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12 pages, 2402 KiB

Open AccessArticle

α-Bisabolol Attenuates Doxorubicin Induced Renal Toxicity by Modulating NF-κB/MAPK Signaling and Caspase-Dependent Apoptosis in Rats

by Seenipandi Arunachalam, M. F. Nagoor Meeran, Sheikh Azimullah, Niraj Kumar Jha, Dhanya Saraswathiamma, Sandeep Subramanya, Alia Albawardi and Shreesh Ojha

Int. J. Mol. Sci. 2022, 23(18), 10528; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810528 - 10 Sep 2022

Cited by 6 | Viewed by 2068

Abstract

Doxorubicin (DOX) is a well-known and effective antineoplastic agent of the anthracycline family. But, multiple organ toxicities compromise its invaluable therapeutic usage. Among many toxicity types, nephrotoxicity is one of the major concerns. In recent years many approaches, including bioactive agents of natural [...] Read more.

Doxorubicin (DOX) is a well-known and effective antineoplastic agent of the anthracycline family. But, multiple organ toxicities compromise its invaluable therapeutic usage. Among many toxicity types, nephrotoxicity is one of the major concerns. In recent years many approaches, including bioactive agents of natural origin, have been explored to provide protective effects against chemotherapy-related complications. α-Bisabolol is a naturally occurring monocyclic sesquiterpene alcohol identified in the essential oils of various aromatic plants and possesses a wide range of pharmacological properties such as antioxidant, anti-inflammatory, analgesic, cardioprotective, antibiotic, anti-irritant, and anticancer activities. The present study aimed to evaluate the effects of α-Bisabolol on DOX-induced nephrotoxicity in Wistar male albino rats. Nephrotoxicity was induced in rats by injecting a single dose of DOX (12.5 mg/kg, i.p.), and the test compound, α-Bisabolol (25 mg/kg) was administered intraperitoneally along with DOX as a co-treatment daily for 5 days. DOX-injected rats showed reduction in body weight along with a concomitant fall in antioxidants and increased lipid peroxidation in the kidney. DOX-injection also increased levels/expressions of proinflammatory cytokines namely tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) and inflammatory mediators like inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and activated nuclear factor kappa-B (NF-κB)/mitogen-activated protein kinases (MAPK) signaling in the kidney tissues. DOX also triggered apoptotic cell death, evidenced by the increased expression of pro-apoptotic markers like BCL2-Associated X Protein (Bax), cleaved caspase-3, caspase- 9, and cytochrome-C) and a decrease in the expressions of anti-apoptotic markers namely B-cell lymphoma 2 (Bcl2) and B-cell lymphoma-extra large (Bcl-xL) in the kidney. These biochemical alterations were additionally supported by light microscopic findings, which revealed structural alterations in the kidney. However, treatment with α-Bisabolol prevented body weight loss, restored antioxidants, mitigated lipid peroxidation, and inhibited the rise in proinflammatory cytokines, as well as favorably modulated the expressions of NF-κB/MAPK signaling and apoptosis markers in DOX-induced nephrotoxicity. Based on the results observed, it can be concluded that α-Bisabolol has potential to attenuate DOX-induced nephrotoxicity by inhibiting oxidative stress and inflammation mediated activation of NF-κB/MAPK signaling alongwith intrinsic pathway of apoptosis in rats. The study findings are suggestive of protective potential of α-Bisabolol in DOX associated nephrotoxicity and this could be potentially useful in minimizing the adverse effects of DOX and may be a potential agent or adjuvant for renal protection. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)

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13 pages, 3577 KiB

Open AccessArticle

Anti-Inflammatory Mechanism of An Alkaloid Rutaecarpine in LTA-Stimulated RAW 264.7 Cells: Pivotal Role on NF-κB and ERK/p38 Signaling Molecules

by Thanasekaran Jayakumar, Chun-Ming Yang, Ting-Lin Yen, Chia-Yuan Hsu, Joen-Rong Sheu, Chih-Wei Hsia, Manjunath Manubolu, Wei-Chieh Huang, Cheng-Ying Hsieh and Chih-Hsuan Hsia

Int. J. Mol. Sci. 2022, 23(11), 5889; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115889 - 24 May 2022

Cited by 12 | Viewed by 2030

Abstract

Lipoteichoic acid (LTA) is a key cell wall component and virulence factor of Gram-positive bacteria. LTA contributes a major role in infection and it mediates inflammatory responses in the host. Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from Evodia rutaecarpa, has shown a variety of [...] Read more.

Lipoteichoic acid (LTA) is a key cell wall component and virulence factor of Gram-positive bacteria. LTA contributes a major role in infection and it mediates inflammatory responses in the host. Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from Evodia rutaecarpa, has shown a variety of fascinating biological properties such as anti-thrombotic, anticancer, anti-obesity and thermoregulatory, vasorelaxing activity. It has also potent effects on the cardiovascular and endocrine systems. Herein, we investigated rutaecarpine’s (Rut) anti-inflammatory effects in LTA-stimulated RAW macrophage cells. The Western blot and spectrophotometric results revealed that Rut inhibited the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin (IL)-1β in the LTA-induced macrophage cells. Successively, our mechanistic studies publicized that Rut inhibited LTA-induced phosphorylation of mitogen-activated protein kinase (MAPK) including the extracellular signal-regulated kinase (ERK), and p38, but not c-Jun NH2-terminal kinase (JNK). In addition, the respective Western blot and confocal image analyses exhibited that Rut reserved nuclear transcription factor kappa-B (NF-κB) by hindering inhibitor of nuclear factor κB-α (IκBα) and NF-κB p65 phosphorylation and p65 nuclear translocation. These results indicate that Rut exhibits its anti-inflammatory effects mainly through attenuating NF-κB and ERK/p38 signaling pathways. Overall, this result suggests that Rut could be a potential therapeutic agent for the treatment of Gram-positive bacteria induced inflammatory diseases. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)

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12 pages, 1356 KiB

Open AccessArticle

Chemosensitization of U-87 MG Glioblastoma Cells by Neobavaisoflavone towards Doxorubicin and Etoposide

by Mateusz Maszczyk, Klaudia Banach, Marta Karkoszka, Zuzanna Rzepka, Jakub Rok, Artur Beberok and Dorota Wrześniok

Int. J. Mol. Sci. 2022, 23(10), 5621; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105621 - 17 May 2022

Cited by 8 | Viewed by 2019

Abstract

Glioblastoma (GB) is the most common type of glioma, which is distinguished by high mortality. Due to the rapid progression of the tumor and drug resistance, the treatment is often ineffective. The development of novel therapies in a big part concerns the application [...] Read more.

Glioblastoma (GB) is the most common type of glioma, which is distinguished by high mortality. Due to the rapid progression of the tumor and drug resistance, the treatment is often ineffective. The development of novel therapies in a big part concerns the application of anti-cancer agents already used in clinical practice, unfortunately often with limited effects. This could be overcome through the use of compounds that possess chemosensitizing properties. In our previous work, it has been shown that neobavaisoflavone (NBIF) enhances the in vitro activity of doxorubicin in GB cells. The aim of this study was a further investigation of the possible chemosensitizing effects of this isoflavone. The experimental panel involving image cytometry techniques, such as count assay, examination of mitochondrial membrane potential, Annexin V assay, and cell cycle analysis, was performed in human glioblastoma U-87 MG cells and normal human astrocytes (NHA) treated with NBIF, doxorubicin, etoposide, and their mixes with NBIF. NBIF in co-treatment with etoposide or doxorubicin caused an increase in the population of apoptotic cells and prompted alterations in the cell cycle. NBIF enhances the pro-apoptotic activity of etoposide and doxorubicin in U-87 MG cells, which could be a sign of the chemosensitizing properties of the isoflavone. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)

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15 pages, 3050 KiB

Open AccessArticle

Targeting MAPK/NF-κB Pathways in Anti-Inflammatory Potential of Rutaecarpine: Impact on Src/FAK-Mediated Macrophage Migration

by Thanasekaran Jayakumar, Kao-Chang Lin, Chao-Chien Chang, Chih-Wei Hsia, Manjunath Manubolu, Wei-Chieh Huang, Joen-Rong Sheu and Chih-Hsuan Hsia

Int. J. Mol. Sci. 2022, 23(1), 92; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010092 - 22 Dec 2021

Cited by 16 | Viewed by 2649

Abstract

Studies have discovered that different extracts of Evodia rutaecarpa and its phytochemicals show a variety of biological activities associated with inflammation. Although rutaecarpine, an alkaloid isolated from the unripe fruit of E. rutaecarpa, has been exposed to have anti-inflammatory properties, the mechanism [...] Read more.

Studies have discovered that different extracts of Evodia rutaecarpa and its phytochemicals show a variety of biological activities associated with inflammation. Although rutaecarpine, an alkaloid isolated from the unripe fruit of E. rutaecarpa, has been exposed to have anti-inflammatory properties, the mechanism of action has not been well studied. Thus, this study investigated the molecular mechanisms of rutaecarpine (RUT) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. RUT reserved the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukin (IL)-1β in the LPS-induced macrophages. RUT showed an inhibitory effect on the mitogen-activated protein kinases (MAPKs), and it also inhibited nuclear transcription factor kappa-B (NF-κB) by hindering IκBα and NF-κB p65 phosphorylation and p65 nuclear translocation. The phospho-PI3K and Akt was concentration-dependently suppressed by RUT. However, RUT not only suggestively reduced the migratory ability of macrophages and their numbers induced by LPS but also inhibited the phospho-Src, and FAK. Taken together, these results indicate that RUT participates a vital role in the inhibition of LPS-induced inflammatory processes in RAW 264.7 macrophages and that the mechanisms involve PI3K/Akt and MAPK-mediated downregulation of NF-κB signaling pathways. Notably, reducing the migration and number of cells induced by LPS via inhibiting of Src/FAK pathway was also included to the anti-inflammatory mechanism of RUT. Therefore, RUT may have potential benefits as a therapeutic agent against chronic inflammatory diseases. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)

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16 pages, 18025 KiB

Open AccessArticle

Benzyl Isothiocyanate, a Vegetable-Derived Compound, Induces Apoptosis via ROS Accumulation and DNA Damage in Canine Lymphoma and Leukemia Cells

by Marta Henklewska, Aleksandra Pawlak, Rong-Fang Li, Jine Yi, Iwona Zbyryt and Bożena Obmińska-Mrukowicz

Int. J. Mol. Sci. 2021, 22(21), 11772; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111772 - 29 Oct 2021

Cited by 13 | Viewed by 2025

Abstract

Treatment of neoplastic diseases in companion animals is one of the most important problems of modern veterinary medicine. Given the growing interest in substances of natural origin as potential anti-cancer drugs, our goal was to examine the effectiveness of benzyl isothiocyanate (BITC), a [...] Read more.

Treatment of neoplastic diseases in companion animals is one of the most important problems of modern veterinary medicine. Given the growing interest in substances of natural origin as potential anti-cancer drugs, our goal was to examine the effectiveness of benzyl isothiocyanate (BITC), a compound found in cruciferous vegetables, against canine lymphoma and leukemia. These are the one of the most common canine cancer types, and chemotherapy is the only treatment option. The study involved established cell lines originating from various hematopoietic malignancies: CLBL-1, GL-1, CLB70 and CNK-89, immortalized noncancerous cell lines: MDCK and NIH-3T3 and canine peripheral blood mononuclear cells (PBMCs). The cytotoxic activity of BITC, apoptosis induction, caspase activity and ROS generation were evaluated by flow cytometry. H2AX phosphorylation was assessed by western blot. The study showed that the compound was especially active against B lymphocyte-derived malignant cells. Their death resulted from caspase-dependent apoptosis. BITC induced ROS accumulation, and glutathione precursor N-acetyl-l-cysteine reversed the effect of the compound, thus proving the role of oxidative stress in BITC activity. In addition, exposure to the compound induced DNA damage in the tested cells. This is the first study that provides information on the activity of BITC in canine hematopoietic malignancies and suggests that the compound may be particularly useful in B-cell neoplasms treatment. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)

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Review

Jump to: Research

22 pages, 390 KiB

Open AccessReview

Cancer Therapy Challenge: It Is Time to Look in the “St. Patrick’s Well” of the Nature

by Gregorio Bonsignore, Mauro Patrone, Federica Grosso, Simona Martinotti and Elia Ranzato

Int. J. Mol. Sci. 2021, 22(19), 10380; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910380 - 26 Sep 2021

Cited by 7 | Viewed by 1996

Abstract

Cancer still remains a leading cause of death despite improvements in diagnosis, drug discovery and therapy approach. Therefore, there is a strong need to improve methodologies as well as to increase the number of approaches available. Natural compounds of different origins (i.e., from [...] Read more.

Cancer still remains a leading cause of death despite improvements in diagnosis, drug discovery and therapy approach. Therefore, there is a strong need to improve methodologies as well as to increase the number of approaches available. Natural compounds of different origins (i.e., from fungi, plants, microbes, etc.) represent an interesting approach for fighting cancer. In particular, synergistic strategies may represent an intriguing approach, combining natural compounds with classic chemotherapeutic drugs to increase therapeutic efficacy and lower the required drug concentrations. In this review, we focus primarily on those natural compounds utilized in synergistic approached to treating cancer, with particular attention to those compounds that have gained the most research interest. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)

19 pages, 2528 KiB

Open AccessReview

Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma

by Hui Xie, Felix K.-H. Chun, Jochen Rutz and Roman A. Blaheta

Int. J. Mol. Sci. 2021, 22(11), 5938; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115938 - 31 May 2021

Cited by 17 | Viewed by 3568

Abstract

Sulforaphane (SFN) is a natural glucosinolate found in cruciferous vegetables that acts as a chemopreventive agent, but its mechanism of action is not clear. Due to antioxidative mechanisms being thought central in preventing cancer progression, SFN could play a role in oxidative processes. [...] Read more.

Sulforaphane (SFN) is a natural glucosinolate found in cruciferous vegetables that acts as a chemopreventive agent, but its mechanism of action is not clear. Due to antioxidative mechanisms being thought central in preventing cancer progression, SFN could play a role in oxidative processes. Since redox imbalance with increased levels of reactive oxygen species (ROS) is involved in the initiation and progression of bladder cancer, this mechanism might be involved when chemoresistance occurs. This review summarizes current understanding regarding the influence of SFN on ROS and ROS-related pathways and appraises a possible role of SFN in bladder cancer treatment. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)

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46 pages, 30502 KiB

Open AccessReview

Selected Monocyclic Monoterpenes and Their Derivatives as Effective Anticancer Therapeutic Agents

by Mariola Zielińska-Błajet, Przemysław Pietrusiak and Joanna Feder-Kubis

Int. J. Mol. Sci. 2021, 22(9), 4763; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094763 - 30 Apr 2021

Cited by 18 | Viewed by 3855

Abstract

Terpenes—a diverse group of secondary metabolites—constitute the largest class of natural products abundant in almost every plant species. The properties of concrete terpenes and essential oils have been intensively studied due to their widespread use in the pharmaceutical, food and cosmetics industries. Despite [...] Read more.

Terpenes—a diverse group of secondary metabolites—constitute the largest class of natural products abundant in almost every plant species. The properties of concrete terpenes and essential oils have been intensively studied due to their widespread use in the pharmaceutical, food and cosmetics industries. Despite the popularity of these aromatic compounds, their derivatives, terpenoids, are still not comprehensively characterized despite exhibiting potent bioactive properties. This review aims to assess the anticancer properties of selected monoterpenes including carvone, carvacrol, perillyl alcohol, perillaldehyde, limonene, menthol and their derivatives while also evaluating potential applications as novel anticancer treatments. Special attention is paid to functional groups that improve the bioactivity of monoterpene molecules. This review also covers the therapeutic potential of deep eutectic solvents that contain monoterpene substances. Taken together, the literature supports the use of monoterpene derivatives in the development of new alternatives for disease treatment and prevention. Full article

(This article belongs to the Special Issue Antitumor/Anti-inflammatory Activities of Natural Compounds from Plants 2.0)

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