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13 pages, 3108 KiB

Open AccessArticle

Combined Lycium barbarum Polysaccharides with Plasmon-Activated Water Affect IFN-γ/TNF-α Induced Inflammation in Caco-2 Cells

by Yu Zhi Lian, Yu-Chuan Liu, Chun-Chao Chang, Tomonori Nochi and Jane C.-J. Chao

Pharmaceuticals 2023, 16(10), 1455; https://doi.org/10.3390/ph16101455 - 13 Oct 2023

Viewed by 1208

Abstract

The effects of Lycium barbarum polysaccharides (LBP) and plasmon-activated water (PAW) against IFN-γ/TNF-α induced inflammation in human colon Caco-2 cells were investigated. Cells were divided into the control, induction, LBP treatment (100–500 μg/mL), and combination groups with PAW. Inflammation was induced 24 h with 10 ng/mL IFN-γ when cell confluency reached >90%, and various doses of LBP with or without PAW were treated for 3 h, and subsequently 50 ng/mL TNF-α was added for another 24 h to provoke inflammation. Combination of LBP with PAW significantly decreased the secretion of IL-6 and IL-8. Cyclooxygenase-2 and inducible NO synthase expression was attenuated in all LBP-treated groups with or without PAW. NLRP3 inflammasome and related protein PYCARD expression were inhibited by LBP at the highest dose (500 μg/mL). All doses of LBP alone significantly decreased p-ERK expression, but combination with PAW increased p-ERK expression compared to those without PAW. Additionally, 250 and 500 μg/mL of LBP with or without PAW inhibited procaspase-3/caspase-3 expression. Therefore, LBP possesses anti-inflammation and anti-apoptosis by inhibiting the secretion of inflammatory cytokines and the expression of NLRP3 inflammasome-related protein. The combination with PAW exerts additive or synergistic effect on anti-inflammation. Full article

(This article belongs to the Special Issue Polysaccharides as Drug Candidates)

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14 pages, 1613 KiB

Open AccessArticle

Potential Involvement of Oxidative Stress, Apoptosis and Proinflammation in Ipconazole-Induced Cytotoxicity in Human Endothelial-like Cells

by Iris Ruiz-Yance, Junior Siguas, Brandy Bardales, Ingrid Robles-Castañeda, Karen Cordova, Alina Ypushima, Esteban Estela-Villar, Carlos Quintana-Criollo, Darwin Estacio and José-Luis Rodríguez

Toxics 2023, 11(10), 839; https://doi.org/10.3390/toxics11100839 - 5 Oct 2023

Viewed by 1266

Abstract

Triazole fungicides are widely used in the world, mainly in agriculture, but their abuse and possible toxic effects are being reported in some in vivo and in vitro studies that have demonstrated their danger to human health. This in vitro study evaluated the cytotoxicity, oxidative stress and proinflammation of EA.hy926 endothelial cells in response to ipconazole exposure. Using the MTT assay, ipconazole was found to produce a dose-dependent reduction (*** p < 0.001; concentrations of 20, 50 and 100 µM) of cell viability in EA.hy926 with an IC₅₀ of 29 µM. Also, ipconazole induced a significant increase in ROS generation (** p < 0.01), caspase 3/7 (** p < 0.01), cell death (BAX, APAF1, BNIP3, CASP3 and AKT1) and proinflammatory (NLRP3, CASP1, IL1β, NFκB, IL6 and TNFα) biomarkers, as well as a reduction in antioxidant (NRF2 and GPx) biomarkers. These results demonstrated that oxidative stress, proinflammatory activity and cell death could be responsible for the cytotoxic effect produced by the fungicide ipconazole, such that this triazole compound should be considered as a possible risk factor in the development of alterations in cellular homeostasis. Full article

(This article belongs to the Section Agrochemicals and Food Toxicology)

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30 pages, 4300 KiB

Open AccessArticle

Punicalagin’s Protective Effects on Parkinson’s Progression in Socially Isolated and Socialized Rats: Insights into Multifaceted Pathway

by Hoda A. Salem, Karema Abu-Elfotuh, Sharifa Alzahrani, Nermin I. Rizk, Howaida S. Ali, Nehal Elsherbiny, Alhanouf Aljohani, Ahmed M. E. Hamdan, Panneerselvam Chellasamy, Nada S. Abdou, Ayah M. H. Gowifel, Alshaymaa Darwish, Osama Mohamed Ibrahim and Zakaria Y. Abd Elmageed

Pharmaceutics 2023, 15(10), 2420; https://doi.org/10.3390/pharmaceutics15102420 - 4 Oct 2023

Cited by 2 | Viewed by 1465

Abstract

Parkinson’s disease (PD) is a gradual deterioration of dopaminergic neurons, leading to motor impairments. Social isolation (SI), a recognized stressor, has recently gained attention as a potential influencing factor in the progress of neurodegenerative illnesses. We aimed to investigate the intricate relationship between SI and PD progression, both independently and in the presence of manganese chloride (MnCl₂), while evaluating the punicalagin (PUN) therapeutic effects, a natural compound established for its cytoprotective, anti-inflammatory, and anti-apoptotic activities. In this five-week experiment, seven groups of male albino rats were organized: G1 (normal control), G2 (SI), G3 (MnCl₂), G4 (SI + MnCl₂), G5 (SI + PUN), G6 (MnCl₂ + PUN), and G7 (SI + PUN + MnCl₂). The results revealed significant changes in behavior, biochemistry, and histopathology in rats exposed to SI and/or MnCl₂, with the most pronounced effects detected in the SI rats concurrently exposed to MnCl₂. These effects were associated with augmented oxidative stress biomarkers and reduced antioxidant activity of the Nrf2/HO-1 pathway. Additionally, inflammatory pathways (HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1 and JAK-2/STAT-3) were upregulated, while dysregulation of signaling pathways (PI3K/AKT/GSK-3β/CREB), sustained endoplasmic reticulum stress by activation PERK/CHOP/Bcl-2, and impaired autophagy (AMPK/SIRT-1/Beclin-1 axis) were observed. Apoptosis induction and a decrease in monoamine levels were also noted. Remarkably, treatment with PUN effectively alleviated behaviour, histopathological changes, and biochemical alterations induced by SI and/or MnCl₂. These findings emphasize the role of SI in PD progress and propose PUN as a potential therapeutic intervention to mitigate PD. PUN’s mechanisms of action involve modulation of pathways such as HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1, JAK-2/STAT-3, PI3K/AKT/GSK-3β/CREB, AMPK/SIRT-1, Nrf2/HO-1, and PERK/CHOP/Bcl-2. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside, 2nd Edition)

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19 pages, 2902 KiB

Open AccessArticle

Hepatic SPARC Expression Is Associated with Inflammasome Activation during the Progression of Non-Alcoholic Fatty Liver Disease in Both Mice and Morbidly Obese Patients

by Agostina M. Onorato, Lucía Lameroli Mauriz, Juan Bayo, Esteban Fiore, María José Cantero, Barbara Bueloni, Mariana García, Cecilia Lagües, Pedro Martínez-Duartez, Gabriel Menaldi, Nicolas Paleari, Catalina Atorrasagasti and Guillermo D. Mazzolini

Int. J. Mol. Sci. 2023, 24(19), 14843; https://doi.org/10.3390/ijms241914843 - 2 Oct 2023

Cited by 1 | Viewed by 1155

Abstract

The severity of non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to steatohepatitis, and it is not yet clearly understood which patients will progress to liver fibrosis or cirrhosis. SPARC (Secreted Protein Acidic and Rich in Cysteine) has been involved in NAFLD pathogenesis in mice and humans. The aim of this study was to investigate the role of SPARC in inflammasome activation, and to evaluate the relationship between the hepatic expression of inflammasome genes and the biochemical and histological characteristics of NAFLD in obese patients. In vitro studies were conducted in a macrophage cell line and primary hepatocyte cultures to assess the effect of SPARC on inflammasome. A NAFLD model was established in SPARC knockout (SPARC^−/−) and SPARC^+/+ mice to explore inflammasome activation. A hepatic RNAseq database from NAFLD patients was analyzed to identify genes associated with SPARC expression. The results were validated in a prospective cohort of 59 morbidly obese patients with NAFLD undergoing bariatric surgery. Our results reveal that SPARC alone or in combination with saturated fatty acids promoted IL-1β expression in cell cultures. SPARC^−/− mice had reduced hepatic inflammasome activation during the progression of NAFLD. NAFLD patients showed increased expression of SPARC, NLRP3, CASP1, and IL-1β. Gene ontology analysis revealed that genes positively correlated with SPARC are linked to inflammasome-related pathways during the progression of the disease, enabling the differentiation of patients between steatosis and steatohepatitis. In conclusion, SPARC may play a role in hepatic inflammasome activation in NAFLD. Full article

(This article belongs to the Special Issue Molecular Advances in Liver Inflammation and Fibrosis)

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34 pages, 2073 KiB

Open AccessReview

The Dual Role of the Innate Immune System in the Effectiveness of mRNA Therapeutics

by Albert Muslimov, Valeriy Tereshchenko, Daniil Shevyrev, Anna Rogova, Kirill Lepik, Vasiliy Reshetnikov and Roman Ivanov

Int. J. Mol. Sci. 2023, 24(19), 14820; https://doi.org/10.3390/ijms241914820 - 1 Oct 2023

Cited by 4 | Viewed by 4222

Abstract

Advances in molecular biology have revolutionized the use of messenger RNA (mRNA) as a therapeutic. The concept of nucleic acid therapy with mRNA originated in 1990 when Wolff et al. reported successful expression of proteins in target organs by direct injection of either plasmid DNA or mRNA. It took decades to bring the transfection efficiency of mRNA closer to that of DNA. The next few decades were dedicated to turning in vitro-transcribed (IVT) mRNA from a promising delivery tool for gene therapy into a full-blown therapeutic modality, which changed the biotech market rapidly. Hundreds of clinical trials are currently underway using mRNA for prophylaxis and therapy of infectious diseases and cancers, in regenerative medicine, and genome editing. The potential of IVT mRNA to induce an innate immune response favors its use for vaccination and immunotherapy. Nonetheless, in non-immunotherapy applications, the intrinsic immunostimulatory activity of mRNA directly hinders the desired therapeutic effect since it can seriously impair the target protein expression. Targeting the same innate immune factors can increase the effectiveness of mRNA therapeutics for some indications and decrease it for others, and vice versa. The review aims to present the innate immunity-related ‘barriers’ or ‘springboards’ that may affect the development of immunotherapies and non-immunotherapy applications of mRNA medicines. Full article

(This article belongs to the Section Molecular Immunology)

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22 pages, 58661 KiB

Open AccessArticle

Ursolic Acid Alleviates Neuroinflammation after Intracerebral Hemorrhage by Mediating Microglial Pyroptosis via the NF-κB/NLRP3/GSDMD Pathway

by Pan Lei, Zhiyang Li, Qiuwei Hua, Ping Song, Lun Gao, Long Zhou and Qiang Cai

Int. J. Mol. Sci. 2023, 24(19), 14771; https://doi.org/10.3390/ijms241914771 - 30 Sep 2023

Cited by 7 | Viewed by 1790

Abstract

The neuroinflammatory response after intracerebral hemorrhage (ICH) causes a large amount of neuronal loss, and inhibiting the inflammatory response can improve the prognosis. In previous laboratory studies and clinical trials, ursolic acid (UA) inhibited the inflammatory response, but whether it can be administered to inhibit the neuroinflammatory response after cerebral hemorrhage is unknown. The aim of this study was to investigate the effects of ursolic acid after cerebral hemorrhage. Online databases were used to obtain potential therapeutic targets of ursolic acid for the treatment of cerebral hemorrhage, and possible mechanisms were analyzed by KEGG, GO, and molecular docking. A rat model of cerebral hemorrhage was established using collagenase, and an in vitro cerebral hemorrhage model was constructed by adding hemin to BV2 cell culture medium. Enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), immunofluorescence, TUNEL staining, and calcein/PI staining were used to investigate the degree of microglial M1 polarization, changes in the levels of inflammatory factors, activation of the NF-κB pathway, and changes in the indicators of cellular death after ursolic acid treatment. In addition, phorbol 12-myristate 13-acetate (PMA) was used to activate the NF-κB pathway to verify that ursolic acid exerts its anti-neuroinflammatory effects by regulating the NF-κB/NLRP3/GSDMD pathway. Network pharmacology and bioinformatics analyses revealed that ursolic acid may exert its therapeutic effects on cerebral hemorrhage through multiple pathways. Together, in vivo and in vitro experiments showed that ursolic acid inhibited microglial M1 polarization and significantly reduced the levels of p-NF-κB, GSDMD-N, cleaved caspase-1, TNF-α, IL-6, and IL-1β, which were significantly inhibited by the use of PMA. Ursolic acid inhibits microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway to alleviate neuroinflammatory responses after cerebral hemorrhage. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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22 pages, 7678 KiB

Open AccessArticle

Unlocking the Power of Onion Peel Extracts: Antimicrobial and Anti-Inflammatory Effects Improve Wound Healing through Repressing Notch-1/NLRP3/Caspase-1 Signaling

by Rafik Mounir, Walaa A. Alshareef, Eman A. El Gebaly, Alaadin E. El-Haddad, Abdallah M. Said Ahmed, Osama G. Mohamed, Eman T. Enan, Shaimaa Mosallam, Ashootosh Tripathi, Heba Mohammed Refat M. Selim, Sarah I. Bukhari, Rihaf Alfaraj, Ghada M. Ragab, Amira A. El-Gazar and Soad Z. El-Emam

Pharmaceuticals 2023, 16(10), 1379; https://doi.org/10.3390/ph16101379 - 28 Sep 2023

Cited by 3 | Viewed by 5658

Abstract

Onion peels are often discarded, representing an unlimited amount of food by-products; however, they are a valuable source of bioactive phenolics. Thus, we utilized UPLC-MS/MS to analyze the metabolomic profiles of red (RO) and yellow (YO) onion peel extracts. The cytotoxic (SRB assay), anti-inflammatory (Griess assay), and antimicrobial (sensitivity test, MIC, antibiofilm, and SP-SDS tests) properties were assessed in vitro. Additionally, histological analysis, immunohistochemistry, and ELISA tests were conducted to investigate the healing potential in excisional skin wound injury and Candida albicans infection in vivo. RO extract demonstrated antibacterial activity, limited skin infection with C. albicans, and improved the skin’s appearance due to the abundance of quercetin and anthocyanin derivatives. Both extracts reduced lipopolysaccharide-induced nitric oxide release in vitro and showed a negligible cytotoxic effect on MCF-7 and HT29 cells. When extracts were tested in vivo for their ability to promote tissue regeneration, it was found that YO peel extract had the greatest impact. Further biochemical analysis revealed that YO extract suppressed NLRP3/caspase-1 signaling and decreased inflammatory cytokines. Furthermore, YO extract decreased Notch-1 levels and boosted VEGF-mediated angiogenesis. Our findings imply that onion peel extract can effectively treat wounds by reducing microbial infection, reducing inflammation, and promoting tissue regeneration. Full article

(This article belongs to the Section Medicinal Chemistry)

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13 pages, 2676 KiB

Open AccessArticle

Whole-Grain Highland Barley Attenuates Atherosclerosis Associated with NLRP3 Inflammasome Pathway and Gut Microbiota in ApoE^−/− Mice

by Tong Wu, Qinye Yu, Yingting Luo, Zijian Dai, Yuhong Zhang, Chao Wang, Qun Shen and Yong Xue

Nutrients 2023, 15(19), 4186; https://doi.org/10.3390/nu15194186 - 28 Sep 2023

Cited by 2 | Viewed by 1329

Abstract

The efficacy and mechanism of highland barley in the treatment of atherosclerosis have received little attention. Herein, we aimed to explore whether highland barley supplementation can prevent atherosclerosis progression and improve gut microbiota disorder in apolipoprotein E knockout (ApoE^−/−) mice. Male ApoE^−/− mice were fed a high-fat diet with whole-grain highland barley (WHB) or refined highland barley for 18 weeks. WHB substantially inhibited the formation of atherosclerotic plaques, reduced serum tumor necrosis factor-α, and downregulated the expression of NLRP3 in the aorta. Furthermore, the 16S rRNA analysis revealed that highland barley supplementation helped to restore the dysregulation of the gut microbiota, as evidenced by an increase in the relative abundance of specific beneficial bacteria known for their anti-inflammatory properties, such as Lachnospiraceae, Lactobacillus, Muribaculaceae, and Bifidobacterium. Highland barley supplementation might alleviate atherosclerotic plaque formation by modulating the NLRP3 inflammasome pathway and the synthesis of anti-inflammatory metabolites by the gut microbiota. Full article

(This article belongs to the Special Issue Effects of Diet–Microbiome Interactions on Chronic Diseases)

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Abstract

Autophagy is a highly conserved intracellular degradation pathway in eukaryotic organisms, playing an adaptive role in various pathophysiological processes throughout evolution. Inflammation is the immune system’s response to external stimuli and tissue damage. However, persistent inflammatory reactions can lead to a range of inflammatory diseases and cancers. The interaction between autophagy and inflammation is particularly evident during viral infections. As a crucial regulator of inflammation, autophagy can either promote or inhibit the occurrence of inflammatory responses. In turn, inflammation can establish negative feedback loops by modulating autophagy to suppress excessive inflammatory reactions. This interaction is pivotal in the pathogenesis of viral diseases. Therefore, elucidating the regulatory roles of autophagy and inflammation in viral infections will significantly enhance our understanding of the mechanisms underlying related diseases. Furthermore, it will provide new insights and theoretical foundations for disease prevention, treatment, and drug development. Full article

16 pages, 2468 KiB

Open AccessArticle

Novel Heme Oxygenase-1 Inducers Palliate Inflammatory Pain and Emotional Disorders by Regulating NLRP3 Inflammasome and Activating the Antioxidant Pathway

by Montse Pérez-Fernández, Irene Suárez-Rojas, Xue Bai, Ignacio Martínez-Martel, Valeria Ciaffaglione, Valeria Pittalà, Loredana Salerno and Olga Pol

Antioxidants 2023, 12(10), 1794; https://doi.org/10.3390/antiox12101794 - 23 Sep 2023

Viewed by 1474

Abstract

Chronic pain caused by persistent inflammation is current in multiple diseases and has a strong negative impact on society. It is commonly associated with several mental illnesses, which can exert a negative influence on pain perception, and needs to be eradicated. Nevertheless, actual therapies are not sufficiently safe and effective. Recent reports demonstrate that the induction of heme oxygenase-1 (HO-1) enzyme produces analgesic effects in animals with osteoarthritis pain and reverses the grip strength loss caused by sciatic nerve crush. In this research, we evaluated the potential use of three new HO-1 inducers, 1m, 1a, and 1b, as well as dimethyl fumarate (DMF), for treating persistent inflammatory pain induced by the subplantar injection of complete Freud’s adjuvant and the functional deficits and emotional sickness associated. The modulator role of these treatments on the inflammatory and antioxidant pathways were also assessed. Our findings revealed that repeated treatment, for four days, with 1m, 1a, 1b, or DMF inhibited inflammatory pain, reversed grip strength deficits, and reversed the linked anxious- and depressive-like behaviors, with 1m being the most effective. These treatments also suppressed the up-regulation of the inflammasome NLRP3 and activated the expression of the Nrf2 transcription factor and the HO-1 and superoxide dismutase 1 enzymes in the paw and/or amygdala, thus revealing the anti-inflammatory and antioxidant capacity of these compounds during inflammatory pain. Results suggest the use of 1m, 1a, 1b, and DMF, particularly 1m, as promising therapies for inflammatory pain and the accompanying functional disabilities and emotional diseases. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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