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13 pages, 1980 KiB

Open AccessArticle

Liquiritin and Liquiritigenin Induce Melanogenesis via Enhancement of p38 and PKA Signaling Pathways

by Takuhiro Uto, Tomoe Ohta, Akihisa Yamashita, Shunsuke Fujii and Yukihiro Shoyama

Medicines 2019, 6(2), 68; https://doi.org/10.3390/medicines6020068 - 22 Jun 2019

Cited by 22 | Viewed by 5746

Abstract

Background: Liquiritin (LQ) and its aglycone, liquiritigenin (LQG), are major flavonoids in licorice root (Glycyrrhiza spp.). Our preliminary screening identified LQ and LQG, which promote melanin synthesis in the melanoma cells. In this study, we investigated the molecular mechanism of melanin synthesis [...] Read more.

Background: Liquiritin (LQ) and its aglycone, liquiritigenin (LQG), are major flavonoids in licorice root (Glycyrrhiza spp.). Our preliminary screening identified LQ and LQG, which promote melanin synthesis in the melanoma cells. In this study, we investigated the molecular mechanism of melanin synthesis activated by LQ and LQG. Methods: Murine (B16-F1) and human (HMVII) melanoma cell lines were treated with LQ or LQG. After incubation, melanin contents, intracellular tyrosinase activity, and cell viability were evaluated. Protein levels were determined using Western blotting. Results: LQ and LQG activated melanin synthesis and intracellular tyrosinase activity. The induction of melanin and intracellular tyrosinase activity by LQG was higher than that by LQ. LQ and LQG induced the expression of tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. LQ and LQG also enhanced microphthalmia-associated transcription factor (MITF) expression, and cyclic AMP-responsive element-binding protein (CREB) phosphorylation. The phosphorylation of p38 and extracellular signal-regulated kinase (ERK), but not Akt, was significantly increased by LQ or LQG. Furthermore, LQ- or LQG-mediated melanin synthesis was partially blocked by p38 inhibitor (SB203580) and protein kinase A (PKA) inhibitor (H-89); however, ERK kinase (MEK) inhibitor (U0126) and phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002) had no effect. Conclusions: The results suggest that LQ and LQG enhance melanin synthesis by upregulating the expression of melanogenic enzymes, which were activated by p38 and PKA signaling pathways, leading to MITF expression and CREB phosphorylation. Full article

(This article belongs to the Special Issue Plant-Derived Medicines and Biological Activity Evaluation)

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12 pages, 2435 KiB

Open AccessArticle

Screening of Crude Drugs Used in Japanese Kampo Formulas for Autophagy-Mediated Cell Survival of the Human Hepatocellular Carcinoma Cell Line

by Shinya Okubo, Hisa Komori, Asuka Kuwahara, Tomoe Ohta, Yukihiro Shoyama and Takuhiro Uto

Medicines 2019, 6(2), 63; https://doi.org/10.3390/medicines6020063 - 3 Jun 2019

Cited by 7 | Viewed by 4133

Abstract

Background: Autophagy is a catabolic process through which dysfunctional proteins and organelles are degraded, and that is associated with the proliferation of cancer cells. The aim of this study was to screen approximately 130 kinds of crude drugs used in Japanese Kampo formulas [...] Read more.

Background: Autophagy is a catabolic process through which dysfunctional proteins and organelles are degraded, and that is associated with the proliferation of cancer cells. The aim of this study was to screen approximately 130 kinds of crude drugs used in Japanese Kampo formulas to identify crude drugs that would regulate the proliferation through autophagy of human hepatocellular carcinoma HepG2 cells. Methods: Extracts of each crude drug were prepared using methanol. Protein levels were determined using Western blotting. Cell viability was measured by MTT assay. Results: Among the 130 crude extracts, 24 of them increased LC3-II expression. Among these, Goboshi (burdock fruit), Soboku (sappan wood), Mokko (saussurea root), Rengyo (forsythia fruit), and Hikai (dioscorea) notably suppressed the proliferation of HepG2 cells and increased p62 expression levels, which suggested that these five extracts downregulate the autophagic activity resulting in the accumulation of p62. On the other hand, Hishinomi (water chestnut), Biwayo (loquat leaf), and Binroji (areca) induced cell growth and decreased or were uninvolved with p62 expression levels, which implied that these three extracts might induce autophagy modulators for cell growth. Conclusions: The results suggest that the compounds contained in the crude drugs selected for this study could control cell viability by regulating autophagic activity in HepG2 cells. The isolation and identification of the active compounds in these drugs might lead to the development of agents for autophagy research and cancer chemoprevention. Full article

(This article belongs to the Special Issue Plant-Derived Medicines and Biological Activity Evaluation)

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11 pages, 1192 KiB

Open AccessArticle

Analgesic and Anti-Inflammatory Activities of Quercetin-3-methoxy-4′-glucosyl-7-glucoside Isolated from Indian Medicinal Plant Melothria heterophylla

by Arijit Mondal, Tapan Kumar Maity and Anupam Bishayee

Medicines 2019, 6(2), 59; https://doi.org/10.3390/medicines6020059 - 27 May 2019

Cited by 23 | Viewed by 5002

Abstract

Background: Melothria heterophylla (family: Cucurbitaceae), commonly known as kudari, is used in the Indian traditional medicine to treat various inflammation-associated diseases, such as asthma, arthritis and pain. However, the anti-inflammatory active components of this plant have not been identified yet. The aim of [...] Read more.

Background: Melothria heterophylla (family: Cucurbitaceae), commonly known as kudari, is used in the Indian traditional medicine to treat various inflammation-associated diseases, such as asthma, arthritis and pain. However, the anti-inflammatory active components of this plant have not been identified yet. The aim of this study was to investigate the potential analgesic and anti-inflammatory activities of a compound, quercetin-3-methoxy-4′-glucosyl-7-glucoside, isolated from M. heterophylla. Methods: The anti-inflammatory activity was determined using carrageenan- and dextran-induced rat paw edema as well as cotton pellet-induced granuloma in rats, whereas the analgesic activity was analyzed using acetic acid-induced writhing, hot plate and tail flick response in mice. The test compound was orally administered at a dose of 5, 10 or 15 mg/kg. The cyclooxygenase-1 (COX-1)- and COX-2-inhibitory capacity of the test compound was studied by enzyme immunosorbent assay. Results: Quercetin-3-methoxy-4′-glucosyl-7-glucoglucoside at 15 mg/kg exhibited a maximum inhibition of carrageenan-induced inflammation (50.3%, p < 0.05), dextran (52.8%, p < 0.05), and cotton pellets (41.4%, p < 0.05) compared to control animals. At the same dose, it showed a 73.1% inhibition (p < 0.05) of the pain threshold in acetic acid-induced writhing model. It also exhibited a considerable analgesic activity by prolonging the reaction time of the animals based on hot plate as well as tail flick response. The test compound was found to inhibit COX-1 (IC₅₀ 2.76 µg/mL) and more efficiently, COX-2 (IC₅₀ 1.99 µg/mL). Conclusions: Quercetin-3-methoxy-4′-glucosyl-7-glucoside possessed substantial analgesic and anti-inflammatory activities possibly due to inhibition of prostaglandin production, supporting the ethnomedicinal application of M. heterophylla to treat various inflammatory disorders. Full article

(This article belongs to the Special Issue Plant-Derived Medicines and Biological Activity Evaluation)

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21 pages, 4282 KiB

Open AccessArticle

The Membrane-Active Phytopeptide Cycloviolacin O2 Simultaneously Targets HIV-1-infected Cells and Infectious Viral Particles to Potentiate the Efficacy of Antiretroviral Drugs

by Samantha L. Gerlach, Partha K. Chandra, Upal Roy, Sunithi Gunasekera, Ulf Göransson, William C. Wimley, Stephen E. Braun and Debasis Mondal

Medicines 2019, 6(1), 33; https://doi.org/10.3390/medicines6010033 - 28 Feb 2019

Cited by 17 | Viewed by 4571

Abstract

Background: Novel strategies to increase the efficacy of antiretroviral (ARV) drugs will be of crucial importance. We hypothesize that membranes of HIV-1-infected cells and enveloped HIV-1 particles may be preferentially targeted by the phytopeptide, cycloviolacin O2 (CyO2) to significantly enhance ARV efficacy. Methods: [...] Read more.

Background: Novel strategies to increase the efficacy of antiretroviral (ARV) drugs will be of crucial importance. We hypothesize that membranes of HIV-1-infected cells and enveloped HIV-1 particles may be preferentially targeted by the phytopeptide, cycloviolacin O2 (CyO2) to significantly enhance ARV efficacy. Methods: Physiologically safe concentrations of CyO2 were determined via red blood cell (RBC) hemolysis. SYTOX-green dye-uptake and radiolabeled saquinavir (³H-SQV) uptake assays were used to measure pore-formation and drug uptake, respectively. ELISA, reporter assays and ultracentrifugation were conducted to analyze the antiviral efficacy of HIV-1 protease and fusion inhibitors alone and co-exposed to CyO2. Results: CyO2 concentrations below 0.5 μM did not show substantial hemolytic activity, yet these concentrations enabled rapid pore-formation in HIV-infected T-cells and monocytes and increased drug uptake. ELISA for HIV-1 p24 indicated that CyO2 enhances the antiviral efficacy of both SQV and nelfinavir. CyO2 (< 0.5 μM) alone decreases HIV-1 p24 production, but it did not affect the transcription regulatory function of the HIV-1 long terminal repeat (LTR). Ultracentrifugation studies clearly showed that CyO2 exposure disrupted viral integrity and decreased the p24 content of viral particles. Furthermore, direct HIV-1 inactivation by CyO2 enhanced the efficacy of enfuvirtide. Conclusions: The membrane-active properties of CyO2 may help suppress viral load and augment antiretroviral drug efficacy. Full article

(This article belongs to the Special Issue Plant-Derived Medicines and Biological Activity Evaluation)

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27 pages, 2221 KiB

Open AccessArticle

Medicinal Plants Used in the Ejisu-Juaben Municipality, Southern Ghana: An Ethnobotanical Study

by Kwame Sarpong Appiah, Clement Peprah Oppong, Hossein Korrani Mardani, Richard Ansong Omari, Sylvia Kpabitey, Christiana Adukwei Amoatey, Siaw Onwona-Agyeman, Yosei Oikawa, Keisuke Katsura and Yoshiharu Fujii

Medicines 2019, 6(1), 1; https://doi.org/10.3390/medicines6010001 - 20 Dec 2018

Cited by 36 | Viewed by 10165

Abstract

Background: The in-depth traditional knowledge of medicinal plants is at risk of extinction due to the dependency on oral transmission, and as such, there is an urgent need to document such knowledge. This study aimed to document indigenous uses of medicinal plants among [...] Read more.

Background: The in-depth traditional knowledge of medicinal plants is at risk of extinction due to the dependency on oral transmission, and as such, there is an urgent need to document such knowledge. This study aimed to document indigenous uses of medicinal plants among community members in the Ejisu-Juaben Municipality. Methods: Data was collected in 2016 from community members and local herbalists in the Ejisu-Juaben Municipality through a semi-structured questionnaire. Statistical tools and ethnobotanical indices, i.e., informant consensus factor (ICF), fidelity level (FL), and use value (UV) were used to analyse the data. Results: One hundred and six medicinal plants belonging to 45 families were reported to cure 68 different human diseases. The most frequently used plant part in this study was the leaves (52%). Decoction (57.5%) and oral administration (58.3%) were the most utilised herbal preparation and administration route respectively. Cleistopholis patens had the highest UV (0.54) with pain & fevers and skin diseases having the highest ICF values (0.88 and 0.85 respectively). Furthermore, new medicinal uses of Hilleria latifolia and ten other species were recorded for the treatment of the traditional local disease, aseram. Conclusions: The current knowledge and uses of medicinal plants are still high in the study area based on the high degree of consensus among informants. This study could allow for the preservation of knowledge and biodiversity of medicinal plants, both of which are threatened with extinction. Full article

(This article belongs to the Special Issue Plant-Derived Medicines and Biological Activity Evaluation)

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18 pages, 4687 KiB

Open AccessArticle

Reversal of Multidrug Resistance in Human Colon Cancer and Human Leukemia Cells by Three Plant Extracts and Their Major Secondary Metabolites

by Jun-Xian Zhou and Michael Wink

Medicines 2018, 5(4), 123; https://doi.org/10.3390/medicines5040123 - 13 Nov 2018

Cited by 25 | Viewed by 4666

Abstract

Background: We studied the effect of three plant extracts (Glycyrrhiza glabra, Paeonia lactiflora, Eriobotrya japonica) and six of their major secondary metabolites (glycyrrhizic acid, 18β glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, paeoniflorin, ursolic acid) on the multidrug resistant human colon cancer [...] Read more.

Background: We studied the effect of three plant extracts (Glycyrrhiza glabra, Paeonia lactiflora, Eriobotrya japonica) and six of their major secondary metabolites (glycyrrhizic acid, 18β glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, paeoniflorin, ursolic acid) on the multidrug resistant human colon cancer cell line Caco-2 and human leukemia cell line CEM/ADR 5000 as compared to the corresponding sensitive cell line CCRF-CEM, and human colon cancer cells HCT-116, which do not over-express ATP-binding cassette (ABC) transporters. Methods: The cytotoxicity of single substances in sensitive and resistant cells was investigated by MTT assay. We also applied combinations of extracts or single compounds with the chemotherapeutic agent doxorubicin or doxorubicin plus the saponin digitonin. The intracellular retention of the ABC transporter substrates rhodamine 123 and calcein was examined by flow cytometry to explore the effect of the substances on the activity of ABC transporters P-glycoprotein and MRP1. Real-time PCR was applied to analyse the gene expression changes of ABCB1, ABCC1, caspase 3, caspase 8, AhR, CYP1A1, and GSTP1 in resistant cells under the treatment of the substances. Results: All the substances moderately inhibited cell growth in sensitive and resistant cells to some degree. Whereas ursolic acid showed IC₅₀ of 14 and 22 µM in CEM/ADR 5000 and Caco-2 cells, respectively, glycyrrhizic acid and paeoniflorin were inactive with IC₅₀ values above 400 μM. Except for liquiritigenin and isoliquiritigenin, all the other substances reversed MDR in CEM/ADR 5000 and Caco-2 cells to doxorubicin. Ue, ga, 18ga, and urs were powerful reversal agents. In CEM/ADR 5000 cells, high concentrations of all the substances, except Paeonia lactiflora extract, increased calcein or rhodamine 123 retention in a dose-dependent manner. In Caco-2 cells, all the substances, except liquiritigenin, retained rhodamine 123 in a dose-dependent manner. We also examined the effect of the plant secondary metabolite (PSM) panel on the expression of ABCB1, ABCC1, caspase 3, caspase 8, AhR, CYP1A1, and GSTP1 genes in MDR cells. Conclusions: The extracts and individual PSM could reverse MDR in CEM/ADR 5000 and Caco-2 cells, which overexpress ABC transporters, in two- and three-drug combinations. Most of the PSM also inhibited the activity of ABC transporters to some degree, albeit at high concentrations. Ue, ga, 18ga, and urs were identified as potential multidrug resistance (MDR) modulator candidates, which need to be characterized and validated in further studies. Full article

(This article belongs to the Special Issue Plant-Derived Medicines and Biological Activity Evaluation)

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18 pages, 760 KiB

Open AccessReview

Phytochemical Modulation of MiRNAs in Colorectal Cancer

by Aravinda Ganapathy and Uthayashanker Ezekiel

Medicines 2019, 6(2), 48; https://doi.org/10.3390/medicines6020048 - 5 Apr 2019

Cited by 12 | Viewed by 4038

Abstract

Colorectal cancer (CRC) is one of the leading causes of death in the United States. Chemotherapy and radiotherapy are some of the most commonly used treatments, but are often associated with severe side effects, and are not entirely curative. It is therefore important [...] Read more.

Colorectal cancer (CRC) is one of the leading causes of death in the United States. Chemotherapy and radiotherapy are some of the most commonly used treatments, but are often associated with severe side effects, and are not entirely curative. It is therefore important to consider other preventative treatment options. Phytochemicals are naturally occurring bioactive compounds which have been shown to play a role in cancer prevention and treatment, especially in regards to a person’s lifestyle and diet. Recent evidence has shown that phytochemicals may exert their chemopreventative effects by targeting micro RNAs (miRNAs), which regulate the downstream expression of tumor suppressors and oncogenes. MiRNAs are small, endogenous, noncoding RNAs that regulate several biological processes through post-translational regulation. The dysregulation of miRNA expression has been shown to be associated with colorectal cancer. In this review, we will summarize and discuss several phytochemicals, which have been shown to exert chemopreventative effects in colorectal cancer by the modulation of miRNA expression. Full article

(This article belongs to the Special Issue Plant-Derived Medicines and Biological Activity Evaluation)

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81 pages, 1274 KiB

Open AccessFeature PaperReview

The Phytochemistry of Cherokee Aromatic Medicinal Plants

by William N. Setzer

Medicines 2018, 5(4), 121; https://doi.org/10.3390/medicines5040121 - 12 Nov 2018

Cited by 19 | Viewed by 17898

Abstract

Background: Native Americans have had a rich ethnobotanical heritage for treating diseases, ailments, and injuries. Cherokee traditional medicine has provided numerous aromatic and medicinal plants that not only were used by the Cherokee people, but were also adopted for use by European settlers [...] Read more.

Background: Native Americans have had a rich ethnobotanical heritage for treating diseases, ailments, and injuries. Cherokee traditional medicine has provided numerous aromatic and medicinal plants that not only were used by the Cherokee people, but were also adopted for use by European settlers in North America. Methods: The aim of this review was to examine the Cherokee ethnobotanical literature and the published phytochemical investigations on Cherokee medicinal plants and to correlate phytochemical constituents with traditional uses and biological activities. Results: Several Cherokee medicinal plants are still in use today as herbal medicines, including, for example, yarrow (Achillea millefolium), black cohosh (Cimicifuga racemosa), American ginseng (Panax quinquefolius), and blue skullcap (Scutellaria lateriflora). This review presents a summary of the traditional uses, phytochemical constituents, and biological activities of Cherokee aromatic and medicinal plants. Conclusions: The list is not complete, however, as there is still much work needed in phytochemical investigation and pharmacological evaluation of many traditional herbal medicines. Full article

(This article belongs to the Special Issue Plant-Derived Medicines and Biological Activity Evaluation)

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