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Mehdikhani F, Hajimehdipoor H, Tansaz M, Maresca M, Rajabi S. Sesquiterpene Lactones as Promising Phytochemicals to Cease Metastatic Propagation of Cancer. Biomolecules 2025; 15:268. [PMID: 40001571 PMCID: PMC11852507 DOI: 10.3390/biom15020268] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/03/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Cancer metastasis remains the most challenging issue in cancer therapy. Recent reports show that cancer metastasis accounts for over 90% of cancer-associated deaths in the world. Metastasis is a multi-step process by which cancer cells spread to distant tissues and organs beyond the primary site. The metastatic propagation of different cancers is under the surveillance of several regulating processes and factors related to cellular signaling pathways. Plant-derived phytochemicals are bioactive components of plants with a variety of biological and medicinal activities. Several phytochemicals have been shown to target various molecular factors in cancer cells to tackle metastasis. Sesquiterpene lactones, as a diverse group of plant-derived phytochemicals with a variety of biological activities, have been shown to suppress the promotion and progression of different cancer types by acting on multiple cell-signaling pathways. This review article briefly describes the process of metastasis and its components. Then, sesquiterpene lactones with the ability to target and inhibit invasion, migration, and metastasis along with the molecular mechanisms of their effects on different cancers are described in detail.
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Affiliation(s)
- Fatemeh Mehdikhani
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran;
| | - Homa Hajimehdipoor
- Department of Traditional Pharmacy, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1516745811, Iran;
| | - Mojgan Tansaz
- Department of Traditional Medicine, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1516745811, Iran;
| | - Marc Maresca
- Aix Marseille University, CNRS, Centrale Med, ISM2, 13013 Marseille, France
| | - Sadegh Rajabi
- Traditional Medicine and Materia Medica Research Center, Shahid Beheshti University of Medical Sciences, Tehran 1516745811, Iran
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Gumisiriza H, Olet EA, Mwikali L, Akatuhebwa R, Kembabazi O, Omara T, Lejju JB. Ethnopharmacology, phytochemistry, pharmacology and toxicity of the genus Gouania. Heliyon 2024; 10:e40933. [PMID: 39720023 PMCID: PMC11665460 DOI: 10.1016/j.heliyon.2024.e40933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 12/01/2024] [Accepted: 12/03/2024] [Indexed: 12/26/2024] Open
Abstract
The genus Gouania (Rhamnaceae) comprises at least 50 recognized species distributed across tropical and subtropical regions. Gouania species have been ethnomedicinally used to treat a variety of ailments. Despite their widespread medicinal use, there is no comprehensive documentation that consolidates the ethnobotanical knowledge, phytochemicals, pharmacological properties, and toxicity of Gouania species. Herein, this review details the ethnopharmacology, phytochemical constituents, pharmacological properties and toxicity of Gouania species to provide perspectives for future research on this genus. Based on available literature, herbal preparations from Gouania species have been used to treat ailments related to the digestive, cardiovascular, respiratory, skin, musculoskeletal, reproductive, endocrine and urological systems. Extracts and isolated compounds from seven Gouania species (G. leptostachya, G. longipetala, G. lupulozdes, G. macrocarpa, G. longispicata, G. obtusifolia, and G. ulmifolia) have demonstrated promising anticancer, antimicrobial, antioxidant, and antiviral properties, supporting their ethnomedicinal uses. To date, 64 compounds (including 6 phenolic compounds, 24 flavonoids, and 34 terpenoids) have been isolated and characterized in the genus mainly as gouaniasides I-IX, gouanogenins, and gouanic acids. Most Gouania species remain unexplored for their potential bioactivities. The identification of more than 54 % as novel compounds from just seven Gouania species highlights the genus as a promising source for discovering new therapeutic agents to combat the growing challenge of multidrug-resistant pathogens. Conducting extensive phytochemical and pharmacological analyses across a broader array of Gouania species could unveil a more comprehensive profile of bioactive compounds, and pave way for innovative treatments against a diverse range of pathogens and diseases.
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Affiliation(s)
- Hannington Gumisiriza
- Department of Chemistry, Mbarara University of Science and Technology, P.O. Box 1410, Mbarara, Uganda
| | - Eunice Apio Olet
- Department of Biology, Mbarara University of Science and Technology, P.O. Box 1410, Mbarara, Uganda
| | - Lydia Mwikali
- Department of Chemistry, Mbarara University of Science and Technology, P.O. Box 1410, Mbarara, Uganda
| | - Racheal Akatuhebwa
- Department of Agriculture, Agribusiness, and Environment, Bishop Stuart University, P.O. Box 09, Mbarara, Uganda
| | - Owen Kembabazi
- Department of Marketing and International Business, Makerere University Business School, P.O. Box 1337, Kampala, Uganda
| | - Timothy Omara
- Department of Chemistry, College of Natural Sciences, Makerere University, P.O. Box 7062, Kampala, Uganda
| | - Julius Bunny Lejju
- Department of Biology, Mbarara University of Science and Technology, P.O. Box 1410, Mbarara, Uganda
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He XF, Li TZ, Ma YB, Wang MF, Chen JJ. Unusual cadinane-involved sesquiterpenoid dimers from Artemisia annua and their antihepatoma effect. PHYTOCHEMISTRY 2024; 226:114216. [PMID: 38972444 DOI: 10.1016/j.phytochem.2024.114216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/05/2024] [Accepted: 07/05/2024] [Indexed: 07/09/2024]
Abstract
Artemisia annua L. ("Qinghao" in Chinese) is a famous traditional Chinese medicinal herb and has been used to treat malaria and various tumors. Our preliminary screening indicated that the EtOAc extract of A. annua manifested activity against HepG2, Huh7, and SK-Hep-1 cell lines with inhibitory ratios of 53.2%, 52.1%, and 59.6% at 200 μg/mL, respectively. Bioassay-guided isolation of A. annua afforded 14 unusual cadinane-involved sesquiterpenoid dimers, artemannuins A‒N (1-14), of which the structures were elucidated by extensive spectral analyses, ECD calculations, and single-crystal X-ray diffraction. Structurally, these compounds were classified into five different types based on the coupled modes of two monomeric sesquiterpenoids. Among them, compounds 1-9 represented the first examples of sesquiterpenoid dimers formed via the C-3‒C-3' single bond of two 5(4 → 3)-abeo-cadinane sesquiterpenoid monomers, while compounds 13 and 14 were dimers fused by cadinane and humulane sesquiterpenoids via an ester bond. Methylated derivatives of 1, 4, 6, and 8 showed antihepatoma activity against HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values ranging from 30.5 to 57.2 μM.
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Affiliation(s)
- Xiao-Feng He
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China
| | - Tian-Ze Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China
| | - Yun-Bao Ma
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China
| | - Meng-Fei Wang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Ji-Jun Chen
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
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Pérez-Mejía N, Villarreal ML, Sánchez-Carranza JN, González-Maya L, González-Cortazar M, Ortíz-Caltempa A, Alvarez L. Phytochemical Profiles and Cytotoxic Activity of Bursera fagaroides (Kunth) Engl. Leaves and Its Callus Culture. PLANTS (BASEL, SWITZERLAND) 2024; 13:1622. [PMID: 38931054 PMCID: PMC11207444 DOI: 10.3390/plants13121622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/31/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024]
Abstract
Bursera fagaroides, popularly used in México, possesses bioactive lignans. These compounds are low in the bark, and its extraction endangers the life of the trees. The aim of the present investigation was to search for alternative sources of cytotoxic compounds in B. fagaroides prepared as leaves and in vitro callus cultures. The friable callus of B. fagaroides was established using a combination of plant growth regulators: 4 mgL-1 of 2,4-dichlorophenoxyacetic acid (2,4-D), 1 mgL-1 Naphthaleneacetic Acid (NAA) and 1 mgL-1 Zeatin. The maximum cell growth was at day 28 with a specific growth rate of μ = 0.059 days-1 and duplication time td = 11.8 days. HPLC quantification of the dichloromethane callus biomass extract showed that Scopoletin, with a concentration of 10.7 µg g-1 dry weight, was the main compound inducible as a phytoalexin by the addition of high concentrations of 2,4-D, as well as by the absence of nutrients in the culture medium. In this same extract, the compounds γ-sitosterol and stigmasterol were also identified by GC-MS analysis. Open column chromatography was used to separate and identify yatein, acetyl podophyllotoxin and 7',8'-dehydropodophyllotoxin in the leaves of the wild plant. Cytotoxic activity on four cancer cell lines was tested, with PC-3 prostate carcinoma (IC50 of 12.6 ± 4.6 µgmL-1) being the most sensitive to the wild-type plant extract and HeLa cervical carcinoma (IC50 of 72 ± 5 µgmL-1) being the most sensitive to the callus culture extract.
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Affiliation(s)
- Nancy Pérez-Mejía
- Centro de Investigación en Biotecnología, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca C. P. 62209, Mexico; (N.P.-M.); (M.L.V.)
| | - María Luisa Villarreal
- Centro de Investigación en Biotecnología, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca C. P. 62209, Mexico; (N.P.-M.); (M.L.V.)
| | - Jessica Nayelli Sánchez-Carranza
- Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca C. P. 62209, Mexico; (J.N.S.-C.); (L.G.-M.)
| | - Leticia González-Maya
- Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca C. P. 62209, Mexico; (J.N.S.-C.); (L.G.-M.)
| | - Manasés González-Cortazar
- Centro de Investigación Biomédica del Sur, IMSS, Calle República Argentina No. 1, Col. Centro, Xochitepec C. P. 62790, Mexico;
| | - Anabel Ortíz-Caltempa
- Centro de Investigación en Biotecnología, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca C. P. 62209, Mexico; (N.P.-M.); (M.L.V.)
| | - Laura Alvarez
- Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, Cuernavaca C. P. 62209, Mexico
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Karimian Ensaf P, Goodarzi MT, Homayouni Tabrizi M, Neamati A, Hosseinyzadeh SS. A novel nanoformulation of parthenolide coated with polydopamine shows selective cytotoxicity and induces apoptosis in gastric cancer cells. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4435-4445. [PMID: 38108837 DOI: 10.1007/s00210-023-02907-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
An anticancer agent derived from a natural product, parthenolide (PN), was studied to formulate PN into poly(lactic-co-glycolic acid) (PLGA). Polydopamine (PDA) was employed to modify the surface of PN-PLGA. Following characterization, the PN-PLGA-PDA was evaluated for its in vitro release, cytotoxicity, and ability to induce apoptosis using flow cytometry and real-time quantitative PCR. According to the present study, PN-PLGA-PDA had a size of 195.5 nm which is acceptable for efficient enhanced permeation and retention (EPR) performance. The SEM results confirmed the size and spherical shape of the nanoparticles. The percentage of encapsulation efficiency was 96.9%. The zeta potential of PN-PLGA-PDA was - 31.8 mV which was suitable for its stability. FTIR spectra of the PN-PLGA-PDA indicated the chemical stability of the PN due to intermolecular hydrogen bonds between polymer and drug. The release of PN from PN-PLGA-PDA in PBS (pH 7.4) was only 20% during the first 48 h and less than 40% during 144 h. PN-PLGA-PDA exhibited anticancer properties in a dose-dependent manner that was more cytotoxic against cancer cells than normal cells. Moreover, real-time qPCR results indicated that the formulation activated apoptosis genes to exert its cytotoxic effect and activate the NF-kB pathway. Based on our findings, PN-PLGA-PDA could serve as a potential treatment for cancer.
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Affiliation(s)
| | | | | | - Ali Neamati
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Samira Sadat Hosseinyzadeh
- Department of Chemistry, Shahrood Branch, Islamic Azad University, Shahrood, Iran
- Department of Chemistry, Herbal Medicines Raw Materials Research Center, Shahrood Branch, Islamic Azad University, Shahrood, Iran
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Arrieche D, Olea AF, Jara-Gutiérrez C, Villena J, Pardo-Baeza J, García-Davis S, Viteri R, Taborga L, Carrasco H. Ethanolic Extract from Fruits of Pintoa chilensis, a Chilean Extremophile Plant. Assessment of Antioxidant Activity and In Vitro Cytotoxicity. PLANTS (BASEL, SWITZERLAND) 2024; 13:1409. [PMID: 38794478 PMCID: PMC11125100 DOI: 10.3390/plants13101409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/08/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024]
Abstract
Pintoa chilensis is a shrub with yellow flowers that reach up to two meters high, endemic of the Atacama Region in Chile. This species grows under special environmental conditions such as low altitude, arid areas, and directly sun-exposed habitats. In the present study, ethanolic extract was obtained from fruits of P. chilensis, and then partitioned in solvents of increasing polarity to obtain five fractions: hexane (HF), dichloromethane (DF), ethyl acetate (AF), and the residual water fraction (QF). The antioxidant activity of extracts was evaluated by using the DPPH, ABTS, and FRAP methods. The results show that the antioxidant capacity of P. chilensis is higher than that reported for other plants growing in similar environments. This effect is attributed to the highest content of flavonoids and total phenols found in P. chilensis. On the other hand, the cell viability of a breast cancer cell line (MCF-7) and a non-tumor cell line (MCF-10A) was assessed in the presence of different extract fractions. The results indicate that the hexane fraction (HF) exhibits the highest cytotoxicity on both cell lines (IC50 values equal to 35 and 45 µg/mL), whereas the dichloromethane fraction (DF) is the most selective one. The GC-MS analysis of the dichloromethane fraction (DF) shows the presence of fatty acids, sugars, and polyols as major components.
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Affiliation(s)
- Dioni Arrieche
- Laboratorio de Productos Naturales, Departamento de Química, Universidad Técnica Federico Santa María, Avenida España 1680, Valparaíso 2340000, Chile;
| | - Andrés F. Olea
- Grupo QBAB, Instituto de Ciencias Aplicadas, Facultad de Ingeniería, Universidad Autónoma de Chile, San Miguel, Santiago 8900000, Chile;
| | - Carlos Jara-Gutiérrez
- Centro Interdisciplinario de Investigación Biomédica e Ingeniería para la Salud (MEDING), Escuela de Kinesiología, Facultad de Medicina, Universidad de Valparaíso, Valparaíso 2362905, Chile; (C.J.-G.); (J.V.)
| | - Joan Villena
- Centro Interdisciplinario de Investigación Biomédica e Ingeniería para la Salud (MEDING), Escuela de Kinesiología, Facultad de Medicina, Universidad de Valparaíso, Valparaíso 2362905, Chile; (C.J.-G.); (J.V.)
| | - Javier Pardo-Baeza
- Programa de Conservación de Flora Nativa del Norte de Chile, Biorestauración Consultores, Copiapó 1530000, Chile;
| | - Sara García-Davis
- Instituto Universitario de Bio—Orgánica “Antonio González” (IUBO-AG), Universidad de La Laguna (ULL), 38200 San Cristóbal de La Laguna, Spain;
| | - Rafael Viteri
- Escuela de Ciencias Ambientales, Universidad Espíritu Santo, Guayaquil 092301, Ecuador;
| | - Lautaro Taborga
- Laboratorio de Productos Naturales, Departamento de Química, Universidad Técnica Federico Santa María, Avenida España 1680, Valparaíso 2340000, Chile;
| | - Héctor Carrasco
- Grupo QBAB, Instituto de Ciencias Aplicadas, Facultad de Ingeniería, Universidad Autónoma de Chile, San Miguel, Santiago 8900000, Chile;
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Denda Y, Matsuo Y, Sugita S, Eguchi Y, Nonoyama K, Murase H, Kato T, Imafuji H, Saito K, Morimoto M, Ogawa R, Takahashi H, Mitsui A, Kimura M, Takiguchi S. The Natural Product Parthenolide Inhibits Both Angiogenesis and Invasiveness and Improves Gemcitabine Resistance by Suppressing Nuclear Factor κB Activation in Pancreatic Cancer Cell Lines. Nutrients 2024; 16:705. [PMID: 38474833 PMCID: PMC10934733 DOI: 10.3390/nu16050705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/18/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024] Open
Abstract
We previously established pancreatic cancer (PaCa) cell lines resistant to gemcitabine and found that the activity of nuclear factor κB (NF-κB) was enhanced upon the acquisition of gemcitabine resistance. Parthenolide, the main active ingredient in feverfew, has been reported to exhibit antitumor activity by suppressing the NF-κB signaling pathway in several types of cancers. However, the antitumor effect of parthenolide on gemcitabine-resistant PaCa has not been elucidated. Here, we confirmed that parthenolide significantly inhibits the proliferation of both gemcitabine-resistant and normal PaCa cells at concentrations of 10 µM and higher, and that the NF-κB activity is significantly inhibited, even by 1 µM parthenolide. In Matrigel invasion assays and angiogenesis assays, the invasive and angiogenic potentials were higher in gemcitabine-resistant than normal PaCa cells and were inhibited by a low concentration of parthenolide. Furthermore, Western blotting showed suppressed MRP1 expression in gemcitabine-resistant PaCa treated with a low parthenolide concentration. In a colony formation assay, the addition of 1 µM parthenolide improved the sensitivity of gemcitabine-resistant PaCa cell lines to gemcitabine. These results suggest that parthenolide may be used as a novel therapeutic agent for the treatment of gemcitabine-resistant PaCa.
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Affiliation(s)
| | - Yoichi Matsuo
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan; (Y.D.); (S.S.); (Y.E.); (K.N.); (H.M.); (T.K.); (H.I.); (K.S.); (M.M.); (R.O.); (H.T.); (A.M.); (M.K.); (S.T.)
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Ensaf PK, Goodarzi MT, Tabrizi MH, Neamati A, Hosseinyzadeh SS. Novel formulation of parthenolide-loaded liposome coated with chitosan and evaluation of its potential anticancer effects in vitro. Mol Biol Rep 2024; 51:369. [PMID: 38411765 DOI: 10.1007/s11033-024-09325-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/07/2024] [Indexed: 02/28/2024]
Abstract
BACKGROUND In this study the formulation of parthenolide (PN), an anticancer agent extracted from a natural product, into a liposome (PN-liposome), was examined. The surface of the PN-liposome was modified using chitosan (PN-chitosome). By using real-time quantitative PCR and flow cytometry, we examined the release of PN-chitosomes, cytotoxicity, and ability to induce apoptosis in vitro. METHODS AND RESULTS According to the present study, PN-chitosomes had a size of 251 nm which is acceptable for efficient enhanced permeation and retention (EPR) performance. PN-chitosomes were confirmed to be spherical in shape and size through FESEM analysis. In terms of encapsulation efficiency, 94.5% was achieved. PN-chitosome possessed a zeta potential of 34.72 mV, which was suitable for its stability. According to the FTIR spectra of PN and PN-chitosome, PN was chemically stable due to the intermolecular interaction between the liposome and the drug. After 48 h, only 10% of the PN was released from the PN-chitosome in PBS (pH 7.4), and less than 20% was released after 144 h. CONCLUSION In a dose-dependent manner, PN-chitosome exhibited anticancer properties that were more cytotoxic against cancer cells than normal cells. Moreover, the formulation activated both the apoptosis pathway and cytotoxic genes in real-time qPCR experiments. According to the cytotoxicity and activating apoptosis of the prepared modified particle, PN-chitosome may be helpful in the treatment of cancer.
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Affiliation(s)
| | | | | | - Ali Neamati
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
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Leibinger M, Zeitler C, Paulat M, Gobrecht P, Hilla A, Andreadaki A, Guthoff R, Fischer D. Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration. eLife 2023; 12:RP88279. [PMID: 37846146 PMCID: PMC10581688 DOI: 10.7554/elife.88279] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2023] Open
Abstract
Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of Pten knockout or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury. Here we demonstrate that the beneficial hIL-6 and Pten knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Hence, cotreatment with parthenolide, a compound blocking microtubule detyrosination, synergistically accelerates neurite growth of cultured murine CNS neurons and primary RGCs isolated from adult human eyes. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) facilitates axon regeneration in the injured optic nerve and spinal cord. Moreover, combinatorial treatment further improves hIL-6-induced axon regeneration and locomotor recovery after severe SCI. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a promising drug candidate for treating CNS injuries.
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Affiliation(s)
- Marco Leibinger
- Center for Pharmacology, Institute II, Medical Faculty and University of CologneCologneGermany
- Department of Cell Physiology, Ruhr University of BochumBochumGermany
| | - Charlotte Zeitler
- Center for Pharmacology, Institute II, Medical Faculty and University of CologneCologneGermany
- Department of Cell Physiology, Ruhr University of BochumBochumGermany
| | - Miriam Paulat
- Department of Cell Physiology, Ruhr University of BochumBochumGermany
| | - Philipp Gobrecht
- Center for Pharmacology, Institute II, Medical Faculty and University of CologneCologneGermany
- Department of Cell Physiology, Ruhr University of BochumBochumGermany
| | - Alexander Hilla
- Department of Cell Physiology, Ruhr University of BochumBochumGermany
| | - Anastasia Andreadaki
- Center for Pharmacology, Institute II, Medical Faculty and University of CologneCologneGermany
- Department of Cell Physiology, Ruhr University of BochumBochumGermany
| | - Rainer Guthoff
- Eye Hospital, Heinrich Heine University DüsseldorfDüsseldorfGermany
| | - Dietmar Fischer
- Center for Pharmacology, Institute II, Medical Faculty and University of CologneCologneGermany
- Department of Cell Physiology, Ruhr University of BochumBochumGermany
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Sánchez-Ramos M, Encarnación-García JG, Marquina-Bahena S, Sánchez-Carranza JN, Bernabé-Antonio A, Domínguez-Villegas V, Cabañas-García E, Cruz-Sosa F. Cytotoxic Activity of Wild Plant and Callus Extracts of Ageratina pichinchensis and 2,3-Dihydrobenzofuran Isolated from a Callus Culture. Pharmaceuticals (Basel) 2023; 16:1400. [PMID: 37895871 PMCID: PMC10609924 DOI: 10.3390/ph16101400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/23/2023] [Accepted: 09/29/2023] [Indexed: 10/29/2023] Open
Abstract
Ageratina pichinchensis (Kunth) R.M. King & H. Rob. belongs to the Asteraceae family and is a plant native to Mexico to which several biological properties are attributed. In this study, the cytotoxic effect of four extracts from the wild plants and two extracts from A. pichinchensis callus culture were evaluated against carcinogenic cell lines including prostate carcinoma, cervical cancer, hepatocellular carcinoma, hepatoma human, lung cancer, and cellular keratinocytes. The extracts were obtained with ethyl acetate and methanol using both leaves and stems or the callus. Only the ethyl acetate extract of the callus culture influenced the cervical cancer cell line (HeLa) with an IC50 of 94.79 ± 2.0 µg/mL. From the ethyl acetate callus extract, 2,3-dihydrobenzofuran was isolated and purified and also evaluated against cancer cells. The cytotoxic evaluation of this compound showed a significant effect against the HeLa cell line with an IC50 of 23.86 ± 2.5 µg/mL. Our results contribute to the development of biotechnological alternatives and extraction processes to produce compounds with possible potential against certain types of human cancer.
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Affiliation(s)
- Mariana Sánchez-Ramos
- Departament of Biotechnology Autonomous Metropolitan University-Iztapalapa Campus, Av. Ferrocarril de San Rafael Atlixco 186, Col. Leyes de Reforma 1ª. Sección, Alcaldía Iztapalapa, México City 09310, Mexico
| | - José Guillermo Encarnación-García
- Faculty of Chemical Science and Engineering, Autonomous University of the State of Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca 62209, Morelos, Mexico; (J.G.E.-G.); (V.D.-V.)
| | - Silvia Marquina-Bahena
- Chemical Research Center—IICBA, Autonomous University of the State of Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca 62209, Morelos, Mexico;
| | - Jessica Nayelli Sánchez-Carranza
- Faculty of Pharmacy, Autonomous University of the State of Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca 62209, Morelos, Mexico;
| | - Antonio Bernabé-Antonio
- Departament of Wood, Pulp and Paper, University Center of Exact Sciences and Engineering, University of Guadalajara, Km. 15.5 Guadalajara-Nogales, Col. Las Agujas, Zapopan 45200, Jalisco, Mexico;
| | - Valeri Domínguez-Villegas
- Faculty of Chemical Science and Engineering, Autonomous University of the State of Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca 62209, Morelos, Mexico; (J.G.E.-G.); (V.D.-V.)
| | - Emmanuel Cabañas-García
- Scientific and Technological Studies Center No. 18, National Polytechnic Institute, Blvd. Del Bote 202 Cerro del Gato, Ejido La Escondida, Co. Ciudad Administrativa, Zacatecas 98160, Zacatecas, Mexico;
| | - Francisco Cruz-Sosa
- Departament of Biotechnology Autonomous Metropolitan University-Iztapalapa Campus, Av. Ferrocarril de San Rafael Atlixco 186, Col. Leyes de Reforma 1ª. Sección, Alcaldía Iztapalapa, México City 09310, Mexico
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Liu J, Cui M, Wang Y, Wang J. Trends in parthenolide research over the past two decades: A bibliometric analysis. Heliyon 2023; 9:e17843. [PMID: 37483705 PMCID: PMC10362189 DOI: 10.1016/j.heliyon.2023.e17843] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/24/2023] [Accepted: 06/29/2023] [Indexed: 07/25/2023] Open
Abstract
Parthenolide (PTL) is a new compound extracted from traditional Chinese medicine. In recent years, it has been proven to play an undeniable role in tumors, autoimmune diseases, and inflammatory diseases. Similarly, an increasing number of experiments have also confirmed the biological mechanism of PTL in these diseases. In order to better understand the development trend and potential hot spots of PTL in cancer and other diseases, we conducted a detailed bibliometric analysis. The purpose of presenting this bibliometric analysis was to highlight and inform researchers of the important research directions, co-occurrence relationships and research status in this field. Publications related to PTL research from 2002 to 2022 were extracted on the web of science core collection (WoSCC) platform. CiteSpace, VOSviewers and R package "bibliometrix" were applied to build relevant network diagrams. The bibliometric analysis was presented in terms of performance analysis (including publication statistics, top publishing countries, top publishing institutions, publishing journals and co-cited journals, authors and co-cited authors, co-cited references statistics, citation bursts statistics, keyword statistics and trend topic statistics) and science mapping (including citations by country, citations by institution, citations by journal, citations by author, co-citation analysis, and keyword co-occurrence). The detailed discussion of the results explained the focus and latest trends from the bibliometric analysis. Finally, the current status and shortcomings of the research field on PTLwere clearly pointed out for reference by scholars.
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Affiliation(s)
- Jiye Liu
- Department of Family Medicine, Shengjing Hospital of China Medical University, 110000 Shenyang, Liaoning, China
- Department of Rehabilitation Medicine, Huludao Central Hospital, 125000 Huludao, Liaoning, China
| | - Meng Cui
- Department of Hospice Care, Shengjing Hospital of China Medical University, 110004 Shenyang, Liaoning, China
| | - Yibing Wang
- Department of Urology Surgery, Shengjing Hospital of China Medical University, 110000 Shenyang, Liaoning, China
| | - Jiahe Wang
- Department of Family Medicine, Shengjing Hospital of China Medical University, 110000 Shenyang, Liaoning, China
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Li Y, Xu H, Tan X, Cui Q, Gu W, Pan Z, Yang L, Wu S, Wang X, Li D. Parthenolide inhibits proliferation of cells infected with Kaposi's sarcoma-associated herpesvirus by suppression of the NF-κB signaling pathway. Arch Virol 2023; 168:39. [PMID: 36609933 DOI: 10.1007/s00705-022-05626-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 10/19/2022] [Indexed: 01/09/2023]
Abstract
The disease caused by Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the major causes of death of individuals with acquired immunodeficiency syndrome (AIDS). Development of anti-KSHV drugs is thus crucial. In this study, we investigated the effect of parthenolide (PTL) on the proliferation and NF-κB signaling pathway of KSHV-infected cells. iSLK.219 and KSHV-infected SH-SY5Y cells (SK-RG) were treated with PTL, TaqMan real-time quantitative PCR was used to determine the number of copies of the KSHV genome, and mRNA and protein expression of KSHV genes were analyzed by real-time PCR and immunocytochemistry. A cell viability test was used to measure cell proliferation, and flow cytometry was used to examine the effect of the drug on the cell cycle. Cyclin D1, CDK6, CDK4, and NF-κB-related proteins, including IKKβ, P-p65, and P-IKB-α, were detected by Western blot. The results showed that PTL altered the morphology of the cells, reduced the KSHV copy number, and suppressed the production of ORF50, K8.1, and v-GPCR mRNA and the LANA, ORF50, and K8.1 proteins. It blocked the G1 phase in iSLK.219 cells and decreased the levels of cyclin D1, CDK6, and CDK4 as well as the levels of NF-κB signaling proteins, including IKKβ, P-p65, and P-IKB-α. Together, these results suggest that PTL is a candidate drug that can decrease KSHV pathogenicity by suppressing cell proliferation and inhibiting the NF-κB signaling pathway in KSHV-infected cells.
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Affiliation(s)
- Ying Li
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases/NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi University, Shihezi, 832002, Xinjiang, China
- School of Medicine, Tarim University, Alaer, 843300, Xinjiang, China
| | - Huiling Xu
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases/NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Xiaohua Tan
- School of Medicine, Hangzhou Normal University, Hangzhou, 310036, Zhejiang, China
| | - Qinghua Cui
- Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, 38 Xueyuan Rd, Beijing, 100191, China
| | - Wenyi Gu
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland (UQ), Corner College and Cooper Roads (Building 75), St Lucia, Brisbane, QLD, 4072, Australia
| | - Zemin Pan
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases/NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Lei Yang
- School of Medicine, Hangzhou Normal University, Hangzhou, 310036, Zhejiang, China
| | - Shuyuan Wu
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases/NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Xiaolu Wang
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases/NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi University, Shihezi, 832002, Xinjiang, China
| | - Dongmei Li
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases/NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi University, Shihezi, 832002, Xinjiang, China.
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Wang Q, Liu J, Yin W, Sun D, Man Z, Jiang S, Ran X, Su Y, Wang Y, Dong J. Generation of multicellular tumor spheroids with micro-well array for anticancer drug combination screening based on a valuable biomarker of hepatocellular carcinoma. Front Bioeng Biotechnol 2022; 10:1087656. [PMID: 36532586 PMCID: PMC9751422 DOI: 10.3389/fbioe.2022.1087656] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 11/21/2022] [Indexed: 10/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. More than 30% of patients with diagnosed HCC have abnormally high expression of fibroblast growth factor receptor 4 (FGFR4). Currently, clinical trials for a variety of FGFR4-specific inhibitors have started. However, the effect of these inhibitors is not ideal, and it is necessary to find a drug combination to synergistically exert anti-tumor effects. We found strong correlations between FGFR4 and HCC clinicopathological characteristics in the present study. After grouping patients according to FGFR4 expression, the key gene signatures were inputted the drug-gene related databases, which predicted several potential drug candidates. More importantly, to achieve the reliable and high throughput drug cytotoxicity assessment, we developed an efficient and reproducible agarose hydrogel microwells to generate uniform-sized multicellular tumor spheroids, which provide better mimicry of conventional solid tumors that can precisely represent anticancer drug candidates' effects. Using high content screening, we quickly evaluated the enhanced anti-tumor effects of these combinations. Finally, we demonstrated that Parthenolide is a potential drug that can significantly enhance the clinical efficacy of FGFR4 receptor inhibitors. In general, we offered a new therapeutic way for FGFR4 positive HCC patients.
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Affiliation(s)
- Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Juan Liu
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
| | - Wenzhen Yin
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Dawei Sun
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Zhongsong Man
- Department of General Surgery, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Shangwei Jiang
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Xiufeng Ran
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yuxin Su
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yunfang Wang
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
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Parthenolide alleviates peritoneal fibrosis by inhibiting inflammation via the NF-κB/ TGF-β/Smad signaling axis. J Transl Med 2022; 102:1346-1354. [PMID: 36307537 DOI: 10.1038/s41374-022-00834-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/03/2022] [Indexed: 11/06/2022] Open
Abstract
Peritoneal fibrosis is a common complication of peritoneal dialysis (PD) with a complicated pathogenesis and limited treatments. Parthenolide (PTL), a recognized nuclear factor-κB (NF-κB) inhibitor extracted from Tanacetum balsamita, has been widely used to treat various inflammatory diseases and has been proven to improve peritoneal fibrosis in PD mice by selectively inhibiting the phosphorylation of Smad2/3. Transforming growth factor-β1 (TGF-β1), via Smad-dependent signaling, has a pivotal role in promoting pathogenic of fibrosis. To investigate whether PTL can inhibit peritoneal fibrosis, we affected the interaction between NF-κB and the TGF-β/Smad2/3 pathway. Long dwell peritoneal dialysis fluid (PDF) and peritoneum tissues were collected from continuous ambulatory peritoneal dialysis (CAPD) patients. PTL was administered intragastrically into a PD mouse model by daily infusion of 4.25% dextrose-containing PDF. Treated HMrSV5 cells or rat peritoneal mesothelial cells (RPMCs) were treated with high glucose(138 mM) at the same concentration as 2.5% dextrose-containing PDF and PTL. PD-related peritoneal fibrosis samples indicated an increase in inflammation, and PTL decreased the levels of inflammatory cytokines (L-6, TNF-α, and MCP-1). PTL inhibited high glucose-induced mesothelial-to-mesenchymal transition (MMT), as indicated by a reduced expression of fibrosis markers (fibronectin, collagen I, and α-SMA) and increased expression of the epithelial marker E-cadherin. PTL also significantly decreased TGF-β1 expression and the phosphorylation of IκBα and NF-κBp65. The changes in the levels of TGF-β1 expression and p-p65 or p65 showed similar trends according to western blot, immunohistochemistry, and immunofluorescence assays in vitro and in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to confirm that PTL regulates the transcription of TGF-β1 induced by high glucose through NF-κBp65. In summary, PTL induces a therapeutic effect in peritoneal fibrosis by inhibiting inflammation via the NF-κB/ TGF-β/Smad signaling axis.
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Yi J, Gong X, Yin XY, Wang L, Hou JX, Chen J, Xie B, Chen G, Wang LN, Wang XY, Wang DC, Wei HL. Parthenolide and arsenic trioxide co-trigger autophagy-accompanied apoptosis in hepatocellular carcinoma cells. Front Oncol 2022; 12:988528. [PMID: 36353537 PMCID: PMC9638029 DOI: 10.3389/fonc.2022.988528] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/03/2022] [Indexed: 11/25/2022] Open
Abstract
Although arsenic trioxide (ATO) shows a strong anti-tumor effect in the treatment of acute promyelocytic leukemia, it does not benefit patients with hepatocellular carcinoma (HCC). Thus, combination therapy is proposed to enhance the efficacy of ATO. Parthenolide (PTL), a natural compound, selectively eradicates cancer cells and cancer stem cells with no toxicity to normal cells. In this study, we chose PTL and ATO in combination and found that nontoxic dosage of PTL and ATO co-treatment can synergistically inhibit the in vitro and in vivo proliferation activity of HCC cells through suppressing stemness and self-renewal ability and inducing mitochondria-dependent apoptosis. More importantly, USP7-HUWE1-p53 pathway is involved in PTL enhancing ATO-induced apoptosis of HCC cell lines. Meanwhile, accompanied by induction of apoptosis, PTL and ATO evoke autophagic activity via inhibiting PI3K/Akt/mTOR pathway, and consciously controlling autophagy can improve the anti-HCC efficacy of a combination of PTL and ATO. In short, our conclusion represents a novel promising approach to the treatment of HCC.
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Affiliation(s)
- Juan Yi
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
- *Correspondence: Hu-Lai Wei, ; Juan Yi,
| | - Xia Gong
- Geriatrics Department, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xiao-Yang Yin
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Li Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Jin-Xia Hou
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Jing Chen
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Bei Xie
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Gang Chen
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Li-Na Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Xiao-Yuan Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
| | - Da-Chun Wang
- Biochemistry Department, LanZhou Ke Bao Biotechnology Co., Ltd., Lanzhou, Gansu, China
| | - Hu-Lai Wei
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, Gansu, China
- *Correspondence: Hu-Lai Wei, ; Juan Yi,
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Ho KL, Yong PH, Wang CW, Kuppusamy UR, Ngo CT, Massawe F, Ng ZX. Peperomia pellucida (L.) Kunth and eye diseases: A review on phytochemistry, pharmacology and toxicology. JOURNAL OF INTEGRATIVE MEDICINE 2022; 20:292-304. [PMID: 35153134 DOI: 10.1016/j.joim.2022.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 01/19/2022] [Indexed: 12/13/2022]
Abstract
Peperomia pellucida (L.) Kunth is a medicinal plant used to manage inflammatory illnesses such as conjunctivitis, and gastrointestinal and respiratory tract disorders in tropical and subtropical regions. However, little is known about its pharmacological mechanism of action against eye diseases. This review aims to critically discuss the phytochemistry, pharmacology and toxicology of P. pellucida as well as its roles in the treatment of cataract, glaucoma and diabetic retinopathy. Recent developments in the uses of P. pellucida for healthcare and nutraceutical products by the pharmaceutical industry are also covered in this review. For this review, a literature search was performed with PubMed, ScienceDirect, SciFinder Scholar and Scopus databases, using relevant keywords. Among the various phytochemicals identified from P. pellucida, β-caryophyllene, carotol, dillapiole, ellagic acid, pellucidin A, phytol and vitexin exhibit strong pharmacological activities within the mitogen-activated protein kinase and nuclear factor-κB signalling pathways in inflammatory eye diseases. The antihypertensive, anti-inflammatory, antioxidant, antihyperglycemic and anti-angiogenic activities displayed by P. pellucida extracts in many in vitro, in vivo and clinical studies suggest its potential role in the management of inflammatory eye diseases. P. pellucida extract was non-toxic against normal cell lines but displayed mild toxicity in animal models. The growing public interest in P. pellucida has inspired the nutraceutical and pharmaceutical industries to process the plant into health products. Although the potential pharmacological mechanisms against eye diseases have been summarized, further studies of the interactions among constituent phytochemicals from P. pellucida within various signalling pathways shall support the use of the plant as an alternative therapeutic source.
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Affiliation(s)
- Keat Lam Ho
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Selangor, Malaysia
| | - Phaik Har Yong
- School of Bioscience, Faculty of Medicine, Bioscience and Nursing, MAHSA University, 42610 Selangor, Malaysia
| | - Chee Woon Wang
- Department of Biochemistry, Faculty of Medicine, Bioscience and Nursing, MAHSA University, 42610 Selangor, Malaysia
| | - Umah Rani Kuppusamy
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Chek Tung Ngo
- Optimax Sunway Eye Specialist Centre, Bandar Sunway, 46150 Selangor, Malaysia
| | - Festo Massawe
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Selangor, Malaysia
| | - Zhi Xiang Ng
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Selangor, Malaysia.
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Castañeda R, Cáceres A, Velásquez D, Rodríguez C, Morales D, Castillo A. Medicinal plants used in traditional Mayan medicine for the treatment of central nervous system disorders: An overview. JOURNAL OF ETHNOPHARMACOLOGY 2022; 283:114746. [PMID: 34656668 DOI: 10.1016/j.jep.2021.114746] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/22/2021] [Accepted: 10/11/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE For thousands of years, different cultural groups have used and transformed natural resources for medicinal purposes focused on psychological or neurological conditions. Some of these are recognized as central nervous system (CNS) disorders and diseases, whereas other ethnopsychiatric interpretations are explained in culture-specific terms. In traditional Mayan medicine, several herbs have been part of treatments and rituals focused on cultural and ethnomedical concepts. AIM OF REVIEW This study aims to provide a comprehensive overview of the medicinal plants used in Mesoamerica by traditional healers and Mayan groups to CNS disorders and associate the traditional use with demonstrated pharmacological evidence to establish a solid foundation for directing future research. METHODS A systematic search for primary sources of plant use reports for traditional CNS-related remedies of Mesoamerica were obtained from library catalogs, thesis and scientific databases (PubMed, Scopus, Google Scholar; and Science Direct), and entered in a database with data analyzed in terms of the usage frequency, use by ethnic groups, plant endemism, and pharmacological investigation. RESULTS A total of 155 plants used for ethnopsychiatric conditions in Mesoamerica by Mayan groups were found, encompassing 127 native species. Of these, only 49 native species have reported in vitro or in vivo pharmacological analyses. The most commonly reported ethnopsychiatric conditions are related to anxiety, depression, memory loss, epilepsy, and insomnia. The extent of the scientific evidence available to understand the pharmacological application for their use against CNS disorders varied between different plant species, with the most prominent evidence shown by Annona cherimola, Justicia pectoralis, J. spicigera, Mimosa pudica, Persea americana, Petiveria alliacea, Piper amalago, Psidium guajava, Tagetes erecta and T. lucida. CONCLUSION Available pharmacological data suggest that different plant species used in traditional Mayan medicine may target the CNS, mainly related to GABA, serotonin, acetylcholine, or neuroprotective pathways. However, more research is required, given the limited data regarding mechanism of action at the preclinical in vivo level, identification of active compounds, scarce number of clinical studies, and the dearth of peer-reviewed studies.
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Affiliation(s)
- Rodrigo Castañeda
- School of Pharmacy, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
| | | | - Diana Velásquez
- School of Biology, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
| | - Cesar Rodríguez
- School of Pharmacy, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
| | - David Morales
- School of Pharmacy, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
| | - Andrea Castillo
- School of Pharmacy, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
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Wang MR, Huang LF, Guo C, Yang J, Dong S, Tang JJ, Gao JM. Identification of NLRP3 as a covalent target of 1,6-O,O-diacetylbritannilactone against neuroinflammation by quantitative thiol reactivity profiling (QTRP). Bioorg Chem 2021; 119:105536. [PMID: 34894577 DOI: 10.1016/j.bioorg.2021.105536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 11/02/2022]
Abstract
Neuroinflammation plays a key etiological role in the progressive neuronal damage of neurodegenerative diseases. Our phenotypic-based screening discovered 1,6-O,O-diacetylbritannilactone (OABL, 1) from Inula britannica exhibited the potential anti-neuroinflammatory activity as well as a favorable blood-brain barrier penetration. 1 and its active derivative Br-OABL (2) with insert of Br at the C-14 position both modulated TLR4/NF-kB/MAPK pathways. However, proteome-wide identification of 1 binding proteins remains unclear. Here, we employed an adapted isoTOP-ABPP, quantitative thiol reactivity profiling (QTRP) approach, to identify and quantify thiol reactivity binding proteins in murine microglia BV-2 cells. We screened out 15 proteins co-targeted by 1 and 2, which are involved in cellular response to oxidative stress and negative regulation NF-κB transcription factor in biological processes. In site-specific profiling, NLRP3 was identified as a covalent target of 1 and 2 for the first time, and the Cys483 of NLRP3 NACHT domain was identified as one active-site of NLRP3 cysteine residues that can be covalently modified by the α-methylene-γ-lactone moiety. Furthermore, NLRP3 was validated to be directly binded by 1 and 2 by cellular thermo shift assay (CETSA) and activity-based protein profiling (ABPP), and NLRP3 functions were also verified by small interfering RNA approach. Notably, OABL treatment (i.p., 20 mg/kg/day) for 21 days reduced inflammation in 5XFAD mice brain. Together, we applied the QTRP to uncover the binding proteins of OABL in BV-2 cells, among which NLRP3 was revealed as a new covalent target of 1 and 2 against neuroinflammation.
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Affiliation(s)
- Min-Ran Wang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, Beijing Institute of Lifeomics, Beijing, China
| | - Lan-Fang Huang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China
| | - Cong Guo
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China
| | - Jing Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, Beijing Institute of Lifeomics, Beijing, China
| | - Shuai Dong
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, Hainan, China
| | - Jiang-Jiang Tang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China.
| | - Jin-Ming Gao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China.
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Idres YA, Tousch D, Cazals G, Lebrun A, Naceri S, Bidel LPR, Poucheret P. A Novel Sesquiterpene Lactone Xanthatin-13-(pyrrolidine-2-carboxylic acid) Isolated from Burdock Leaf Up-Regulates Cells' Oxidative Stress Defense Pathway. Antioxidants (Basel) 2021; 10:antiox10101617. [PMID: 34679753 PMCID: PMC8533074 DOI: 10.3390/antiox10101617] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/10/2021] [Accepted: 10/11/2021] [Indexed: 12/18/2022] Open
Abstract
The aim of our study was to identify novel molecules able to induce an adaptative response against oxidative stress during the first stages of metabolic syndrome. A cellular survival in vitro test against H2O2-based test was applied after pretreatment with various natural bitter Asteraceae extracts. This screening revealed potent protection from burdock leaf extract. Using chromatography and LC-MS—RMN, we then isolated and identified an original sesquiterpene lactone bioactive molecule: the Xanthatin-13-(pyrrolidine-2-carboxylic acid) (XPc). A real-time RT-qPCR experiment was carried out on three essential genes involved in oxidative stress protection: GPx, SOD, and G6PD. In presence of XPc, an over-expression of the G6PD gene was recorded, whereas no modification of the two others genes could be observed. A biochemical docking approach demonstrated that XPc had a high probability to directly interact with G6PD at different positions. One of the most probable docking sites corresponds precisely to the binding site of AG1, known to stabilize the G6PD dimeric form and enhance its activity. In conclusion, this novel sesquiterpene lactone XPc might be a promising prophylactic bioactive agent against oxidative stress and inflammation in chronic diseases such as metabolic syndrome or type 2 diabetes.
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Affiliation(s)
- Yanis A. Idres
- UMR 95 Qualisud, University Montpellier, CIRAD, SupAgro Montpellier, 15 Avenue Charles Flahault, BP 14491, CEDEX 5, 34093 Montpellier, France;
- Correspondence: (Y.A.I.); (D.T.); Tel.: +33-658587547 (Y.A.I.); +33-673466032 (D.T.)
| | - Didier Tousch
- UMR 95 Qualisud, University Montpellier, CIRAD, SupAgro Montpellier, 15 Avenue Charles Flahault, BP 14491, CEDEX 5, 34093 Montpellier, France;
- Correspondence: (Y.A.I.); (D.T.); Tel.: +33-658587547 (Y.A.I.); +33-673466032 (D.T.)
| | - Guillaume Cazals
- Laboratoire de Mesure Physique, Université de Montpellier, Place Eugène Bataillon, CEDEX 5, 34093 Montpellier, France; (G.C.); (A.L.)
| | - Aurélien Lebrun
- Laboratoire de Mesure Physique, Université de Montpellier, Place Eugène Bataillon, CEDEX 5, 34093 Montpellier, France; (G.C.); (A.L.)
| | - Sarah Naceri
- Laboratoire de Biologie Fonctionnelle et Adaptative, Université de Paris, CNRS UMR 8251, 35 rue Héléne Brion, 75013 Paris, France;
| | - Luc P. R. Bidel
- INRA, UMR AGAP, CIRAD, SupAgro, 2 Place Pierre Viala, 34060 Montpellier, France;
| | - Patrick Poucheret
- UMR 95 Qualisud, University Montpellier, CIRAD, SupAgro Montpellier, 15 Avenue Charles Flahault, BP 14491, CEDEX 5, 34093 Montpellier, France;
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20
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Tang JJ, Wang MR, Dong S, Huang LF, He QR, Gao JM. 1,10-Seco-Eudesmane sesquiterpenoids as a new type of anti-neuroinflammatory agents by suppressing TLR4/NF-κB/MAPK pathways. Eur J Med Chem 2021; 224:113713. [PMID: 34315042 DOI: 10.1016/j.ejmech.2021.113713] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/14/2021] [Accepted: 07/18/2021] [Indexed: 11/16/2022]
Abstract
Dysregulation of neuroinflammation is a key pathological factor in the progressive neuronal damage of neurodegenerative diseases. An in-house natural products library of 1407 compounds were screened against neuroinflammation in lipopolysaccharide (LPS)-activated microglia cells to identify a novel hit 1,6-O,O-diacetylbritannilactone (OABL) with anti-neuroinflammatory activity. Furthermore, a 1,10-seco-eudesmane sesquiterpenoid library containing 33 compounds was constructed by semisynthesis of a major component 1-O-acetylbritannilactone (ABL) from the traditional Chinese medicinal herb Inula Britannica L. Compound 15 was identified as a promising anti-neuroinflammatory agent by nitrite oxide (NO) production screening. 15 could attenuate tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) productions, and inhibit the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at a submicromolar level. Mechanistic study revealed that 15 significantly modulated TLR4/NF-kB and p38 MAPK pathways, and upregulated the anti-oxidant response HO-1. Besides, 15 promoted the conversion of the microglia from M1 to M2 phenotype by increasing levels of arginase-1 and IL-10. The structure-activity relationships (SARs) analysis indicated that the α-methylene-γ-lactone motifs, epoxidation of C5=C10 bond and bromination of C14 were important to the activity. Parallel artificial membrane permeation assay (PAMPA) also demonstrated that 15 and OABL can overcome the blood-brain barrier (BBB). In all, compound 15 is a promising anti-neuroinflammatory lead with potent anti-inflammatory effects via the blockage of TLR4/NF-κB/MAPK pathways, favorable BBB penetration property, and low cytotoxicity.
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Affiliation(s)
- Jiang-Jiang Tang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China.
| | - Min-Ran Wang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China
| | - Shuai Dong
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China
| | - Lan-Fang Huang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China
| | - Qiu-Rui He
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China
| | - Jin-Ming Gao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China.
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21
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Anti- Helicobacter pylori Activity of Artemisia ludoviciana subsp. mexicana and Two of Its Bioactive Components, Estafiatin and Eupatilin. Molecules 2021; 26:molecules26123654. [PMID: 34203927 PMCID: PMC8232798 DOI: 10.3390/molecules26123654] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/07/2021] [Accepted: 06/11/2021] [Indexed: 12/25/2022] Open
Abstract
Artemisia ludoviciana subsp. mexicana has been traditionally used for the treatment of digestive ailments such as gastritis, whose main etiological agent is Helicobacter pylori. In a previous screening study, the aqueous extract exhibited a good in vitro anti-H. pylori activity. With the aim of determining the efficacy of this species as a treatment for H. pylori related diseases and finding bioactive compounds, its aqueous extract was subjected to solvent partitioning and the fractions obtained were tested for their in vitro anti-H. pylori effect, as well as for their in vivo gastroprotective and anti-inflammatory activities. The aqueous extract showed a MIC = 250 µg/mL. No acute toxicity was induced in mice. A gastroprotection of 69.8 ± 3.8%, as well as anti-inflammatory effects of 47.6 ± 12.4% and 38.8 ± 10.2% (by oral and topical administration, respectively), were attained. Estafiatin and eupatilin were isolated and exhibited anti-H. pylori activity with MBCs of 15.6 and 31.2 µg/mL, respectively. The finding that A. ludoviciana aqueous extract has significant anti-H. pylori, gastroprotective and anti-inflammatory activities is a relevant contribution to the ethnopharmacological knowledge of this species. This work is the first report about the in vivo gastroprotective activity of A. ludoviciana and the anti-H. pylori activity of eupatilin and estafiatin.
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22
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Morais PAB, Francisco CS, de Paula H, Ribeiro R, Eloy MA, Javarini CL, Neto ÁC, Júnior VL. Semisynthetic Triazoles as an Approach in the Discovery of Novel Lead Compounds. CURR ORG CHEM 2021. [DOI: 10.2174/1385272825666210126100227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Historically, medicinal chemistry has been concerned with the approach of organic
chemistry for new drug synthesis. Considering the fruitful collections of new molecular entities,
the dedicated efforts for medicinal chemistry are rewarding. Planning and search for new
and applicable pharmacologic therapies involve the altruistic nature of the scientists. Since
the 19th century, notoriously applying isolated and characterized plant-derived compounds in
modern drug discovery and various stages of clinical development highlight its viability and
significance. Natural products influence a broad range of biological processes, covering transcription,
translation, and post-translational modification, being effective modulators of most
basic cellular processes. The research of new chemical entities through “click chemistry”
continuously opens up a map for the remarkable exploration of chemical space towards leading
natural products optimization by structure-activity relationship. Finally, in this review, we expect to gather a
broad knowledge involving triazolic natural product derivatives, synthetic routes, structures, and their biological activities.
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Affiliation(s)
- Pedro Alves Bezerra Morais
- Centro de Ciencias Exatas, Naturais e da Saude, Universidade Federal do Espirito Santo, 29500000, Alegre, ES, Brazil
| | - Carla Santana Francisco
- Programa de Pos-Graduacao em Quimica, Universidade Federal do Espirito Santo, 29075910, Vitória, ES, Brazil
| | - Heberth de Paula
- Centro de Ciencias Exatas, Naturais e da Saude, Universidade Federal do Espirito Santo, 29500000, Alegre, ES, Brazil
| | - Rayssa Ribeiro
- Programa de Pos- Graduacao em Agroquimica, Universidade Federal do Espirito Santo, 29500000, Alegre, ES, Brazil
| | - Mariana Alves Eloy
- Programa de Pos- Graduacao em Agroquimica, Universidade Federal do Espirito Santo, 29500000, Alegre, ES, Brazil
| | - Clara Lirian Javarini
- Programa de Pos-Graduacao em Quimica, Universidade Federal do Espirito Santo, 29075910, Vitória, ES, Brazil
| | - Álvaro Cunha Neto
- Programa de Pos-Graduacao em Quimica, Universidade Federal do Espirito Santo, 29075910, Vitória, ES, Brazil
| | - Valdemar Lacerda Júnior
- Programa de Pos-Graduacao em Quimica, Universidade Federal do Espirito Santo, 29075910, Vitória, ES, Brazil
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23
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Chopra B, Dhingra AK. Natural products: A lead for drug discovery and development. Phytother Res 2021; 35:4660-4702. [PMID: 33847440 DOI: 10.1002/ptr.7099] [Citation(s) in RCA: 182] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 03/01/2021] [Accepted: 03/09/2021] [Indexed: 12/29/2022]
Abstract
Natural products are used since ancient times in folklore for the treatment of various ailments. Plant-derived products have been recognized for many years as a source of therapeutic agents and structural diversity. A literature survey has been carried out to determine the utility of natural molecules and their modified analogs or derivatives as pharmacological active entities. This review presents a study on the importance of natural products in terms of drug discovery and development. It describes how the natural components can be utilized after small modifications in new perspectives. Various new modifications in structure offer a unique opportunity to establish a new molecular entity with better pharmacological potential. It was concluded that in this current era, new attempts are taken to utilize the compounds derived from natural sources as novel drug candidates, with a focus to find and discover new effective molecules that were referred to as "new entities of natural product drug discovery."
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Affiliation(s)
- Bhawna Chopra
- Department of Pharmaceutical Chemistry, Guru Gobind Singh College of Pharmacy, Yamuna Nagar, India
| | - Ashwani Kumar Dhingra
- Department of Pharmaceutical Chemistry, Guru Gobind Singh College of Pharmacy, Yamuna Nagar, India
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24
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Cuevas-Barragan CE, Buenrostro-Nava MT, Palos-Gómez GM, Ramirez-Padilla EA, Mendoza-Macias BI, Rivas-Caceres RR. Use of Nasoil® via intranasal to control the harmful effects of Covid-19. Microb Pathog 2020; 149:104504. [PMID: 32950636 PMCID: PMC7497547 DOI: 10.1016/j.micpath.2020.104504] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/10/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023]
Abstract
In the absence of vaccines and antiviral drugs available to prevent and treat COVID-19, it becomes imperative to find or use all those products with the potential to fight this virus. This article is an attempt to propose ways to prevent, treat and control the COVID-19 virus, using a product based on plant extracts with the potential to reduce the symptoms caused by the SARS-CoV-2 virus. Nasoil® counts as one of its main components, Asclepias curassavica extracts, and in the present study it has been shown that it is an effective adjuvant in the treatment of Covid-19, increasing the respiratory capacity of the patients (SpO2> 90%) and reducing the symptoms from the first application, improving the patients around the fifth to the eighth application. At a preventive level, the individuals in this study who have applied it (400 individuals) only a 3.15% of these presented symptoms, disappearing when increasing the weekly applications.
Nasoil® protects from the appearance of symptoms by 96% due to Covid-19. Modifying lung microenvironments reduces Covid-19 symptoms. Promoting new interactions in the elastic protein decreases the elastase activity of neutrophils. The combination of plant extracts in Nasoil® help in respiratory problems. Nasoil® is an co-adjuvant for the control and prevention of the SARS-CoV-2 virus.
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Affiliation(s)
| | | | - Gabriela Monserrat Palos-Gómez
- Especialista en Medicina Familiar, Unidad de Medicina Familiar núm, 19, del Instituto Mexicano del Seguro Social, Colima, Colima, Mexico
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25
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Parthenolide as Cooperating Agent for Anti-Cancer Treatment of Various Malignancies. Pharmaceuticals (Basel) 2020; 13:ph13080194. [PMID: 32823992 PMCID: PMC7466132 DOI: 10.3390/ph13080194] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 12/18/2022] Open
Abstract
Primary and acquired resistance of cancer to therapy is often associated with activation of nuclear factor kappa B (NF-κB). Parthenolide (PN) has been shown to inhibit NF-κB signaling and other pro-survival signaling pathways, induce apoptosis and reduce a subpopulation of cancer stem-like cells in several cancers. Multimodal therapies that include PN or its derivatives seem to be promising approaches enhancing sensitivity of cancer cells to therapy and diminishing development of resistance. A number of studies have demonstrated that several drugs with various targets and mechanisms of action can cooperate with PN to eliminate cancer cells or inhibit their proliferation. This review summarizes the current state of knowledge on PN activity and its potential utility as complementary therapy against different cancers.
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26
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The Artemisinin-Derived Autofluorescent Compound BG95 Exerts Strong Anticytomegaloviral Activity Based on a Mitochondrial Targeting Mechanism. Int J Mol Sci 2020; 21:ijms21155578. [PMID: 32759737 PMCID: PMC7432203 DOI: 10.3390/ijms21155578] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/30/2020] [Accepted: 07/31/2020] [Indexed: 01/05/2023] Open
Abstract
Human cytomegalovirus (HCMV) is a major human pathogen associated with severe pathology. Current options of antiviral therapy only partly satisfy the needs of a well-tolerated long-term treatment/prophylaxis free from drug-induced viral resistance. Recently, we reported the strong antiviral properties in vitro and in vivo of the broad-spectrum anti-infective drug artesunate and its optimized derivatives. NF-κB signaling was described as a targeting mechanism and additional target proteins have recently been identified. Here, we analyzed the autofluorescent hybrid compound BG95, which could be utilized for intracellular visualization by confocal imaging and a tracking analysis in virus-infected primary human fibroblasts. As an important finding, BG95 accumulated in mitochondria visualized by anti-prohibitin and MitoTracker staining, and induced statistically significant changes of mitochondrial morphology, distinct from those induced by HCMV infection. Notably, mitochondrial membrane potential was found substantially reduced by BG95, an effect apparently counteracting efficient HCMV replication, which requires active mitochondria and upregulated energy levels. This finding was consistent with binding properties of artesunate-like compounds to mitochondrial proteins and thereby suggested a new mechanistic aspect. Combined, the present study underlines an important role of mitochondria in the multifaceted, host-directed antiviral mechanism of this drug class, postulating a new mitochondria-specific mode of protein targeting.
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27
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Rana S, Kour S, Sonawane YA, Robb CM, Contreras JI, Kizhake S, Zahid M, Karpf AR, Natarajan A. Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK. Chem Biol Drug Des 2020; 96:773-784. [PMID: 32237047 DOI: 10.1111/cbdd.13684] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/04/2020] [Accepted: 03/14/2020] [Indexed: 12/11/2022]
Abstract
The release of an active drug from the prodrug generates a pro-fragment that typically has no biological activity and could result in adverse effects. By combining two drugs, wherein each drug acts as a pro-fragment of the other drug will eliminate the pro-fragment in the prodrug. As they are prodrugs of each other and are symbiotic, we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NFκB inhibitors that contain the reactive α-methylene-γ-butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of α-methylene-γ-butyrolactone containing NFκB inhibitors undergo slow release over a 72 hr period. Using an alkyne-tagged secondary amine prodrug of α-methylene-γ-butyrolactone containing NFκB inhibitor, we demonstrate target engagement. The NFκB-CDK SymProDs were ~20- to 200-fold less active against the corresponding CDK inhibitors in in vitro CDK kinase assays. Growth inhibition studies in a panel of ovarian cancer cell lines revealed potency trends of the SymProDs mirrored those of the single treatments suggesting their dissociation in cells. In conclusion, our results suggest that SymProDs offer a productive path forward for advancing compounds with reactive functionality and can be used as dual targeting agents.
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Affiliation(s)
- Sandeep Rana
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Smit Kour
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yogesh A Sonawane
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Caroline M Robb
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jacob I Contreras
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Smitha Kizhake
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Muhammad Zahid
- Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE, USA
| | - Adam R Karpf
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Amarnath Natarajan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
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28
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Assessing the Effects of Parthenolide on Inflammation, Bone Loss, and Glial Cells within a Collagen Antibody-Induced Arthritis Mouse Model. Mediators Inflamm 2020; 2020:6245798. [PMID: 32189995 PMCID: PMC7073477 DOI: 10.1155/2020/6245798] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 12/16/2019] [Accepted: 01/27/2020] [Indexed: 12/21/2022] Open
Abstract
Rheumatoid arthritis is characterised by a chronic inflammatory response resulting in destruction of the joint and significant pain. Although a range of treatments are available to control disease activity in RA, bone destruction and joint pain exist despite suppression of inflammation. This study is aimed at assessing the effects of parthenolide (PAR) on paw inflammation, bone destruction, and pain-like behaviour in a mild collagen antibody-induced arthritis (CAIA) mouse model. CAIA was induced in BALB/c mice and treated daily with 1 mg/kg or 4 mg/kg PAR. Clinical paw inflammation was scored daily, and mechanical hypersensitivity was assessed on alternate days. At end point, bone volume and swelling in the paws were assessed using micro-CT. Paw tissue sections were assessed for inflammation and pre-/osteoclast-like cells. The lumbar spinal cord and the periaqueductal grey (PAG) and rostral ventromedulla (RVM) regions of the brain were stained for glial fibrillary acidic protein (GFAP) and ionised calcium-binding adaptor molecule 1 (IBA1) to assess for glial reactivity. Paw scores increased in CAIA mice from days 5-10 and were reduced with 1 mg/kg and 4 mg/kg PAR on days 8-10. Osteoclast-like cells on the bone surface of the radiocarpal joint and within the soft tissue of the hind paw were significantly lower following PAR treatment (p < 0.005). GFAP- and IBA1-positive cells in the PAG and RVM were significantly lower following treatment with 1 mg/kg (p < 0.0001 and p = 0.0004, respectively) and 4 mg/kg PAR (p < 0.0001 and p = 0.001, respectively). In the lumbar spinal cord, IBA1-positive cells were significantly lower in CAIA mice treated with 4 mg/kg PAR (p = 0.001). The findings indicate a suppressive effect of both low- and moderate-dose PAR on paw inflammation, osteoclast presence, and glial cell reactivity in a mild CAIA mouse model.
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29
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Freund RRA, Gobrecht P, Fischer D, Arndt HD. Advances in chemistry and bioactivity of parthenolide. Nat Prod Rep 2020; 37:541-565. [DOI: 10.1039/c9np00049f] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
(−)-Parthenolide is a germacrane sesquiterpene lactone, available in ample amounts from the traditional medical plant feverfew (Tanacetum parthenium).
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Affiliation(s)
- Robert R. A. Freund
- Institut für Organische Chemie und Makromolekulare Chemie
- Friedrich-Schiller-Universität
- D-07743 Jena
- Germany
| | - Philipp Gobrecht
- Lehrstuhl für Zellphysiologie
- Ruhr-Universität Bochum
- D-44780 Bochum
- Germany
| | - Dietmar Fischer
- Lehrstuhl für Zellphysiologie
- Ruhr-Universität Bochum
- D-44780 Bochum
- Germany
| | - Hans-Dieter Arndt
- Institut für Organische Chemie und Makromolekulare Chemie
- Friedrich-Schiller-Universität
- D-07743 Jena
- Germany
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30
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Zhang Y, Huang Q, Chen Y, Peng X, Wang Y, Li S, Wu J, Luo C, Gong W, Yin B, Xiao J, Zhou W, Peng F, Long H. Parthenolide, an NF-κB inhibitor, alleviates peritoneal fibrosis by suppressing the TGF-β/Smad pathway. Int Immunopharmacol 2019; 78:106064. [PMID: 31838448 DOI: 10.1016/j.intimp.2019.106064] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 11/14/2019] [Accepted: 11/17/2019] [Indexed: 10/25/2022]
Abstract
Transforming growth factor (TGF)-β/Smad signalling plays a central role in the pathogenesis of peritoneal fibrosis related to peritoneal dialysis (PD). Parthenolide (PTL), a naturally occurring phytochemical, is isolated from the shoots of feverfew (Tanacetum parthenium) and displays analgesia, anti-inflammation and anticancer activities. In this study, we examined the therapeutic potential of PTL on PD-related peritoneal fibrosis induced by daily intraperitoneal injection of 4.25% dextrose-containing PD fluid (PDF) in vivo and TGF-β1-induced epithelial-mesenchymal transition (EMT) in vitro. PTL was administered daily before PDF injection or after 14 days of PDF injection. Both PTL treatments showed a protective effect on peritoneal fibrosis and prevented peritoneal dysfunction. Similarly, PTL suppressed the expression of fibrotic markers (fibronectin and collagen I) and restored the expression of the epithelial marker (E-cadherin) in TGF-β1-treated HMrSV5 cells. Furthermore, PTL inhibited TGF-β1-induced Smad2 and Smad3 phosphorylation and nuclear translocation but did not influence Smad1/5/9 phosphorylation or activate other downstream signalling pathways of TGF-β1, including AKT, extracellular signal-regulated kinase (ERK) or p38. In conclusion, PTL treatment may represent an effective and novel therapy for PD-associated peritoneal fibrosis by suppressing the TGF-β/Smad pathway.
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Affiliation(s)
- Ying Zhang
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; Department of Nephrology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Qianyin Huang
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Yihua Chen
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Xuan Peng
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Yuxian Wang
- Department of Gerontology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Shuting Li
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Jiayu Wu
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Congwei Luo
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Wangqiu Gong
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Bohui Yin
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Jing Xiao
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Weidong Zhou
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Fenfen Peng
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Haibo Long
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
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31
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Ren Y, Li Y, Lv J, Guo X, Zhang J, Zhou D, Zhang Z, Xue Z, Yang G, Xi Q, Liu H, Liu Z, Zhang L, Zhang Q, Yao Z, Zhang R, Da Y. Parthenolide regulates oxidative stress-induced mitophagy and suppresses apoptosis through p53 signaling pathway in C2C12 myoblasts. J Cell Biochem 2019; 120:15695-15708. [PMID: 31144365 DOI: 10.1002/jcb.28839] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/20/2019] [Accepted: 01/24/2019] [Indexed: 12/25/2022]
Abstract
Muscle redox disturbances and oxidative stress have emerged as a common pathogenetic mechanism and potential therapeutic intervention in some muscle diseases. Parthenolide (PTL), a sesquiterpene lactone found in large amounts in the leaves of feverfew, possesses anti-inflammatory, anti-migraine, and anticancer properties. Although PTL was reported to alleviate cancer cachexia and improve skeletal muscle characteristics in a cancer cachexia model, its actions on oxidative stress-induced damage in C2C12 myoblasts have not been reported and the regulatory mechanisms have not yet been defined. In our study, PTL attenuated H2 O2 -induced growth inhibition and morphological changes. Furthermore, PTL exhibited scavenging activity against reactive oxygen species and protected C2C12 cells from apoptosis in response to H2 O2 . Meanwhile, PTL suppressed collapse of the mitochondrial membrane potential, thereby contributing to normalizing H2 O2 -induced autophagy flux and mitophagy, correlating with inhibiting degradation of mitochondrial marker protein TIM23, the increase in LC3-II expression and the reduction of mitochondria DNA. Besides its protective effect on mitochondria, PTL also prevented H2 O2 -induced lysosomes damage in C2C12 cells. In addition, the phosphorylation of p53, cathepsin B, and Bax/Bcl-2 protein levels, and the translocation of Bax from the cytosol to mitochondria induced by H2 O2 in C2C12 cells was significantly reduced by PTL. In conclusion, PTL modulates oxidative stress-induced mitophagy and protects C2C12 myoblasts against apoptosis, suggesting a potential protective effect against oxidative stress-associated skeletal muscle diseases.
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Affiliation(s)
- Yinghui Ren
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China.,Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin, China
| | - Yan Li
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Jienv Lv
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China.,Clinical Laboratory, Hexi Women & Children Healthcare and Family Planning Service Center, Tianjin, China
| | - Xiangdong Guo
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Jieyou Zhang
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Dongmei Zhou
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Zimu Zhang
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Zhenyi Xue
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Guangze Yang
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Qing Xi
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Hongkun Liu
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Zehan Liu
- Surgical Intensive Care Unit, The Third People's Hospital of Chengdu, Chengdu, China
| | - Lijuan Zhang
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Qi Zhang
- Tianjin key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, ITCWM Hospital, Tianjin University Tianjin Nankai Hospital, Tianjin, China
| | - Zhi Yao
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
| | - Rongxin Zhang
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China.,Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yurong Da
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, China
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Dawood M, Ooko E, Efferth T. Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines. Front Pharmacol 2019; 10:542. [PMID: 31164821 PMCID: PMC6536578 DOI: 10.3389/fphar.2019.00542] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 04/30/2019] [Indexed: 12/18/2022] Open
Abstract
Parthenolide (PT) is a sesquiterpene lactone isolated from Tanacetum parthenium. In this study, PT showed varying cytotoxic effects against different solid tumor cell lines. HCT116 (p53+/+) colon carcinoma cells and their parental HCT116 knockout p53 (p53-/-) cell lines showed a resistance degree of 2.36. On the other hand, wild-type U87.MG cells or cells transfected with a deletion-activated EGFR cDNA (U87.MGΔEGFR) exhibited slight sensitivity toward PT. Multidrug-resistant MDA-MB-231-BCRP cells were even more sensitive toward PT than sensitive MDA-MB-231-pcDNA cells with a resistance degree of 0.07 (collateral sensitivity). To the best of our knowledge, hypersensitivity (collateral sensitivity) in MDA-MB-231-BCRP cell line is reported in this study for the first time. We attempted to identify the mechanism of collateral sensitivity. Firstly, we found that PT bound to IKK preventing IκBα degradation and eventually inhibition of the nuclear factor kappa B (NF-κB) pathway. Down-regulation of hypoxia inducing factor 1-alpha (HIF-1α) in MDA-MB-231-BCRP resistant cells may be a second mechanism, since it is a target gene of NF-κB. Moreover, PT also showed epigenetic effect by inhibition of HDAC activity as shown using both molecular docking and HDAC activity assay. Based on COMPARE and hierarchical cluster analyses, we found gene expression profiles that predicted sensitivity or resistance of 47 tumor cell lines toward PT. Interestingly, pathway analyses of gene expression profiles revealed NF-κB and HIF signaling as top networks of these genes, cellular functions and canonical pathways influencing the activity of PT against tumor cells. In conclusion, PT exerted profound cytotoxic activity against various cancer cell lines mainly against BCRP-overexpressing tumor cells, suggesting PT as novel candidate for cancer treatment.
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Affiliation(s)
- Mona Dawood
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany
| | - Edna Ooko
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany
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Casali CI, Erjavec LC, Fernández-Tome MDC. Sequential and synchronized hypertonicity-induced activation of Rel-family transcription factors is required for osmoprotection in renal cells. Heliyon 2019; 4:e01072. [PMID: 30603705 PMCID: PMC6304461 DOI: 10.1016/j.heliyon.2018.e01072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 10/31/2018] [Accepted: 12/14/2018] [Indexed: 01/28/2023] Open
Abstract
NF-κB and TonEBP belong to the Rel-superfamily of transcription factors. Several specific stimuli, including hypertonicity which is a key factor for renal physiology, are able to activate them. It has been reported that, after hypertonic challenge, NF-κB activity can be modulated by TonEBP, considered as the master regulator of transcriptional activity in the presence of changes in environmental tonicity. In the present work we evaluated whether hypertonicity-induced gene transcription mediated by p65/RelA and TonEBP occurs by an independent action of each transcription factor or by acting together. To do this, we evaluated the expression of their specific target genes and cyclooxygenase-2 (COX-2), a common target of both transcription factors, in the renal epithelial cell line Madin-Darby canine kidney (MDCK) subjected to hypertonic environment. The results herein indicate that hypertonicity activates the Rel-family transcription factors p65/RelA and TonEBP in MDCK cells, and that both are required for hypertonic induction of COX-2 and of their specific target genes. In addition, present data show that p65/RelA modulates TonEBP expression and both colocalize in nuclei of hypertonic cultures of MDCK cells. Thus, a sequential and synchronized action p65/RelA → TonEBP would be necessary for the expression of hypertonicity-induced protective genes.
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Affiliation(s)
- Cecilia I Casali
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Buenos Aires, Argentina.,Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini (IQUIFIB)-Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina
| | - Luciana C Erjavec
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Buenos Aires, Argentina
| | - María Del Carmen Fernández-Tome
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Buenos Aires, Argentina.,Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini (IQUIFIB)-Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina
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34
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Peng F, Li H, Li S, Wang Y, Liu W, Gong W, Yin B, Chen S, Zhang Y, Luo C, Zhou W, Chen Y, Li P, Huang Q, Xu Z, Long H. Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway. J Transl Med 2019; 99:1092-1106. [PMID: 30976056 PMCID: PMC6760645 DOI: 10.1038/s41374-019-0245-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 12/13/2018] [Accepted: 02/14/2019] [Indexed: 12/31/2022] Open
Abstract
Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for in vivo use, in two renal fibrosis models-the unilateral ureteral occlusion (UUO) model and an ischaemia-reperfusion injury (IRI) model and used MCL in combination with transforming growth factor beta 1 (TGF-β1) on mouse tubular epithelial cells (mTEC) in vitro. The expression of fibrotic markers (fibronectin and α-SMA) was remarkably reduced, while the expression of the epithelial marker E-cadherin was restored after DMAMCL treatment both in the UUO and IRI mice. MCL function in TGF-β1-induced epithelial-mesenchymal transition (EMT) in mTEC was consistent with the in vivo results. Metadherin (Mtdh) was activated in the fibrotic condition, suggesting that it might be involved in fibrogenesis. Interestingly, we found that while Mtdh was upregulated in the fibrotic condition, DMAMCL/MCL could suppress its expression. The overexpression of Mtdh exerted a pro-fibrotic effect by modulating the BMP/MAPK pathway in mTECs, and MCL could specifically reverse this effect. In conclusion, DMAMCL/MCL treatment represents a novel and effective therapy for renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.
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Affiliation(s)
- Fenfen Peng
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Hongyu Li
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Shuting Li
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Yuxian Wang
- 0000 0000 8877 7471grid.284723.8Department of Gerontology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Wenting Liu
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Wangqiu Gong
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Bohui Yin
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Sijia Chen
- Department of Nephrology, The First Hospital of Changsha, Changsha, 410000 China
| | - Ying Zhang
- 0000 0000 8653 1072grid.410737.6Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260 China
| | - Congwei Luo
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Weidong Zhou
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Yihua Chen
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Peilin Li
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Qianyin Huang
- 0000 0004 1771 3058grid.417404.2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280 China
| | - Zhaozhong Xu
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China.
| | - Haibo Long
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
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Ferreira LT, Figueiredo AC, Orr B, Lopes D, Maiato H. Dissecting the role of the tubulin code in mitosis. Methods Cell Biol 2018; 144:33-74. [PMID: 29804676 DOI: 10.1016/bs.mcb.2018.03.040] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mitosis is an essential process that takes place in all eukaryotes and involves the equal division of genetic material from a parental cell into two identical daughter cells. During mitosis, chromosome movement and segregation are orchestrated by a specialized structure known as the mitotic spindle, composed of a bipolar array of microtubules. The fundamental structure of microtubules comprises of α/β-tubulin heterodimers that associate head-to-tail and laterally to form hollow filaments. In vivo, microtubules are modified by abundant and evolutionarily conserved tubulin posttranslational modifications (PTMs), giving these filaments the potential for a wide chemical diversity. In recent years, the concept of a "tubulin code" has emerged as an extralayer of regulation governing microtubule function. A range of tubulin isoforms, each with a diverse set of PTMs, provides a readable code for microtubule motors and other microtubule-associated proteins. This chapter focuses on the complexity of tubulin PTMs with an emphasis on detyrosination and summarizes the methods currently used in our laboratory to experimentally manipulate these modifications and study their impact in mitosis.
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Affiliation(s)
- Luísa T Ferreira
- Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Ana C Figueiredo
- Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Bernardo Orr
- Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Danilo Lopes
- Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Helder Maiato
- Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
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36
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Abdelhafez OH, Fawzy MA, Fahim JR, Desoukey SY, Krischke M, Mueller MJ, Abdelmohsen UR. Hepatoprotective potential of Malvaviscus arboreus against carbon tetrachloride-induced liver injury in rats. PLoS One 2018; 13:e0202362. [PMID: 30138328 PMCID: PMC6107176 DOI: 10.1371/journal.pone.0202362] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 08/01/2018] [Indexed: 12/15/2022] Open
Abstract
Malvaviscus arboreus Cav. is a medicinal plant belonging to family Malvaceae with both ethnomedical and culinary value; however, its phytochemical and biological profiles have been scarcely studied. Accordingly, this work was designed to explore the chemical composition and the hepatoprotective potential of M. arboreus against carbon tetrachloride (CCl4)-induced hepatotoxicity. The total extract of the aerial parts and its derived fractions (petroleum ether, dichloromethane, ethyl acetate, and aqueous) were orally administered to rats for six consecutive days, followed by injection of CCl4 (1:1 v/v, in olive oil, 1.5 ml/kg, i.p.) on the next day. Results showed that the ethyl acetate and dichloromethane fractions significantly alleviated liver injury in rats as indicated by the reduced levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TB), and malondialdehyde (MDA), along with enhancement of the total antioxidant capacities of their livers, with the maximum effects were recorded by the ethyl acetate fraction. Moreover, the protective actions of both fractions were comparable to those of silymarin (100 mg/kg), and have been also substantiated by histopathological evaluations. On the other hand, liquid chromatography-high resolution electrospray ionization mass spectrometry (LC‒HR‒ESI‒MS) metabolomic profiling of the crude extract of M. arboreus aerial parts showed the presence of a variety of phytochemicals, mostly phenolics, whereas the detailed chemical analysis of the most active fraction (i.e. ethyl acetate) resulted in the isolation and identification of six compounds for the first time in the genus, comprising four phenolic acids; β-resorcylic, caffeic, protocatechuic, and 4-hydroxyphenylacetic acids, in addition to two flavonoids; trifolin and astragalin. Such phenolic principles, together with their probable synergistic antioxidant and liver-protecting properties, seem to contribute to the observed hepatoprotective potential of M. arboreus.
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Affiliation(s)
| | - Michael Atef Fawzy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - John Refaat Fahim
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Samar Yehia Desoukey
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Markus Krischke
- Julius-von-Sachs-Institute of Biosciences, Biocenter, Pharmaceutical Biology, University of Würzburg, Würzburg, Germany
| | - Martin J. Mueller
- Julius-von-Sachs-Institute of Biosciences, Biocenter, Pharmaceutical Biology, University of Würzburg, Würzburg, Germany
- * E-mail: (MJM); (URA)
| | - Usama Ramadan Abdelmohsen
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, Egypt
- Department of Botany II, Julius-von-Sachs-Institute for Biological Sciences, University of Würzburg, Würzburg, Germany
- * E-mail: (MJM); (URA)
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37
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Janganati V, Ponder J, Balasubramaniam M, Bhat-Nakshatri P, Bar EE, Nakshatri H, Jordan CT, Crooks PA. MMB triazole analogs are potent NF-κB inhibitors and anti-cancer agents against both hematological and solid tumor cells. Eur J Med Chem 2018; 157:562-581. [PMID: 30121494 DOI: 10.1016/j.ejmech.2018.08.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 08/03/2018] [Accepted: 08/04/2018] [Indexed: 10/28/2022]
Abstract
Triazole derivatives of melampomagnolide B (MMB) have been synthesized via click chemistry methodologies and screened against a panel of 60 human cancer cell lines. Several derivatives showed promising anti-cancer activity, affording growth inhibition (GI50) values in the nanomolar range (GI50 = 0.02-0.99 μM). Lead compound 7h exhibited EC50 values of 400 nM and 700 nM, respectively, against two AML clinical specimens. Compound 7h was significantly more potent than parthenolide as an inhibitor of p65 phosphorylation in both hematological and solid tumor cell lines, indicating its ability to inhibit the NF-κB pathway. In TMD-231 breast cancer cells, treatment with 7h reduced DNA binding activity of NF-κB through inhibition of IKK-β mediated p65 phosphorylation and caused elevation of basal IκBα levels through inhibition of constitutive IκBα turnover and NF-κB activation. Molecular docking and dynamic modeling studies indicated that 7h interacts with the kinase domain of the monomeric IKKβ subunit, leading to inhibition of IKKβ activation, and compromising phosphorylation of downstream targets of the NF-κB pathway; dynamic modeling studies show that this interaction also causes unwinding of the α-helix of the NEMO binding site on IKKβ. Molecular docking studies with 10, a water-soluble analog of 7h, demonstrate that this analog interacts with the dimerization/oligomerization domain of monomeric IKKβ and may inhibit oligomer formation and subsequent autophosphorylation. Sesquiterpene lactones 7h and 10 are considered ideal candidates for potential clinical development.
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Affiliation(s)
- Venumadhav Janganati
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Jessica Ponder
- Division of Hematology, University of Colorado, Aurora, CO, 80045, USA; Department of Toxicology, University of Colorado, Aurora, CO, 80045, USA
| | | | - Poornima Bhat-Nakshatri
- Department of Surgery, Indiana School of Medicine, Indianapolis, IN, 46202, USA; Department of Biochemistry and Molecular Biology, Indiana School of Medicine, Indianapolis, IN, 46202, USA
| | - Eli E Bar
- Department of Neurological Surgery, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, USA
| | - Harikrishna Nakshatri
- Department of Surgery, Indiana School of Medicine, Indianapolis, IN, 46202, USA; Department of Biochemistry and Molecular Biology, Indiana School of Medicine, Indianapolis, IN, 46202, USA
| | - Craig T Jordan
- Division of Hematology, University of Colorado, Aurora, CO, 80045, USA; Department of Toxicology, University of Colorado, Aurora, CO, 80045, USA
| | - Peter A Crooks
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
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Mabou Tagne A, Marino F, Cosentino M. Tithonia diversifolia (Hemsl.) A. Gray as a medicinal plant: A comprehensive review of its ethnopharmacology, phytochemistry, pharmacotoxicology and clinical relevance. JOURNAL OF ETHNOPHARMACOLOGY 2018; 220:94-116. [PMID: 29596999 DOI: 10.1016/j.jep.2018.03.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 03/22/2018] [Accepted: 03/22/2018] [Indexed: 05/28/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Tithonia diversifolia (TD) is widely valued in several cultures for its medicinal properties. A comprehensive review of the current understanding of this plant species is required due to emerging concerns over its efficacy, toxicity and allergenic potential. AIM OF THE REVIEW We critically summarized the current evidence on the botany, traditional use, phytochemistry, pharmacology and safety of TD, with the view to provide perspectives for developing more attractive pharmaceuticals of plant origin, but also to lay a new foundation for further investigations on this plant. MATERIALS AND METHODS A preliminary consultation of search engines such as Web of Science, PubMed, ScienceDirect and other published/unpublished resources provided an overview of extant literature on TD. Then, we meticulously screened all titles, abstracts and full-texts to establish consistency in the application of inclusion criteria. Studies were considered for inclusion if they dealt with taxonomy, global distribution, local and traditional knowledge, phytochemistry, toxicity and biological effects. RESULTS 1856 articles were retrieved among which 168 were revised and included. Several studies conducted on cell lines and animals provided supporting evidence for some ethnomedicinal claims of extracts from TD. Short-term use of Tithonia extracts were effective and well-tolerated in animals when taken at lower doses. Both the toxic and therapeutic effects were attributed to bioactive principles naturally occurring in this species including sesquiterpene lactones, chlorogenic acid and flavonoids. CONCLUSIONS T. diversifolia is a valuable source of bioactive compounds with significant therapeutic implications and favourable safety index. However, more rigorously designed investigations are needed to recommend the whole plant or its active ingredients as a medication, and should focus on understanding the multi-target network pharmacology of the plant, clarifying the effective doses as well as identifying the potential interactions with prescribed drugs or other chemicals.
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Affiliation(s)
- Alex Mabou Tagne
- Centre for Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy.
| | - Franca Marino
- Centre for Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy
| | - Marco Cosentino
- Centre for Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy
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Involvement of α-methylene-γ- and δ-lactones in the suppression of multidrug resistance in MCF-7 cells. Pharmacol Rep 2018; 70:631-638. [PMID: 29886368 DOI: 10.1016/j.pharep.2018.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 12/06/2017] [Accepted: 01/09/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND The development of multidrug resistance to chemotherapy remains a challenge in the treatment of cancer and is a major factor causing failure of many forms of chemotherapy. The ATP binding cassette (ABC) family of proteins are efflux pumps that transport various potentially dangerous substances out of the cells. Several of the ABC transporters are related to chemoresistance, as the rapidly dividing malignant cells use them to protect themselves from medical interventions. Inhibitors of ABC transporters have the potential to enhance the efficacy of anticancer drugs. Two new synthetic compounds, AD-06 and AD-013, were tested as possible multidrug resistance inhibitors in MCF-7 cells. METHODS The cytotoxicity of new compounds was tested in MCF-7 and MCF-10A cell lines using the MTT method. Gene expression was measured by real-time PCR and changes in the protein levels were evaluated by flow cytometry and ELISA. A method based on the use of a fluorescent dye, being a marker of the ABC transporter activity, was used for screening the tested compounds as potential multidrug resistance inhibitors. RESULTS AD-06 and AD-013 down-regulated NF-κB mRNA levels and decreased the population of cells with activated NF-κB. Both compounds were found to be strong ABCB1 and ABCG2 transporter inhibitors. They showed synergistic effects when incubated with taxol or oxaliplatin. CONCLUSIONS α-Methylene-γ- and -δ-lactones AD-06 and AD-013 are promising lead structures for further development as multidrug resistance inhibitors.
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Schneider-Poetsch T, Yoshida M. Along the Central Dogma-Controlling Gene Expression with Small Molecules. Annu Rev Biochem 2018; 87:391-420. [PMID: 29727582 DOI: 10.1146/annurev-biochem-060614-033923] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The central dogma of molecular biology, that DNA is transcribed into RNA and RNA translated into protein, was coined in the early days of modern biology. Back in the 1950s and 1960s, bacterial genetics first opened the way toward understanding life as the genetically encoded interaction of macromolecules. As molecular biology progressed and our knowledge of gene control deepened, it became increasingly clear that expression relied on many more levels of regulation. In the process of dissecting mechanisms of gene expression, specific small-molecule inhibitors played an important role and became valuable tools of investigation. Small molecules offer significant advantages over genetic tools, as they allow inhibiting a process at any desired time point, whereas mutating or altering the gene of an important regulator would likely result in a dead organism. With the advent of modern sequencing technology, it has become possible to monitor global cellular effects of small-molecule treatment and thereby overcome the limitations of classical biochemistry, which usually looks at a biological system in isolation. This review focuses on several molecules, especially natural products, that have played an important role in dissecting gene expression and have opened up new fields of investigation as well as clinical venues for disease treatment.
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Affiliation(s)
- Tilman Schneider-Poetsch
- Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan;
| | - Minoru Yoshida
- Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan; .,Department of Biotechnology, University of Tokyo, Tokyo 113-8657, Japan
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41
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Lima TC, de Jesus Souza R, da Silva FA, Biavatti MW. The genus Calea L.: A review on traditional uses, phytochemistry, and biological activities. Phytother Res 2018; 32:769-795. [PMID: 29464865 DOI: 10.1002/ptr.6010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 11/17/2017] [Accepted: 12/04/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Tamires Cardoso Lima
- Departamento de Farmácia, CCBS, Universidade Federal de Sergipe (UFS), São Cristóvão, SE, Brazil
| | - Rafaela de Jesus Souza
- Departamento de Ciências Farmacêuticas, CCS, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil
| | | | - Maique Weber Biavatti
- Departamento de Ciências Farmacêuticas, CCS, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil
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Hahn F, Fröhlich T, Frank T, Bertzbach LD, Kohrt S, Kaufer BB, Stamminger T, Tsogoeva SB, Marschall M. Artesunate-derived monomeric, dimeric and trimeric experimental drugs - Their unique mechanistic basis and pronounced antiherpesviral activity. Antiviral Res 2018; 152:104-110. [PMID: 29458133 DOI: 10.1016/j.antiviral.2018.02.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/06/2018] [Accepted: 02/13/2018] [Indexed: 12/24/2022]
Abstract
Human cytomegalovirus (HCMV) is a major human pathogen and is associated with severe pathology, such as life-threatening courses of infection in immunocompromised individuals and neonates. Currently, antiviral therapy is still hampered by a considerable toxicity of the available drugs and induction of viral resistance. Recently, we and others reported the very potent antiviral activity of the broad antiinfective drug artesunate in vitro and in vivo. Here, we investigated further optimized analogs including monomeric, dimeric and trimeric derivatives belonging to this highly interesting chemical group of experimental drugs (sesquiterpenes/trioxanes) and compared these to the previously identified trimeric artesunate compound TF27. We could demonstrate that (i) seven of the eight investigated monomeric, dimeric and trimeric artesunate derivatives, i.e. TF79, TF85, TF87, TF93.2.4, TF111, TF57a and TF57ab, exerted a strong anti-HCMV activity in primary human fibroblasts, (ii) the EC50 values ranged in the low to sub-micromolar concentrations and indicated a higher antiviral potency than the recently described artesunate analogs, (iii) one trimeric compound, TF79, showed a very promising EC50 of 0.03 ± 0.00 μM, which even exceled the antiviral potency of TF27 (EC50 0.04 ± 0.01 μM), (iv) levels of cytotoxicity (quantitative measurement of lactate dehydrogenase release) were low in a range between 100 and 30 μM and thus different from antiviral concentrations, (v) an analysis of protein expression levels indicated a potent block of viral protein expression, and (vi) data from a NF-κB reporter cell system strongly suggested that these compounds share the same antiviral mechanism. Taken together, our data on these novel compounds strongly encourages our earlier concept on the oligomerization and hybridization of artesunate analogs, providing an excellent platform for the generation of antiherpesviral drugs.
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Affiliation(s)
- Friedrich Hahn
- Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany.
| | - Tony Fröhlich
- Institute of Organic Chemistry I, Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany.
| | - Theresa Frank
- Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany.
| | - Luca D Bertzbach
- Institute of Virology, Freie Universität Berlin, Robert Von Ostertag-Str. 7 - 13, 14163 Berlin, Germany.
| | - Stephan Kohrt
- Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany.
| | - Benedikt B Kaufer
- Institute of Virology, Freie Universität Berlin, Robert Von Ostertag-Str. 7 - 13, 14163 Berlin, Germany.
| | - Thomas Stamminger
- Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany.
| | - Svetlana B Tsogoeva
- Institute of Organic Chemistry I, Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany.
| | - Manfred Marschall
- Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany.
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Zhu X, Yuan C, Tian C, Li C, Nie F, Song X, Zeng R, Wu D, Hao X, Li L. The plant sesquiterpene lactone parthenolide inhibits Wnt/β-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1. J Biol Chem 2018; 293:5335-5344. [PMID: 29462785 DOI: 10.1074/jbc.m117.819300] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 01/31/2018] [Indexed: 11/06/2022] Open
Abstract
The Wnt/β-catenin pathway is essential for embryonic development and homeostasis, but excessive activation of this pathway is frequently observed in various human diseases, including cancer. Current therapeutic drugs targeting the Wnt pathway often lack sufficient efficacy, and new compounds targeting this pathway are therefore greatly needed. Here we report that the plant-derived natural product parthenolide (PTL), a sesquiterpene lactone, inhibits Wnt signaling. We found that PTL dose-dependently inhibits Wnt3a- and CHIR99021-induced transcriptional activity assessed with the T-cell factor (TCF)/lymphoid enhancer factor (LEF) firefly luciferase (TOPFlash) assay in HEK293 cells. Further investigations revealed that PTL decreases the levels of the transcription factors TCF4/LEF1 without affecting β-catenin stability or subcellular distribution. Moreover, this effect of PTL on TCF4/LEF1 was related to protein synthesis rather than to proteasome-mediated degradation. Of note, siRNA-mediated knockdown of RPL10, a ribosome protein PTL binds, substantially decreased TCF4/LEF1 protein levels and also Wnt3a-induced TOPFlash activities, suggesting a potential mechanism by which PTL may repress Wnt/β-catenin signaling. In summary, PTL binds RPL10 and thereby potently inhibits the Wnt/β-catenin pathway.
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Affiliation(s)
- Xiaoliang Zhu
- From the State Key Laboratory of Molecular Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Networks, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chunmao Yuan
- the State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China
| | - Chenyang Tian
- From the State Key Laboratory of Molecular Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Networks, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.,the School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Shanghai 201210, China
| | - Chen Li
- the Key Laboratory of Systems Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and
| | - Fen Nie
- From the State Key Laboratory of Molecular Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Networks, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiaomin Song
- From the State Key Laboratory of Molecular Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Networks, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Rong Zeng
- the Key Laboratory of Systems Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and
| | - Dianqing Wu
- the Vascular Biology and Therapeutic Program and Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520
| | - Xiaojiang Hao
- the State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China, .,the State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China
| | - Lin Li
- From the State Key Laboratory of Molecular Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Networks, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China, .,the School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Shanghai 201210, China
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Mendonca MS, Turchan WT, Alpuche ME, Watson CN, Estabrook NC, Chin-Sinex H, Shapiro JB, Imasuen-Williams IE, Rangel G, Gilley DP, Huda N, Crooks PA, Shapiro RH. DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo. Free Radic Biol Med 2017; 112:318-326. [PMID: 28782644 PMCID: PMC6322835 DOI: 10.1016/j.freeradbiomed.2017.08.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 07/20/2017] [Accepted: 08/01/2017] [Indexed: 01/22/2023]
Abstract
Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide can inhibit NF-κB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with dimethylaminoparthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-κB binding activity and slows prostate cancer cell growth. We also show that DMAPT increases single and fractionated X-ray-induced killing of prostate cancer cells through inhibition of DNA double strand break repair and also that DMAPT-induced radiosensitization is, at least partially, dependent upon the alteration of intracellular thiol reduction-oxidation chemistry. Finally, we demonstrate that the treatment of PC-3 prostate tumor xenografts with oral DMAPT in addition to radiation therapy significantly decreases tumor growth and results in significantly smaller tumor volumes compared to xenografts treated with either DMAPT or radiation therapy alone, suggesting that DMAPT might have a potential clinical role as a radiosensitizing agent in the treatment of prostate cancer.
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Affiliation(s)
- Marc S Mendonca
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA; Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202 USA.
| | - William T Turchan
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA; Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Melanie E Alpuche
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Christopher N Watson
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA; Richard L. Roudebush, VA Medical Center, Indianapolis, IN 46202 USA
| | - Neil C Estabrook
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Helen Chin-Sinex
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Jeremy B Shapiro
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Imade E Imasuen-Williams
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Gabriel Rangel
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - David P Gilley
- Department of Chemistry and Applied Sciences, South Dakota School of Mines and Technology, Rapid City, SD 57701 USA
| | - Nazmul Huda
- Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Peter A Crooks
- College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Ronald H Shapiro
- Departments of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202 USA; Richard L. Roudebush, VA Medical Center, Indianapolis, IN 46202 USA
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Martel J, Ko YF, Ojcius DM, Lu CC, Chang CJ, Lin CS, Lai HC, Young JD. Immunomodulatory Properties of Plants and Mushrooms. Trends Pharmacol Sci 2017; 38:967-981. [DOI: 10.1016/j.tips.2017.07.006] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 07/24/2017] [Accepted: 07/27/2017] [Indexed: 01/11/2023]
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Kim SL, Park YR, Lee ST, Kim SW. Parthenolide suppresses hypoxia-inducible factor-1α signaling and hypoxia induced epithelial-mesenchymal transition in colorectal cancer. Int J Oncol 2017; 51:1809-1820. [PMID: 29075793 DOI: 10.3892/ijo.2017.4166] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 09/29/2017] [Indexed: 11/06/2022] Open
Abstract
Activation of hypoxia-inducible factor 1α (HIF‑1α) is frequently observed in solid tumors and it has been associated with various pathophysiological processes, including epithelial‑mesenchymal transition (EMT). Previously, we reported that parthenolide (PT), an inhibitor of nuclear factor-κB (NF-κB), is a promising anticancer agent because it promotes apoptosis of human colorectal cancer (CRC). Here, we investigated a new molecular mechanism by which PT acts on HIF‑1α and hypoxia contributing to EMT by NF‑κB inhibition. Cell viability, DNA binding activity, vascular cell tube formation and cell motility were studied after treatment of PT in hypoxic or normoxic condition. Moreover, effects of PT on hypoxia signaling and hypoxia-induced EMT signaling were investigated. We also examined the inhibitory effect of PT on CRC progression in xenografts. We demonstrated that PT markedly inhibits hypoxia dependent HIF‑1α activity and angiogenesis by preventing NF-κB activation. We also report that PT decreases the level of proteins associated with glucose metabolism, angiogenesis, development and survival that are regulated by HIF‑1α. Furthermore, we verified that PT protects the morphological change from epithelial to mesenchymal state, inhibits matrix metalloproteinase (MMP) enzyme activity and decreases cell motility involved in the -regulation of the hypoxia-induced EMT markers. In addition, PT inhibits growth in CRC xenograft models and regulates NF‑κB, HIF‑1α and EMT specific marker in tissue specimens. Our data demonstrated that PT can inhibit HIF‑1α signaling and hypoxia-induced EMT, suggesting a novel molecular mechanism for HIF‑1α mediated cancer progression and metastasis.
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Affiliation(s)
- Se Lim Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, Jeonju, Republic of Korea
| | - Young Ran Park
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, Jeonju, Republic of Korea
| | - Soo Teik Lee
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, Jeonju, Republic of Korea
| | - Sang-Wook Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, Jeonju, Republic of Korea
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Radan M, Carev I, Tešević V, Politeo O, Čulić VČ. Qualitative HPLC-DAD/ESI-TOF-MS Analysis, Cytotoxic, and Apoptotic Effects of Croatian Endemic Centaurea ragusina L. Aqueous Extracts. Chem Biodivers 2017; 14. [PMID: 28591430 DOI: 10.1002/cbdv.201700099] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 06/02/2017] [Indexed: 11/11/2022]
Abstract
Centaurea ragusina L., an endemic Croatian plant species, revealed a good cytotoxic activity of aqueous extracts (AE) on human bladder (T24) and human glioblastoma (A1235) cancer cell lines. The chemical constituents were tentatively identified using high performance liquid chromatography HPLC-DAD/ESI-TOF-MS in negative ionization mode. The main compounds of herba extract were sesquiterpene lactones: solstitialin A 3,13-diacetate and epoxyrepdiolide; organic acid: quinic acid. The main compounds of flower extract were organic acids: quinic acid, citric acid, and malic acid; sesquiterpene lactone: cynaropicrin; phenolic compounds: chlorogenic acid and phenylpropanoid: syringin. The AE of C. ragusina were investigated for correlation of their effects on human bladder (T24) and human glioblastoma (A1235) cancer cell lines using the MTT assay. Although both extracts showed significant dose- and time-dependent cytotoxic activity against both cancer cell lines, the flower extract exhibited slightly higher activity. In order to determine type of cell death induced by treatment, cell lines were exposed subsequently to a treatment with both flower and herba AE. The majority of the cells died by induced apoptosis treatment. Flower AE (26.25%), compared to a leaf AE (22.15%) showed slightly higher percentage of an apoptosis in T24 cells, when compared to a non-treated cells (0.04%).
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Affiliation(s)
- Mila Radan
- Faculty of Chemistry and Technology, University of Split, Ruđera Boškovića 35, HR-21000, Split, Croatia
| | - Ivana Carev
- Faculty of Chemistry and Technology, University of Split, Ruđera Boškovića 35, HR-21000, Split, Croatia
| | - Vele Tešević
- Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, RS-11158, Belgrade, Serbia
| | - Olivera Politeo
- Faculty of Chemistry and Technology, University of Split, Ruđera Boškovića 35, HR-21000, Split, Croatia
| | - Vedrana Čikeš Čulić
- School of Medicine, University of Split, Šoltanska 2, HR-21000, Split, Croatia
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Aravilli RK, Vikram SL, Kohila V. Phytochemicals as potential antidotes for targeting NF-κB in rheumatoid arthritis. 3 Biotech 2017; 7:253. [PMID: 28721679 DOI: 10.1007/s13205-017-0888-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 07/11/2017] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune destructive arthropathy prevalent among people in the age group of 40-70 years. RA induces severe pain, swelling and stiffness of joints resulting in bone damage. RA leads to reduced life expectancy when left untreated. RA is characterized by synovial hyperplasia, infiltration of inflammatory cells resulting in formation of pannus. Synovial hyperplasia is mediated by proinflammatory cytokines, notably IL-1 and TNF-α. NF-κB is a predominant transcription factor in amplifying the inflammatory response. The translocation of activated NF-κB into the nucleus triggers the transcription of several genes that induce proinflammatory cytokine production. The inhibition of NF-κB translocation aids blocking the activation of proinflammatory cascades. The quest for more effective and side-effect free treatment for RA unveiled phytochemicals as efficacious and promising. Phytochemicals have been a source of therapeutic substances for many ailments from ancient times. Their therapeutic ability helps in developing potent and safe drugs targeting immune inflammatory diseases driven by NF-κB including RA. This review highlights the importance of NF-κB inflammatory cascade in RA so as to elucidate the crucial role of phytochemicals that inhibit the activity of NF-κB.
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Affiliation(s)
- R Kowshik Aravilli
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, India
| | - S Laveen Vikram
- Department of Computer Science and Engineering, Alagappa University, Karaikudi, India
| | - V Kohila
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, India.
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Janganati V, Ponder J, Thakkar S, Jordan CT, Crooks PA. Succinamide derivatives of melampomagnolide B and their anti-cancer activities. Bioorg Med Chem 2017; 25:3694-3705. [PMID: 28545815 PMCID: PMC5531864 DOI: 10.1016/j.bmc.2017.05.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 05/01/2017] [Accepted: 05/04/2017] [Indexed: 12/21/2022]
Abstract
A series of succinamide derivatives of melampomagnolide B have been synthesized by coupling MMB monosuccinate (2) with various heterocyclic amines to afford compounds 3a-3l. MMB monosuccinate was also reacted with terminal diaminoalkanes to afford dimeric succinamido analogs of MMB (4a-4h). These succinamide analogs of MMB were evaluated for their anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 3d-3i and dimers 4f-4g exhibited promising anti-cancer activity with GI50 values ranging from 0.28 to 33.5µM against most of the cell lines in the panel. The dimeric analogs 4f and 4g were identified as lead compounds with GI50 values in the nanomolar range (GI50=280-980nM) against several cell lines in the panel; i.e. leukemia cell lines CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226 and SR; and solid tumor cell lines NCI-H522 (non-small cell lung cancer), SW-620 and HCT-116 (colon cancer), LOX IMVI (melanoma), RXF 393 (renal cancer), and MCF7, BT-549 and MDA-MB-468 (breast cancer). Succinamide analogs 3a, 3c-3l and 4b-4h were also evaluated for their apoptotic activity against M9-ENL1 acute myelogenous leukemia cells; compounds 3h-3j and 4g were equipotent with parthenolide, exhibiting LC50 values in the range 4.1-8.1μM. Molecular docking studies indicate that these molecules interact covalently with the highly conserved Cys-46 residue of the N-terminal lobe (1-109) of human IKKβ to inhibit the NFκB transcription factor complex, resulting in down-regulation of anti-apoptotic genes under NFκB control.
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Affiliation(s)
- Venumadhav Janganati
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Jessica Ponder
- Department of Toxicology, University of Colorado, Aurora, CO 80045, USA
| | - Shraddha Thakkar
- National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Craig T Jordan
- Division of Hematology, University of Colorado, Aurora, CO 80045, USA
| | - Peter A Crooks
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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50
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Volk-Draper LD, Hall KL, Wilber AC, Ran S. Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4. PLoS One 2017; 12:e0179257. [PMID: 28598999 PMCID: PMC5466303 DOI: 10.1371/journal.pone.0179257] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 05/28/2017] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Myeloid-derived lymphatic endothelial cells (M-LECP) are induced by inflammation and play an important role in adult lymphangiogenesis. However, the mechanisms driving M-LECP differentiation are currently unclear. We previously showed that activation of Toll-like receptor-4 (TLR4) induces myeloid-lymphatic transition (MLT) of immortalized mouse myeloid cells. Here the goals were to assess the potential of different TLR4 ligands to induce pro-lymphatic reprogramming in human and mouse primary myeloid cells and to identify transcriptional changes regulating this process. METHODOLOGY/PRINCIPAL FINDINGS Human and mouse myeloid cells were reprogrammed to the lymphatic phenotype by TLR4 ligands including lipopolysaccharide (LPS), recombinant high mobility group box 1 protein (HMGB1), and paclitaxel. TLR4 induced similar MLT in cells from mice of different strains and immune status. Commonly induced genes were detected by transcriptional profiling in human and mouse myeloid cells from either immunocompetent or immunodeficient mice. Shared trends included: (1) novel expression of lymphatic-specific markers vascular endothelial growth factor receptor-3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin (PDPN) largely absent prior to induction; (2) lack of notable changes in blood vessel-specific markers; (3) transient expression of VEGFR-3, but sustained increase of vascular endothelial growth factor-C (VEGF-C) and a variety of inflammatory cytokines; (4) dependency of VEGFR-3 upregulation and other LEC genes on NF-κB; and (5) novel expression of lymphatic-specific (e.g., PROX1) and stem/progenitor (e.g., E2F1) transcription factors known for their roles in adult and embryonic vascular formation. M-LECP generated by TLR4 ligands in vitro were functional in vivo as demonstrated by significantly increased lymphatic vessel density and lymphatic metastasis detected in orthotopic breast cancer models. CONCLUSIONS/SIGNIFICANCE We established a novel TLR4-dependent protocol for in vitro production of functionally competent M-LECP from primary human or mouse myeloid cells and identified many potential regulators of this process. This information can be further exploited for research and therapeutic purposes.
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Affiliation(s)
- Lisa D. Volk-Draper
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
| | - Kelly L. Hall
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
| | - Andrew C. Wilber
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
- Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, United States of America
| | - Sophia Ran
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States of America
- Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, United States of America
- * E-mail:
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