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15 pages, 2792 KiB

Open AccessArticle

Galgravin Isolated from Piper kadsura Ameliorates Lipopolysaccharide (LPS)-Induced Endotoxemia in Mice

by Shih-Ming Ou, Yin-Chieh Hsu, Shu-Ling Fu, Lie-Chwen Lin and Chao-Hsiung Lin

Int. J. Mol. Sci. 2023, 24(23), 16572; https://doi.org/10.3390/ijms242316572 - 21 Nov 2023

Viewed by 745

Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from Piper kadsura, can be used to treat sepsis, models of bacterial lipopolysaccharide (LPS)-activated macrophages and LPS-induced endotoxemia mice were used. Galgravin suppressed [...] Read more.

Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from Piper kadsura, can be used to treat sepsis, models of bacterial lipopolysaccharide (LPS)-activated macrophages and LPS-induced endotoxemia mice were used. Galgravin suppressed NF-κB activation in LPS-activated RAW 264.7 macrophages without causing significant cytotoxicity, in which proinflammatory molecules like TNF-α, IL-6, iNOS, and COX-2 were downregulated. In addition, the expression of TNF-α and IL-6 was also suppressed by galgravin in LPS-activated murine bone marrow-derived macrophages. Moreover, galgravin significantly downregulated the mRNA expression of TNF-α, IL-6, and iNOS in the lungs and decreased TNF-α and IL-6 in the serum and IL-6 in the bronchoalveolar lavage fluid of LPS-challenged mice. The COX-2 expression in tissues, including the lung, liver, and kidney, as well as the lung alveolar hemorrhage, was also reduced by galgravin. The present study reveals the anti-inflammatory effects of galgravin in mouse models and implies its potential application in inflammation diseases. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 3.0)

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16 pages, 2713 KiB

Open AccessArticle

Quaternary Benzophenanthridine Alkaloids Act as Smac Mimetics and Overcome Resistance to Apoptosis

by Petra Kulíšková, Lucie Vašátková and Iva Slaninová

Int. J. Mol. Sci. 2023, 24(20), 15405; https://doi.org/10.3390/ijms242015405 - 20 Oct 2023

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Abstract

Defects in cell death signaling pathways are one of the hallmarks of cancer and can lead to resistance to conventional therapy. Natural products are promising compounds that can overcome this resistance. In the present study we studied the effect of six quaternary benzophenanthridine [...] Read more.

Defects in cell death signaling pathways are one of the hallmarks of cancer and can lead to resistance to conventional therapy. Natural products are promising compounds that can overcome this resistance. In the present study we studied the effect of six quaternary benzophenanthridine alkaloids (QBAs), sanguinarine, chelerythrine, sanguirubine, chelirubine, sanguilutine, and chelilutine, on Jurkat leukemia cells, WT, and cell death deficient lines derived from them, CASP3/7/6^-/- and FADD^-/-, and on solid tumor, human malignant melanoma, A375 cells. We demonstrated the ability of QBAs to overcome the resistance of these deficient cells and identified a novel mechanism for their action. Sanguinarine and sanguirubine completely and chelerythrine, sanguilutine, and chelilutine partially overcame the resistance of CASP3/7/6^-/- and FADD^-/- cells. By detection of cPARP, a marker of apoptosis, and pMLKL, a marker of necroptosis, we proved the ability of QBAs to induce both these cell deaths (bimodal cell death) with apoptosis preceding necroptosis. We identified the new mechanism of the cell death induction by QBAs, the downregulation of the apoptosis inhibitors cIAP1 and cIAP2, i.e., an effect similar to that of Smac mimetics. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 3.0)

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15 pages, 9057 KiB

Open AccessArticle

A Proteomic Study of the Bioactivity of Annona muricata Leaf Extracts in HT-1080 Fibrosarcoma Cells

by Ana Dácil Marrero, Ana R. Quesada, Beatriz Martínez-Poveda, Miguel Ángel Medina and Casimiro Cárdenas

Int. J. Mol. Sci. 2023, 24(15), 12021; https://doi.org/10.3390/ijms241512021 - 27 Jul 2023

Cited by 1 | Viewed by 926

Abstract

Graviola (Annona muricata) is a tropical plant with many traditional ethnobotanic uses and pharmacologic applications. A metabolomic study of both aqueous and DMSO extracts from Annona muricata leaves recently allowed us to identify dozens of bioactive compounds. In the present study, [...] Read more.

Graviola (Annona muricata) is a tropical plant with many traditional ethnobotanic uses and pharmacologic applications. A metabolomic study of both aqueous and DMSO extracts from Annona muricata leaves recently allowed us to identify dozens of bioactive compounds. In the present study, we use a proteomic approach to detect altered patterns in proteins on both conditioned media and extracts of HT-1080 fibrosarcoma cells under treatment conditions, revealing new potential bioactivities of Annona muricata extracts. Our results reveal the complete sets of deregulated proteins after treatment with aqueous and DMSO extracts from Annona muricata leaves. Functional enrichment analysis of proteomic data suggests deregulation of cell cycle and iron metabolism, which are experimentally validated in vitro. Additional experimental data reveal that DMSO extracts protect HT-1080 fibrosarcoma cells and HMEC-1 endothelial cells from ferroptosis. Data from our proteomic study are available via ProteomeXchange with identifier PXD042354. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 3.0)

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18 pages, 1594 KiB

Open AccessArticle

Antiproliferative Activity and Impact on Human Gut Microbiota of New O-Alkyl Derivatives of Naringenin and Their Oximes

by Joanna Kozłowska, Anna Duda-Madej and Dagmara Baczyńska

Int. J. Mol. Sci. 2023, 24(12), 9856; https://doi.org/10.3390/ijms24129856 - 07 Jun 2023

Cited by 1 | Viewed by 1205

Abstract

Naringenin is a 5,7,4′-trihydroxyflavanone naturally occurring mainly in citrus fruits, characterized by a wide spectrum of biological activity. Chemical modifications based on alkylation and oximation in most cases increase its bioactivity. The aim of our research was to evaluate the antiproliferative activity and [...] Read more.

Naringenin is a 5,7,4′-trihydroxyflavanone naturally occurring mainly in citrus fruits, characterized by a wide spectrum of biological activity. Chemical modifications based on alkylation and oximation in most cases increase its bioactivity. The aim of our research was to evaluate the antiproliferative activity and influence on selected representatives of the human gut microbiota of new synthesized O-alkyl derivatives (A1–A10) and their oximes (B1–B10), which contain hexyl, heptyl, octyl, nonyl and undecyl chains attached to the C-7 or to both the C-7 and C-4′ positions in naringenin. To the best of our knowledge, compounds A3, A4, A6, A8–A10 and B3–B10 have not been described in the scientific literature previously. The anticancer activity was tested on human colon cancer cell line HT-29 and mouse embryo fibroblasts 3T3-L1 using the sulforhodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. We also determined the impacts of all compounds on the growth of Gram-positive and Gram-negative bacterial strains, such as Staphylococcus aureus, Enterococcus faecalis and Escherichia coli. The antimicrobial activity was expressed in terms of minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) values. For 7,4′-di-O-hexylnaringenin (A2), 7-O-undecylnaringenin (A9) and their oximes (B2, B9), which were safe for microbiota (MIC > 512 µg/mL) and almost all characterized by high cytotoxicity against the HT-29 cell line (A2: IC₅₀ > 100 µg/mL; A9: IC₅₀ = 17.85 ± 0.65 µg/mL; B2: IC₅₀ = 49.76 ± 1.63 µg/mL; B9: IC₅₀ = 11.42 ± 1.17 µg/mL), apoptosis assays were performed to elucidate their mechanisms of action. Based on our results, new compound B9 induced an apoptotic process via caspase 3/7 activation, which proved its potential as an anticancer agent. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 3.0)

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Review

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34 pages, 6220 KiB

Open AccessReview

Application of Luteolin in Neoplasms and Nonneoplastic Diseases

by Katarzyna Rakoczy, Justyna Kaczor, Adam Sołtyk, Natalia Szymańska, Jakub Stecko, Jakub Sleziak, Julita Kulbacka and Dagmara Baczyńska

Int. J. Mol. Sci. 2023, 24(21), 15995; https://doi.org/10.3390/ijms242115995 - 06 Nov 2023

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Abstract

Researchers are amazed at the multitude of biological effects of 3′,4′,5,7-tetrahydroxyflavone, more commonly known as luteolin, as it simultaneously has antioxidant and pro-oxidant, as well as antimicrobial, anti-inflammatory, and cancer-preventive, properties. The anticancer properties of luteolin constitute a mosaic of pathways due to [...] Read more.

Researchers are amazed at the multitude of biological effects of 3′,4′,5,7-tetrahydroxyflavone, more commonly known as luteolin, as it simultaneously has antioxidant and pro-oxidant, as well as antimicrobial, anti-inflammatory, and cancer-preventive, properties. The anticancer properties of luteolin constitute a mosaic of pathways due to which this flavonoid influences cancer cells. Not only is it able to induce apoptosis and inhibit cancer cell proliferation, but it also suppresses angiogenesis and metastasis. Moreover, luteolin succeeds in cancer cell sensitization to therapeutically induced cytotoxicity. Nevertheless, apart from its promising role in chemoprevention, luteolin exhibits numerous potential utilizations in patients with conditions other than neoplasms, which include inflammatory skin diseases, diabetes mellitus, and COVID-19. This review aims to present the multidimensionality of the luteolin’s impact on both neoplastic and nonneoplastic diseases. When it comes to neoplasms, we intend to describe the complexity of the molecular mechanisms that underlay luteolin’s anticancer effectiveness, as well as to prove the usefulness of integrating this flavonoid in cancer therapy via the analysis of recent research on breast, colon, and lung cancer. Regarding nonneoplastic diseases, this review aims to emphasize the importance of researching the potential of luteolin in areas such as diabetology, virology, and dermatology as it summarizes the most important discoveries in those fields regarding its application. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 3.0)

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33 pages, 1297 KiB

Open AccessReview

From the Bush to the Brain: Preclinical Stages of Ethnobotanical Anti-Inflammatory and Neuroprotective Drug Discovery—An Australian Example

by Payaal Kumar, Shintu Mathew, Rashmi Gamage, Frances Bodkin, Kerrie Doyle, Ilaria Rossetti, Ingrid Wagnon, Xian Zhou, Ritesh Raju, Erika Gyengesi and Gerald Münch

Int. J. Mol. Sci. 2023, 24(13), 11086; https://doi.org/10.3390/ijms241311086 - 04 Jul 2023

Cited by 3 | Viewed by 2855

Abstract

The Australian rainforest is a rich source of medicinal plants that have evolved in the face of dramatic environmental challenges over a million years due to its prolonged geographical isolation from other continents. The rainforest consists of an inherent richness of plant secondary [...] Read more.

The Australian rainforest is a rich source of medicinal plants that have evolved in the face of dramatic environmental challenges over a million years due to its prolonged geographical isolation from other continents. The rainforest consists of an inherent richness of plant secondary metabolites that are the most intense in the rainforest. The search for more potent and more bioavailable compounds from other plant sources is ongoing, and our short review will outline the pathways from the discovery of bioactive plants to the structural identification of active compounds, testing for potency, and then neuroprotection in a triculture system, and finally, the validation in an appropriate neuro-inflammatory mouse model, using some examples from our current research. We will focus on neuroinflammation as a potential treatment target for neurodegenerative diseases including multiple sclerosis (MS), Parkinson’s (PD), and Alzheimer’s disease (AD) for these plant-derived, anti-inflammatory molecules and highlight cytokine suppressive anti-inflammatory drugs (CSAIDs) as a better alternative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) to treat neuroinflammatory disorders. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 3.0)

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23 pages, 1603 KiB

Open AccessReview

The Controversial Roles of Areca Nut: Medicine or Toxin?

by Pei-Feng Liu and Yung-Fu Chang

Int. J. Mol. Sci. 2023, 24(10), 8996; https://doi.org/10.3390/ijms24108996 - 19 May 2023

Cited by 3 | Viewed by 2998

Abstract

Areca nut (AN) is used for traditional herbal medicine and social activities in several countries. It was used as early as about A.D. 25-220 as a remedy. Traditionally, AN was applied for several medicinal functions. However, it was also reported to have toxicological [...] Read more.

Areca nut (AN) is used for traditional herbal medicine and social activities in several countries. It was used as early as about A.D. 25-220 as a remedy. Traditionally, AN was applied for several medicinal functions. However, it was also reported to have toxicological effects. In this review article, we updated recent trends of research in addition to acquire new knowledge about AN. First, the history of AN usage from ancient years was described. Then, the chemical components of AN and their biological functions was compared; arecoline is an especially important compound in AN. AN extract has different effects caused by different components. Thus, the dual effects of AN with pharmacological and toxicological effects were summarized. Finally, we described perspectives, trends and challenges of AN. It will provide the insight of removing or modifying the toxic compounds of AN extractions for enhancing their pharmacological activity to treat several diseases in future applications. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 3.0)

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21 pages, 2572 KiB

Open AccessReview

Anticarcinogenic Effects of Isothiocyanates on Hepatocellular Carcinoma

by Yuting Zhang, Huiting Huang, Libo Jin and Sue Lin

Int. J. Mol. Sci. 2022, 23(22), 13834; https://doi.org/10.3390/ijms232213834 - 10 Nov 2022

Cited by 9 | Viewed by 1814

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for about 90% of cases. Sorafenib, lenvatinib, and the combination of atezolizumab and bevacizumab are considered first-line treatments for advanced HCC. However, clinical application of these drugs has also caused [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for about 90% of cases. Sorafenib, lenvatinib, and the combination of atezolizumab and bevacizumab are considered first-line treatments for advanced HCC. However, clinical application of these drugs has also caused some adverse reactions such as hypertension, elevated aspartate aminotransferases, and proteinuria. At present, natural products and their derivatives have drawn more and more attention due to less side effects as cancer treatments. Isothiocyanates (ITCs) are one type of hydrolysis products from glucosinolates (GLSs), secondary plant metabolites found exclusively in cruciferous vegetables. Accumulating evidence from encouraging in vitro and in vivo animal models has demonstrated that ITCs have multiple biological activities, especially their potentially health-promoting activities (antibacterial, antioxidant, and anticarcinogenic effects). In this review, we aim to comprehensively summarize the chemopreventive, anticancer, and chemosensitizative effects of ITCs on HCC, and explain the underlying molecular mechanisms. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 3.0)

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