Increased Epithelialization

by Ariane Leite Rozza, Fernando Pereira Beserra, Ana Júlia Vieira, Eduardo Oliveira de Souza, Carlos Alberto Hussni, Emanuel Ricardo Monteiro Martinez, Rafael Henrique Nóbrega and Cláudia Helena Pellizzon

Pharmaceutics 2021, 13(11), 1902; https://doi.org/10.3390/pharmaceutics13111902 - 9 Nov 2021

Cited by 28 | Viewed by 8056

Abstract

Wound healing involves inflammatory, proliferative, and remodeling phases, in which various cells and chemical intermediates are involved. This study aimed to investigate the skin wound healing potential of menthol, as well as the mechanisms involved in its effect, after 3, 7, or 14 [...] Read more.

Wound healing involves inflammatory, proliferative, and remodeling phases, in which various cells and chemical intermediates are involved. This study aimed to investigate the skin wound healing potential of menthol, as well as the mechanisms involved in its effect, after 3, 7, or 14 days of treatment, according to the phases of wound healing. Skin wound was performed in the back of Wistar rats, which were topically treated with vehicle cream; collagenase-based cream (1.2 U/g); or menthol-based cream at 0.25%, 0.5%, or 1.0% over 3, 7, or 14 days. Menthol cream at 0.5% accelerated the healing right from the inflammatory phase (3 days) by decreasing mRNA expression of inflammatory cytokines TNF-α and Il-6. At the proliferative phase (7 days), menthol 0.5% increased the activity of antioxidant enzymes SOD, GR, and GPx, as well as the level of GSH, in addition to decreasing the levels of inflammatory cytokines TNF-α, IL-6, and IL-1β and augmenting mRNA expression for Ki-67, a marker of cellular proliferation. At the remodeling phase (14 days), levels of inflammatory cytokines were decreased, and the level of Il-10 and its mRNA expression were increased in the menthol 0.5% group. Menthol presented skin wound healing activity by modulating the antioxidant system of the cells and the inflammatory response, in addition to stimulating epithelialization. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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14 pages, 9691 KiB

Open AccessArticle

Artepillin C Reduces Allergic Airway Inflammation by Induction of Monocytic Myeloid-Derived Suppressor Cells

by Núbia Sabrina Martins, Thais Fernanda de Campos Fraga-Silva, Giseli Furlan Correa, Mèdéton Mahoussi Michaël Boko, Leandra Naira Zambelli Ramalho, Débora Munhoz Rodrigues, Juliana Issa Hori, Diego Luis Costa, Jairo Kenupp Bastos and Vânia Luiza Deperon Bonato

Pharmaceutics 2021, 13(11), 1763; https://doi.org/10.3390/pharmaceutics13111763 - 22 Oct 2021

Cited by 6 | Viewed by 3010

Abstract

Propolis is a natural product produced by bees that is primarily used in complementary and alternative medicine and has anti-inflammatory, antibacterial, antiviral, and antitumoral biological properties. Some studies have reported the beneficial effects of propolis in models of allergic asthma. In a previous [...] Read more.

Propolis is a natural product produced by bees that is primarily used in complementary and alternative medicine and has anti-inflammatory, antibacterial, antiviral, and antitumoral biological properties. Some studies have reported the beneficial effects of propolis in models of allergic asthma. In a previous study, our group showed that green propolis treatment reduced airway inflammation and mucus secretion in an ovalbumin (OVA)-induced asthma model and resulted in increased regulatory T cells (Treg) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) frequencies in the lungs, two leukocyte populations that have immunosuppressive functions. In this study, we evaluated the anti-inflammatory effects of artepillin C (ArtC), the major compound of green propolis, in the context of allergic airway inflammation. Our results show that ArtC induces in vitro differentiation of Treg cells and monocytic MDSC (M-MDSC). Furthermore, in an OVA-induced asthma model, ArtC treatment reduced pulmonary inflammation, eosinophil influx to the airways, mucus and IL-5 secretion along with increased frequency of M-MDSC, but not Treg cells, in the lungs. Using an adoptive transfer model, we confirmed that the effect of ArtC in the reduction in airway inflammation was dependent on M-MDSC. Altogether, our data show that ArtC exhibits an anti-inflammatory effect and might be an adjuvant therapy for allergic asthma. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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14 pages, 1501 KiB

Open AccessArticle

Synthesis and Biochemical Evaluation of Baicalein Prodrugs

by Sang-Hyun Son, Jinhong Kang, Myunghwan Ahn, Soyeon Nam, Yong Woo Jung, Ki Yong Lee, Young Ho Jeon, Youngjoo Byun and Kiho Lee

Pharmaceutics 2021, 13(9), 1516; https://doi.org/10.3390/pharmaceutics13091516 - 19 Sep 2021

Cited by 9 | Viewed by 3617

Abstract

Baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one), a flavonoid analog from Scutellaria baicalensis, possesses several pharmacological activities including antioxidant, antiproliferative, and anti-inflammatory activities. We previously reported that baicalein inhibits the thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) signaling pathways and can be used as an active ingredient in [...] Read more.

Baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one), a flavonoid analog from Scutellaria baicalensis, possesses several pharmacological activities including antioxidant, antiproliferative, and anti-inflammatory activities. We previously reported that baicalein inhibits the thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) signaling pathways and can be used as an active ingredient in the treatment of asthma and atopic dermatitis. However, baicalein is rapidly metabolized to baicalin and baicalein-6-O-glucuronide in vivo, which limits its preclinical and clinical use. In this study, we designed, synthesized, and evaluated baicalein prodrugs that protect the OH group at the 7-position of the A ring in baicalein with the amino acid carbamate functional group. Comprehensive in vitro and in vivo studies identified compound 2 as a baicalein prodrug candidate that improved the plasma exposure of baicalein in mouse animal studies. Our results demonstrated that this prodrug approach could be further adopted to discover oral baicalein prodrugs. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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14 pages, 2049 KiB

Open AccessArticle

Gancaonin N from Glycyrrhiza uralensis Attenuates the Inflammatory Response by Downregulating the NF-κB/MAPK Pathway on an Acute Pneumonia In Vitro Model

by Hyun Min Ko, Seung-Hyeon Lee, Wona Jee, Ji Hoon Jung, Kwan-Il Kim, Hee-Jae Jung and Hyeung-Jin Jang

Pharmaceutics 2021, 13(7), 1028; https://doi.org/10.3390/pharmaceutics13071028 - 6 Jul 2021

Cited by 16 | Viewed by 3374

Abstract

Acute pneumonia is an inflammatory disease caused by several pathogens, with symptoms such as fever and chest pain, to which children are particularly vulnerable. Gancaonin N is a prenylated isoflavone of Glycyrrhiza uralensis that has been used in the treatment of various diseases [...] Read more.

Acute pneumonia is an inflammatory disease caused by several pathogens, with symptoms such as fever and chest pain, to which children are particularly vulnerable. Gancaonin N is a prenylated isoflavone of Glycyrrhiza uralensis that has been used in the treatment of various diseases in oriental medicine. There are little data on the anti-inflammatory efficacy of Gancaonin N, and its effects and mechanisms on acute pneumonia are unknown. Therefore, this study was conducted as a preliminary analysis of the anti-inflammatory effect of Gancaonin N in lipopolysaccharide (LPS)-induced RAW264.7 cells, and to identify its preventive effect on the lung inflammatory response and the molecular mechanisms underlying it. In this study, Gancaonin N inhibited the production of NO and PGE2 in LPS-induced RAW264.7 cells and significantly reduced the expression of iNOS and COX-2 proteins at non-cytotoxic concentrations. In addition, in LPS-induced A549 cells, Gancaonin N significantly reduced the expression of COX-2 and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Moreover, Gancaonin N reduced MAPK signaling pathway phosphorylation and NF-κB nuclear translocation. Therefore, Gancaonin N relieved the inflammatory response by inactivating the MAPK and NF-κB signaling pathways; thus, it is a potential natural anti-inflammatory agent that can be used in the treatment of acute pneumonia. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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19 pages, 2423 KiB

Open AccessArticle

Anti-Inflammatory and Immunomodulatory Effects of the Grifola frondosa Natural Compound o-Orsellinaldehyde on LPS-Challenged Murine Primary Glial Cells. Roles of NF-κβ and MAPK

by Sarah Tomas-Hernandez, Jordi Blanco, Santiago Garcia-Vallvé, Gerard Pujadas, María José Ojeda-Montes, Aleix Gimeno, Lluís Arola, Luisa Minghetti, Raúl Beltrán-Debón and Miquel Mulero

Pharmaceutics 2021, 13(6), 806; https://doi.org/10.3390/pharmaceutics13060806 - 28 May 2021

Cited by 9 | Viewed by 3326

Abstract

In response to foreign or endogenous stimuli, both microglia and astrocytes adopt an activated phenotype that promotes the release of pro-inflammatory mediators. This inflammatory mechanism, known as neuroinflammation, is essential in the defense against foreign invasion and in normal tissue repair; nevertheless, when [...] Read more.

In response to foreign or endogenous stimuli, both microglia and astrocytes adopt an activated phenotype that promotes the release of pro-inflammatory mediators. This inflammatory mechanism, known as neuroinflammation, is essential in the defense against foreign invasion and in normal tissue repair; nevertheless, when constantly activated, this process can become detrimental through the release of neurotoxic factors that amplify underlying disease. In consequence, this study presents the anti-inflammatory and immunomodulatory properties of o-orsellinaldehyde, a natural compound found by an in silico approach in the Grifola frondosa mushroom, in astrocytes and microglia cells. For this purpose, primary microglia and astrocytes were isolated from mice brain and cultured in vitro. Subsequently, cells were exposed to LPS in the absence or presence of increasing concentrations of this natural compound. Specifically, the results shown that o-orsellinaldehyde strongly inhibits the LPS-induced inflammatory response in astrocytes and microglia by decreasing nitrite formation and downregulating iNOS and HO-1 expression. Furthermore, in microglia cells o-orsellinaldehyde inhibits NF-κB activation; and potently counteracts LPS-mediated p38 kinase and JNK phosphorylation (MAPK). In this regard, o-orsellinaldehyde treatment also induces a significant cell immunomodulation by repolarizing microglia toward the M2 anti-inflammatory phenotype. Altogether, these results could partially explain the reported beneficial effects of G. frondosa extracts on inflammatory conditions. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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11 pages, 11791 KiB

Open AccessArticle

Nobiletin Inhibits Inflammatory Reaction in Interleukin-1β-Stimulated Human Periodontal Ligament Cells

by Yoshitaka Hosokawa, Ikuko Hosokawa, Kazumi Ozaki and Takashi Matsuo

Pharmaceutics 2021, 13(5), 667; https://doi.org/10.3390/pharmaceutics13050667 - 7 May 2021

Cited by 13 | Viewed by 2536

Abstract

The immune response in periodontal lesions is involved in the progression of periodontal disease. Therefore, it is important to find a bioactive substance that has anti-inflammatory effects in periodontal lesions. This study aimed to examine if nobiletin, which is found in the peel [...] Read more.

The immune response in periodontal lesions is involved in the progression of periodontal disease. Therefore, it is important to find a bioactive substance that has anti-inflammatory effects in periodontal lesions. This study aimed to examine if nobiletin, which is found in the peel of citrus fruits, could inhibit inflammatory responses in interleukin (IL)-1β-stimulated human periodontal ligament cells (HPDLCs). The release of cytokines (IL-6, IL-8, CXCL10, CCL20, and CCL2) and matrix metalloproteinases (MMP-1 and MMP-3) was assessed by ELISA. The expression of cell adhesion molecules (ICAM-1and VCAM-1) and the activation of signal transduction pathways (nuclear factor (NF)-κB, mitogen-activated protein kinases (MAPKs) and protein kinase B (Akt)) in HPDLCs were detected by Western blot analysis. Our experiments revealed that nobiletin decreased the expression of inflammatory cytokines, cell adhesion molecules, and MMPs in IL-1β-stimulated HPDLCs. Moreover, we revealed that nobiletin treatment could suppress the activation of the NF-κB, MAPKs, and Akt pathways. These findings indicate that nobiletin could inhibit inflammatory reactions in IL-1β-stimulated HPDLCs by inhibiting multiple signal transduction pathways, including NF-κB, MAPKs, and Akt. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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12 pages, 2160 KiB

Open AccessArticle

Anti-Inflammatory Effects of a Polyphenol, Catechin-7,4′-O-Digallate, from Woodfordia uniflora by Regulating NF-κB Signaling Pathway in Mouse Macrophages

by Eui Jin Kim, Ji Bin Seo, Jae Sik Yu, Seoyoung Lee, Jae Sung Lim, Jeong Uk Choi, Chang-Min Lee, Luay Rashan, Ki Hyun Kim and Young-Chang Cho

Pharmaceutics 2021, 13(3), 408; https://doi.org/10.3390/pharmaceutics13030408 - 19 Mar 2021

Cited by 13 | Viewed by 3400

Abstract

Inflammation is a defense mechanism that protects the body from infections. However, chronic inflammation causes damage to body tissues. Thus, controlling inflammation and investigating anti-inflammatory mechanisms are keys to preventing and treating inflammatory diseases, such as sepsis and rheumatoid arthritis. In continuation with [...] Read more.

Inflammation is a defense mechanism that protects the body from infections. However, chronic inflammation causes damage to body tissues. Thus, controlling inflammation and investigating anti-inflammatory mechanisms are keys to preventing and treating inflammatory diseases, such as sepsis and rheumatoid arthritis. In continuation with our work related to the discovery of bioactive natural products, a polyphenol, catechin-7,4′-O-digallate (CDG), was isolated from Woodfordia uniflora, which has been used as a sedative and remedy for skin infections in the Dhofar region of Oman. Thus far, no study has reported the anti-inflammatory compounds derived from W. uniflora and the mechanisms underlying their action. To investigate the effects of CDG on the regulation of inflammation, we measured the reduction in nitric oxide (NO) production following CDG treatment in immortalized mouse Kupffer cells (ImKCs). CDG treatment inhibited NO production through the downregulation of inducible nitric oxide synthase expression in lipopolysaccharide (LPS)-stimulated ImKCs. The anti-inflammatory effects of CDG were mediated via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, an important inflammatory-response-associated signaling pathway. Moreover, CDG treatment has regulated the expression of pro-inflammatory cytokines, such as IL-6 and IL-1β. These results suggested the anti-inflammatory action of CDG in LPS-stimulated ImKCs. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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15 pages, 3172 KiB

Open AccessArticle

6-Gingerol, a Bioactive Compound of Ginger Attenuates Renal Damage in Streptozotocin-Induced Diabetic Rats by Regulating the Oxidative Stress and Inflammation

by Saleh A. Almatroodi, Abdullah M. Alnuqaydan, Ali Yousif Babiker, Mashael Abdullah Almogbel, Amjad Ali Khan and Arshad Husain Rahmani

Pharmaceutics 2021, 13(3), 317; https://doi.org/10.3390/pharmaceutics13030317 - 28 Feb 2021

Cited by 56 | Viewed by 3381

Abstract

The aim of present study is to investigate the role of 6-gingerol in ameliorating the renal injury in streptozotocin (STZ)-induced diabetic rats. The diabetes was induced by using a single dose of freshly prepared STZ (55 mg/kg body weight) intraperitoneally which causes the [...] Read more.

The aim of present study is to investigate the role of 6-gingerol in ameliorating the renal injury in streptozotocin (STZ)-induced diabetic rats. The diabetes was induced by using a single dose of freshly prepared STZ (55 mg/kg body weight) intraperitoneally which causes the degeneration of pancreatic Langerhans islet β-cells. The diabetic rats were treated with oral gavage of 6-gingerol (10 mg/kg b.w.). The treatment plan was continued for 8 weeks successively and the body weight and fasting blood glucose levels were weekly checked. The biochemical parameters like lipid profile, kidney profile, antioxidant enzyme levels, lipid peroxidation and anti-inflammatory marker levels were investigated after the treatment plant. The pathological condition of kidneys was examined by haematoxylin-eosin (H&E) staining besides this analysis of NF-κB protein expression by immuno-histochemistry was performed. Some of the major parameters in diabetes control vs. normal control were reported as fasting blood glucose (234 ± 10 vs. 102 ± 8 mg/dL), serum creatinine (109.7 ± 7.2 vs. 78.9 ± 4.5 μmol/L) and urea (39.9 ± 1.8 vs. 18.6 mg/dL), lipid profile levels were significantly enhanced in diabetic rats. Moreover, diabetic rats were marked with decreased antioxidant enzyme levels and increased inflammatory markers. Treatment with 6-gingerol significantly restored the fasting blood glucose level, hyperlipidaemia, Malondialdehyde (MDA) and inflammatory marker levels, NF-κB protein expression and augmented the antioxidant enzyme levels in the kidneys of diabetic rats. The kidney damage was significantly normalized by the treatment of 6-gingerol and it provides an evidence that this novel compound plays a significant role in the protection of kidney damage. These findings demonstrate that 6-gingerol reduces lipid parameters, inflammation and oxidative stress in diabetic rats, thereby inhibiting the renal damage. Our results demonstrate that use of 6-gingerol could be a novel therapeutic approach to prevent the kidney damage associated with the diabetes mellitus. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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18 pages, 1248 KiB

Open AccessReview

Neuroinflammation as a Therapeutic Target in Retinitis Pigmentosa and Quercetin as Its Potential Modulator

by Joseph Thomas Ortega and Beata Jastrzebska

Pharmaceutics 2021, 13(11), 1935; https://doi.org/10.3390/pharmaceutics13111935 - 16 Nov 2021

Cited by 23 | Viewed by 3416

Abstract

The retina is a multilayer neuronal tissue located in the back of the eye that transduces the environmental light into a neural impulse. Many eye diseases caused by endogenous or exogenous harm lead to retina degeneration with neuroinflammation being a major hallmark of [...] Read more.

The retina is a multilayer neuronal tissue located in the back of the eye that transduces the environmental light into a neural impulse. Many eye diseases caused by endogenous or exogenous harm lead to retina degeneration with neuroinflammation being a major hallmark of these pathologies. One of the most prevalent retinopathies is retinitis pigmentosa (RP), a clinically and genetically heterogeneous hereditary disorder that causes a decline in vision and eventually blindness. Most RP cases are related to mutations in the rod visual receptor, rhodopsin. The mutant protein triggers inflammatory reactions resulting in the activation of microglia to clear degenerating photoreceptor cells. However, sustained insult caused by the abnormal genetic background exacerbates the inflammatory response and increases oxidative stress in the retina, leading to a decline in rod photoreceptors followed by cone photoreceptors. Thus, inhibition of inflammation in RP has received attention and has been explored as a potential therapeutic strategy. However, pharmacological modulation of the retinal inflammatory response in combination with rhodopsin small molecule chaperones would likely be a more advantageous therapeutic approach to combat RP. Flavonoids, which exhibit antioxidant and anti-inflammatory properties, and modulate the stability and folding of rod opsin, could be a valid option in developing treatment strategies against RP. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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39 pages, 2479 KiB

Open AccessReview

Sesquiterpene Lactones: Promising Natural Compounds to Fight Inflammation

by Melanie S. Matos, José D. Anastácio and Cláudia Nunes dos Santos

Pharmaceutics 2021, 13(7), 991; https://doi.org/10.3390/pharmaceutics13070991 - 30 Jun 2021

Cited by 56 | Viewed by 5640

Abstract

Inflammation is a crucial and complex process that reestablishes the physiological state after a noxious stimulus. In pathological conditions the inflammatory state may persist, leading to chronic inflammation and causing tissue damage. Sesquiterpene lactones (SLs) are composed of a large and diverse group [...] Read more.

Inflammation is a crucial and complex process that reestablishes the physiological state after a noxious stimulus. In pathological conditions the inflammatory state may persist, leading to chronic inflammation and causing tissue damage. Sesquiterpene lactones (SLs) are composed of a large and diverse group of highly bioactive plant secondary metabolites, characterized by a 15-carbon backbone structure. In recent years, the interest in SLs has risen due to their vast array of biological activities beneficial for human health. The anti-inflammatory potential of these compounds results from their ability to target and inhibit various key pro-inflammatory molecules enrolled in diverse inflammatory pathways, and prevent or reduce the inflammatory damage on tissues. Research on the anti-inflammatory mechanisms of SLs has thrived over the last years, and numerous compounds from diverse plants have been studied, using in silico, in vitro, and in vivo assays. Besides their anti-inflammatory potential, their cytotoxicity, structure–activity relationships, and pharmacokinetics have been investigated. This review aims to gather the most relevant results and insights concerning the anti-inflammatory potential of SL-rich extracts and pure SLs, focusing on their effects in different inflammatory pathways and on different molecular players. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside)

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