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1.
Phytomedicine ; 64: 153078, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31505440

RESUMO

BACKGROUND: A central topic is to bring traditional medicine to a new horizon by integrating the latest advances in genomic, metabolomic, and system biological approaches, in order to re-examine the wisdom and knowledge of traditional Chinese medicine (TCM) and other traditional medicines. PURPOSE: A new consortium has been formed at a conference of the Harvard Medical School, Boston, on October 29-30, 2018. The main goal was to build a collaborative platform for the scientific investigation of traditional medicine with cutting edge sciences and technologies at the forefront of biomedicine. RESULTS: Traditional medicines are largely experience-based, but the scientific basis is largely non-satisfactory. Therefore, the transformation from experience-based to evidence-based medicine would be an important step forward. The consortium covers three main fields: TCM diagnostics, acupuncture and TCM pharmacology. Diseases occur because of regulatory imbalances of holistic physiological display and genetic information/expression related to systems biology and energy consumption/release (e.g. cold and hot) within body. As organs are interconnected by meridians, affecting the meridians by acupuncture and medicinal herbs restores healthy organ function and body balance. There are two concepts in herbal medicine: The traditional way is based on complex herbal mixtures. The second concept is related to Western pharmacological drug development including the isolation of bioactive phytochemicals, which are subjected to preclinical and clinical investigations. CONCLUSION: Development of collaborative scientific project to integrate the best of both worlds - Western and Eastern medicine into a "One World Integrative Medicine" for the sake of patients worldwide.

2.
Phytomedicine ; 64: 153070, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31514082

RESUMO

BACKGROUND: The genus Sophora (Fabaceae) represents one of the important medicinal plant genera regarding its chemical constituents and outstanding pharmacological activities. PURPOSE: In this review, we surveyed the latest findings on the bioactivities of different Sophora extracts and isolated phytochemicals during the past 8 years (2011-2019) updating the latest review article in 2011. The aim of this review is to focus on the molecular pharmacology of Sophora species to provide the rationale basis for the development of novel drugs. RESULTS: Sophora and its bioactive compounds possess outstanding pharmacological properties, especially as anticancer and anti-inflammatory drugs, in addition to its antioxidant, antibacterial, antifungal and antiviral properties. CONCLUSION: Based on their use in traditional medicine, Sophora species exert a plethora of cellular and molecular activities, which render them as attractive candidates for rationale drug development. Randomized, placebo-controlled clinical trials are required for further integration of Sophora-based phototherapies into conventional medicine.

3.
Eur J Pharmacol ; 861: 172618, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31430456

RESUMO

Pinolenic acid (PLA), a natural compound isolated from pine nut oil, has been reported to exert bioactivity against lipid anabolism. Nonetheless, the underlying mechanisms still poorly elucidated. The aim of this study is to comprehensively demonstrate the effects of PLA on oleic acid (OA)-induced non-alcoholic fatty liver disease (NAFLD) and their relationship with the lipid metabolic regulation. The results demonstrated that treatment with PLA dramatically inhibited lipid accumulation, oxidative stress as well as inflammatory responses induced by oleic acid in HepG2 cells. PLA also obviously decreased the levels of cellular triglyceride (TG), total cholesterol (TC), malondialdehyde (MDA), reactive oxygen species (ROS) and nitric oxide (NO). As well as PLA stilled promoted the antioxidant enzymes activity including superoxide dismutase (SOD) and glutathione peroxidase (GPX). Furthermore, PLA could increase the expressions of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase1 (HO-1) to alleviate oxidative damage. It also could reduce lipogenesis-related transcription factors expression, such as sterol regulatory element-binding protein 1 (SREBP1c), fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1). PLA treatment resulted in increasing phosphorylation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) expression. However, pretreatment with compound C (inhibitor of AMPK) inhibited the effect of PLA on promoting the expression of p-AMPK, SIRT1 and PPARα for lipolysis. Taken together, these results demonstrated that PLA possessed the potential to prevent lipid accumulation in OA-induced HepG2 cells via upregulating the AMPK/SIRT1 signaling pathway, which supported the development of new drug candidate against non-alcoholic steatohepatitis.

4.
Pharmacol Res ; 147: 104346, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31295570

RESUMO

A growing number of evidences from clinical and preclinical studies have shown that dysregulation of microRNA (miRNA) function contributes to the progression of cancer and thus miRNA can be an effective target in therapy. Dietary phytochemicals, such as quercetin, are natural products that have potential anti-cancer properties due to their proven antioxidant, anti-inflammatory, and anti-proliferative effects. Available experimental studies indicate that quercetin could modulate multiple cancer-relevant miRNAs including let-7, miR-21, miR-146a and miR-155, thereby inhibiting cancer initiation and development. This paper reviews the data supporting the use of quercetin for miRNA-mediated chemopreventive and therapeutic strategies in various cancers, with the aim to comprehensively understand its health-promoting benefits and pharmacological potential. Integration of technology platforms for miRNAs biomarker and drug discovery is also presented.

5.
J Ethnopharmacol ; 242: 112049, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31265888

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Rhinella schneideri and Rhinella marina are toad venoms distributed in different parts of the world, including Brazil, Columbia and amazon. Venoms extracted from different species have many clinical applications such as antimicrobial cardiotonics and treatment of cancer. Aim of the study; In this study, we aim to investigate the effect of venoms extracted from R. schneideri and R. marina on cancer cells and verify possible mechanism of action. MATERIAL AND METHOD: Cytotoxicity analyses was performed using the resazurin reduction assay, where different concentrations of venoms were tested against sensitive CCRF-CEM and P-gp overexpressing ADR/CEM5000 leukemia cells. Programmed cell death was investigated using the flow cytometric annexin V/propidium iodide apoptosis assay. Furthermore, we analyzed flow cytometric cell cycle analyses of CCRF-CEM cells. Effect on tubulin formation was tested using molecular docking and fluorescence microscopy of U2OS-GFP-α-tubulin osteosarcoma cells treated for 24 h with venoms. RESULTS: Cytotoxicity assays revealed a strong activity towards wild-type CCRF-CEM cells (IC50 values of 0.202 ±â€¯0.005 µg/ml and 0.18 ±â€¯0.007 µg/ml for R. schneideri and R. marina, respectively) and multidrug-resistant CEM/ADR5000 cells (IC50 0.403 ±â€¯0.084 µg/ml and 0.32 ±â€¯0.077 µg/ml for R. schneideri and R. marina, respectively). The venoms induced apoptosis as major mechanism of cell death. The venoms induced strong G2/M cell arrest in CCRF-CEM cells. We suggested tubulin as a major target for the venoms. In silico molecular docking of the major constituents of the venoms, i.e. bufalin, marinobufagin, telocinbufagin, hellebrigenin, showed strong binding affinities to tubulin. This result was verified in vitro. The venoms dysregulated microtubule arrangement of U2OS cells expressing GFP-labeled tubulin. Toxicity predictions by QSAR methodology highlighted the toxic features of bufadienolides. CONCLUSION: Our study demonstrated the importance of toad venoms as source of cytotoxic compounds that may serve as lead compounds for the development of novel anticancer drugs.

6.
Phytomedicine ; : 153034, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31345603
7.
Phytomedicine ; : 152998, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31301971

RESUMO

BACKGROUND: Artemisinin was isolated and identified in 1972, which was the starting point for a new era in antimalarial drug therapy. Furthermore, numerous studies have demonstrated that artemisinin and its derivatives exhibit considerable anticancer activity both in vitro, in vivo, and even in clinical Phase I/II trials. P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) is one of the most serious causes of chemotherapy failure in cancer treatment. Interestingly, many artemisinin derivatives exhibit excellent ability to overcome P-gp mediated MDR and even show collateral sensitivity against MDR cancer cells. Furthermore, some artemisinin derivatives show P-gp-mediated MDR reversal activity. Therefore, the interaction between P-gp and artemisinin derivatives is important to develop novel combination treatment protocols with artemisinin derivatives and established anticancer drugs that are P-gp substrates. PURPOSE: This systematic review provides an updated overview on the interaction between artemisinin derivatives and P-gp and the effect of artemisinin derivatives on the P-gp expression level. RESULTS: Artemisinin derivatives exhibit multi-specific interactions with P-gp. The currently used artemisinin derivatives are not transported by P-gp. However, some of novel synthetized artemisinin derivatives exhibit P-gp substrate properties. Furthermore, many artemisinin derivatives act as P-gp inhibitors, which exhibit the potential to reverse MDR towards clinically used anticancer drugs. CONCLUSION: Therefore, studies on the interaction between artemisinin derivatives and P-gp provide important information for the development of novel anti-cancer artemisinin derivatives to reverse P-gp mediated MDR and for the design of rational artemisinin-based combination therapies against cancer.

8.
Anticancer Res ; 39(7): 3585-3593, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262883

RESUMO

BACKGROUND: The oncogenic role of epidermal growth factor receptor (EGFR) has been intensively studied. However, its emerging role in drug resistance has not been fully addressed. MATERIALS AND METHODS: This study systematically investigated the correlation of mRNA and protein expression of EGFR, as well as gene amplification and mutations with the log-transformed half-maximal inhibitory concentration (log10IC50) values obtained from the NCI panel of 60 human tumor cell lines against 83 standard anticancer agents and the top 10 natural cytotoxic products previously screened by us. RESULTS: EGFR protein expression, rather than other measurements, was most frequently associated with drug response. Log10IC50 and EGFR protein level were significantly positively correlated under all investigated DNA topoisomerase (TOPO) II inhibitors, followed by 81% of alkylating agents and platinum-based compounds, 71% of anti-hormones, 66% of TOPO I inhibitors and 50% of antibiotics. Furthermore, 60% of cytotoxic natural products did not reveal significant correlations. CONCLUSION: Collectively, we showed a broad-spectrum of cross-resistance towards clinical drugs mediated by EGFR. Natural cytotoxic products may be further developed as novel drugs to overcome EGFR-associated resistance to clinically established anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/fisiologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , RNA Mensageiro/metabolismo
9.
Phytomedicine ; 62: 152970, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31181403

RESUMO

BACKGROUND: Gastric ulcer is one of the main prevalent gastrointestinal multi-etiological disorders with many associated complications and adverse effects. Our aim was to develop safer antiulcer therapies based on methanol or ethyl acetate extracts of tubers and aerial parts from Cyperus alternifolius. METHODS: Gastric ulceration was experimentally generated by administration of single oral doses of indomethacin (30 mg/kg) to fasted rats. The animals received methanol or ethyl acetate extracts of C. alternifolius tuber and methanol or ethyl acetate extracts of aerial parts at two dose levels (50 or 100 mg/kg). Ranitidine (50 mg/kg) was used as standard anti-ulcer drug. After 4 h, the ulcer number and the total ulcer score were determined and TNF-α was assessed. Also, pathological and histochemical examination for gastric mucosa were performed. The metabolome heterogeneity of the different extracts was explored using (UPLC-MS) aided by supervised pattern recognition, i.e., orthogonal partial least squares discriminate analysis (OPLS-DA). A second OPLS-DA model was employed to link the UPLC-MS derived metabolome of the different extracts to their antiulcer activity to identify activity mediating metabolites. RESULTS: The extracts significantly reduced ulcer number, total ulcer score and TNF-α content in the stomach. Methanol or ethyl acetate extracts of tubers were most effective even more than ranitidine. In parallel, the histopathological examination showed an improvement of damaged mucosa. A high PAS reaction was observed in the treated groups indicating a relieve of the mucosal layer. A mechanistic clue of the C. alternifolius antiulcer potential was provided by the identification of its bioactive compounds using OPLS-DA. Both methanol extracts of tubers and aerial parts were more enriched in phenolic acids. The ethyl acetate extract of the aerial part was more abundant in two aldehydes. A mechanism of action was postulated based on their reported actions viz. α-carbonic anhydrase inhibition, anti-inflammatory and analgesic activity by its antioxidant activity and downregulation of several inflammatory mediators. CONCLUSION: This is the first study to report on the antiulcer activity of C. alternifolius tubers with identification of the key bioactive compounds and the mode of action. Future phytochemical and biological evaluation of the identified bioactive compounds are needed to confirm the plant tubers as safer alternative or adjunct therapy compared to conventional antiulcer drugs.

10.
J Ethnopharmacol ; 243: 112007, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31170516

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Over the past thousand years, Islamic physicians have collected cultural, philosophical, sociological and historical backgrounds for understanding diseases and medications. The Prophet Mohammed (Peace Be Upon Him (PBUH) said: "There is no disease that Allah has created, except that Allah also has created its cure." Therefore, Islamic scholars are encouraged to explore and use both traditional and modern forms of medicine. AIM OF THE STUDY: (1) To identify some of the medicinal plants mentioned in the Holy Qur'ân and Ahadith textbooks of the period 700-1500 AD; (2) to compare them with presently used traditional medicines; (3) to evaluate their value based on modern research; and (4) to investigate the contributions of Islamic scholars to the development of the scientific branches, particularly medicine. MATERIALS AND METHODS: A literature search was performed relating to 12 medicinal plants mentioned in the Holy Qur'ân and Ahadith using textbooks, Al-Azhar scholars, published articles, the plant list website (http://www.theplantlist.org/), the medicinal plant names services website (http://mpns.kew.org/mpns-portal/) and web databases (PubMed, Science Direct, and Google Scholar). RESULTS AND DISCUSSION: The Islamic Golden Age was a step towards modern medicine, with unique insights and multi-disciplinary aspects. Traditional Islamic Medicine has had a significant impact on the development of various medical, scientific and educational activities. Innumerable Muslim and non-Muslim physicians have built on the strong foundation of Traditional Islamic Medicine by translating the described natural remedies and effects. The influences of different ancient cultures on the traditional uses of natural products were also documented in Islamic Scriptures in the last part of the second millennium. The divine teachings of Islam combine natural and practical healing and incorporate inherited science and technology. CONCLUSION: In this review, we discuss Traditional Islamic Medicine with reference to both medical recommendations mentioned in the Holy Qur'ân and Prophetic Traditional Medicine (al-Tibb al-Nabawi). Although the molecular mechanisms and functions of some of the listed medicinal plants and their derivatives have been intensively studied, some traditional remedies have yet to be translated into clinical applications.

11.
Invest New Drugs ; 2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31254176

RESUMO

Vitamin K3, also known as menadione, is a synthetic lipid-soluble 2-methyl-1,4- naphthoquinone analogs of vitamin K. The vitamin K derivatives exhibit potent cytotoxicity against several cancer cell lines through ROS induction and mitochondrial dysfunction. We investigated vitamin K3-inspired derivatives as potential apoptotic inducers and analyzed their mechanisms beyond apoptosis. The cytotoxicity of a panel of vitamin K3 analogs was screened against 10 doxorubicin-sensitive and -resistant cancer cell lines overexpressing ATP-binding cassette transporters (P-glycoprotein, ABCB5, BCRP) or oncogenes (ΔEGFR) or with knockout of tumor suppressors (p53), Cell cycle arrest, apoptosis, cell migration, and microtubule formation were further investigated. The online tool SwissTargetPrediction was utilized for target prediction. Among the screened compounds, one vitamin K3 thio-derivative (No. 45, VKT-1) exhibited the most potent cytotoxicity specifically against both drug-sensitive and -resistant cancer cell lines. In addition, VKT-1 arrested the cells at the G2/M phase and induced apoptosis as detected by flow cytometry. As predicted by SwissTargetPrediction, VKT-1 targeted microtubule-associated tau protein. Indeed, VKT-1 dramatically inhibited cell migration and microtubule formation in vitro. In conclusion, the synthetic vitamin K3 thio-derivative (VKT-1) inhibited doxorubicin-sensitive and -resistant tumor cells by cell arrest, apoptosis induction, as well as, migration inhibition, and microtubule deterioration of U2OS-GFP-α-tubulin cells.

12.
Phytomedicine ; 62: 152945, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31132750

RESUMO

BACKGROUND: Cucurbitacin E (CuE) is an oxygenated tetracyclic triterpenoid isolated from the fruits of Citrullus colocynthis (L.) Schrad. PURPOSE: This study outlines CuE's cytotoxic activity against drug-resistant tumor cell lines. Three members of ABC transporters superfamily, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and ABCB5 were investigated, whose overexpression in tumors is tightly linked to multidrug resistance. Further factors of drug resistance studied were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). METHODS: Cytotoxicity assays (resazurin assays) were used to investigate the activity of Citrullus colocynthis and CuE towards multidrug resistant cancer cells. Molecular docking (In silico) has been carried out to explore the CuE's mode of binding to ABC transporters (P-gp, BCRP and ABCB5). The visualization of doxorubicin uptake was done by a Spinning Disc Confocal Microscope. The assessment of proteins expression was done by western blotting analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to cucurbitacins (CuA, CuB, CuE, CuD, CuI, and CuK). RESULTS: Multidrug-resistant cells overexpressing P-gp or BCRP were cross-resistant to CuE. By contrast, TP53 knock-out cells were sensitive to CuE. Remarkably, resistant cells transfected with oncogenic ΔEGFR or ABCB5 were hypersensitive (collateral sensitive) to CuE. In silico analyses demonstrated that CuE is a substrate for P-gp and BCRP. Immunoblot analyses highlighted that CuE targeted EGFR and silenced its downstream signaling cascades. The most striking result that emerged from the doxorubicin uptake by ABCB5 overexpressing cells is that CuE is an effective inhibitor for ABCB5 transporter when compared with verapamil. The COMPARE analyses of transcriptome-wide expression profiles of tumor cell lines of the NCI identified common genes involved in cell cycle regulation, cellular adhesion and intracellular communication for different cucurbitacins. CONCLUSION: CuE represents a potential therapeutic candidate for the treatment of certain types of refractory tumors. To best of our knowledge, this is the first time to identify CuE and verapamil as inhibitors for ABCB5 transporter.

13.
Phytomedicine ; 59: 152771, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31055230

RESUMO

BACKGROUND: The multidrug resistance (MDR) phenotype encounters a major challenge to the success of established chemotherapy in cancer patients. We hypothesized that cytotoxic medicinal plants with novel phytochemicals can overcome MDR and kill MDR-cells with similar efficacy as drug sensitive cells. PURPOSE: We evaluated plant extracts from an unexplored ecosystem in Egypt with unusual climate and nutrient conditions for their activity against sensitive and multidrug-resistant cancer cell lines. MATERIAL AND METHODS/STUDY DESIGN: Methylene chloride: methanol (1:1) and methanol: H2O (7:3) extracts of 40 plants were prepared resulting in a sum of 76 fraction containing compounds with varying polarity. The resazurin reduction assay was employed to evaluate the cytotoxicity of these extracts on five matched pairs of drug-sensitive and their drug-resistant cell lines. Flow cytometry and Western blotting was used to determine cell cycle analyses, apoptosis, and autophagy. Reactive oxygen species (ROS) were measured spectrophotometrically. RESULTS: Extracts derived from Withania obtusifolia (WO), Jasonia candicans (JC), Centaurea lippii (CL), and Pulicaria undulata (PU) were the most active ones among 76 extracts from 40 Egyptian medicinal plants. They showed a significant reduction of cell viability on drug-sensitive CCRF-CEM leukemia cell line with IC50 values less than 7 µg/ml. Low cross-resistance degrees were observed in multidrug-resistant CEM/ADR5000 cells towards CL (1.82-fold) and JC (6.09-fold). All other drug-resistant cell lines did not reveal cross-resistance to the four extracts. Further mechanistic assessment have been studied for these four extracts. CONCLUSION: The methylene chloride: methanol (1:1) fractions of WO, JC, CL, and PU are promising cytotoxic extracts that could be used to combat MDR cancer cells through different cell death pathways.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Magnoliopsida/química , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Centaurea/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Egito , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Pulicaria/química , Espécies Reativas de Oxigênio/metabolismo , Withania/química
14.
Br J Pharmacol ; 176(16): 2922-2944, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124139

RESUMO

BACKGROUND AND PURPOSE: Celastrol exhibits anti-arthritic effects in rheumatoid arthritis (RA), but the role of celastrol-mediated Ca2+ mobilization in treatment of RA remains undefined. Here, we describe a regulatory role for celastrol-induced Ca2+ signalling in synovial fibroblasts of RA patients and adjuvant-induced arthritis (AIA) in rats. EXPERIMENTAL APPROACH: We used computational docking, Ca2+ dynamics and functional assays to study the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA). In rheumatoid arthritis synovial fibroblasts (RASFs)/rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), mechanisms of Ca2+ -mediated autophagy were analysed by histological, immunohistochemical and flow cytometric techniques. Anti-arthritic effects of celastrol, autophagy induction, and growth rate of synovial fibroblasts in AIA rats were monitored by microCT and immunofluorescence staining. mRNA from joint tissues of AIA rats was isolated for transcriptional analysis of inflammatory genes, using siRNA methods to study calmodulin, calpains, and calcineurin. KEY RESULTS: Celastrol inhibited SERCA to induce autophagy-dependent cytotoxicity in RASFs/RAFLS via Ca2+ /calmodulin-dependent kinase kinase-ß-AMP-activated protein kinase-mTOR pathway and repressed arthritis symptoms in AIA rats. BAPTA/AM hampered the in vitro and in vivo effectiveness of celastrol. Inflammatory- and autoimmunity-associated genes down-regulated by celastrol in joint tissues of AIA rat were restored by BAPTA/AM. Knockdown of calmodulin, calpains, and calcineurin in RAFLS confirmed the role of Ca2+ in celastrol-regulated gene expression. CONCLUSION AND IMPLICATIONS: Celastrol triggered Ca2+ signalling to induce autophagic cell death in RASFs/RAFLS and ameliorated arthritis in AIA rats mediated by calcium-dependent/-binding proteins facilitating the exploitation of anti-arthritic drugs based on manipulation of Ca2+ signalling.

15.
Pharmacol Res ; 146: 104275, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100335

RESUMO

Malaria affects 200 million people worldwide. Today, the most successful treatments are artemisinin-based combination therapies (ACT). Resistance has already been described for the elder anti-malarials chloroquine, sulfadoxine-pyrimethamine and mefloquine. Unfortunately, over the last few years there has also been an emerging resistance to the successfully used drug artemisinin, especially in African and Asian countries. A systematic PubMed literature research was conducted for studies published between January 2002 and December 2018. Despite ACTs continue to be first line treatment, the number of studies is rising reporting on artemisinin resistance mutations. Most publications reported on kelch13 mutations (45 studies), the second most frequent mutations were found in pfmdr1 (32 studies). PfATPase6 mutations have been mainly studied in Asian countries (4 of 6 studies). Bearing this in mind, there is a pressing need to further examine the role and spread of mutations conferring artemisinin resistance. A further decline of treatment efficacy could result in increased rates of malaria-related deaths.

16.
Aging (Albany NY) ; 11(9): 2797-2811, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089001

RESUMO

Platelet lysate (PL) contains a cocktail of growth factors that actively participates in cartilage repair. This study was designed to determine the effect and mechanism of PL on osteoarthritis (OA). An arthritis model was established to mimic human OA by intra-articular injection of monoiodoacetate (MIA) to Sprague Dawley (SD) rats. The model was weekly treated with PL by intra-articular injection. Thermal withdrawal latency, mechanical withdrawal threshold, and treadmill gait were tested for pain behavior observation. Histopathological and immunohistochemical analyses were conducted for evaluating cartilage degradation. Real time PCRs and Western blots were conducted to elucidate the mechanism of PL on primary chondrocytes. Results showed that, in vivo, PL significantly attenuated pain symptoms and exerted chondrocyte-protective and extracellular matrix (ECM)-modifying effect on the arthritic cartilage in a dose-dependent manner. The in situ expressions of type II Collagen (Col2) and matrix metalloproteinase 13 (Mmp13) in the arthritic cartilage was abnormal and was restored by PL. In vitro, PL significantly restored tumor necrosis factor α (TNF-α)-suppressed anabolic gene expression (Col2 and aggrecan) and TNF-α-increased catabolic gene expression (Col10, Mmp13, Adamts5, and Adamts9) in chondrocytes. The effects were mediated by TNF-α downstream signaling, including inhibition of NF-κB and c-Jun activities. This study provides certain knowledge of anti-OA effect and TNF signaling-related mechanism of PL, placing it as a promising and alternative option for OA therapy in the future.

17.
Cancer Lett ; 459: 248-267, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31132429

RESUMO

Phytochemicals gained considerable interest during the past years as source to develop new treatment options for chemoprevention and cancer therapy. Motivated by the fact that a majority of established anticancer drugs are derived in one way or another from natural resources, we focused on shikonin, a naphthoquinone with high potentials to be further developed as preventive or therapeutic drug to fight cancer. Shikonin is the major chemical component of Lithospermum erythrorhizon (Purple Cromwell) roots. Traditionally, the root extract has been applied to cure dermatitis, burns, and wounds. Over the past three decades, the anti-inflammatory and anticancer effects of root extracts, isolated shikonin as well as semi-synthetic and synthetic derivatives and nanoformulations have been described. In vitro and in vivo experiments were conducted to understand the effect of shikonin at cellular and molecular levels. Preliminary clinical trials indicate the potential of shikonin for translation into clinical oncology. Shikonin exerts additive and synergistic interactions in combination with established chemotherapeutics, immunotherapeutic approaches, radiotherapy and other treatment modalities, which further underscores the potential of this phytochemical to be integrated into standard treatment regimens.

18.
Cancer Lett ; 459: 13-14, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31145932
19.
Phytomedicine ; : 152832, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31031043

RESUMO

BACKGROUND: Successful cancer chemotherapy is hampered by resistance of cancer cells to established anticancer drugs. Numerous natural products reveal cytotoxicity towards tumor cells. PURPOSE: The present study was aimed to determine the cytotoxicity of a betaine-type alkaloid, ungeremine, towards 9 cancer cell lines including various sensitive and drug-resistant phenotypes. The mode of action of this compound was further investigated. METHODS: The cytotoxicity, ferroptotic and necroptotic cell death were determined by the resazurin reduction assay. Caspase activation was evaluated using the caspase-Glo assay. Flow cytometry was applied for the analysis of cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). Apoptotic, necroptotic and autophagic markers were determined by Western blotting. CCRF-CEM leukemia cells were used for all mechanistic studies. RESULTS: Ungeremine displayed cytotoxic activity towards the 9 cancer cell lines tested, including drug-sensitive and MDR phenotypes. The IC50values obtained varied from 3.67 µM (in MDA-MB-231-BCRP breast carcinoma cells) to 75.24 µM (against in CEM/ADR5000 leukemia cells) for ungeremine and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against CEM/ADR5000 cells) for doxorubicin (control drug). Ungeremine induced ferroptosis, necroptosis, autophagy as well as apoptosis mediated by caspase activation, MMP alteration and increase ROS production. CONCLUSION: The present investigation showed that ungeremine is a promising cytotoxic compoundthat could be further explored in the future to develop new anticancer drugs to fight sensitive and resistant phenotypes.

20.
Phytomedicine ; : 152881, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30987861

RESUMO

INTRODUCTION: The adaptogens modulate expression of genes playing key roles in development of aging-related disorders, which are considered as low-grade systemic inflammatory conditions characterized by an imbalance between pro-and anti-inflammatory eicosanoids. AIM OF THE STUDY: We compared the effects of anti-inflammatory and adaptogenic plant extracts on the expression of genes involved in biosynthesis of eicosanoids with the purpose to find those plants, which selectively upregulated the expression of anti-inflammatory lipoxins signaling pathways and inhibited pro-inflammatory signaling pathways associated with biosynthesis of leukotrienes, prostaglandins and thromboxanes. MATERIALS AND METHODS: We conducted transcriptome-wide RNA sequencing to profile gene expression alterations in T98G neuroglia cells upon treatment of plant extract and analyzed the relevance of deregulated genes to eicosanoids signaling pathways using in silico models. RESULTS: For the first time, we demonstrated that Rhodiola rosea, Withania somnifera and Eleutherococcus senticosus downregulate the expression of key genes (ALOX5AP, DPEP2, LTC4S) involved biosynthesis of leukotrienes A, B, C, D and E, resulting in inhibition of leukotriene signaling pathway suggesting their potential benefits in Alzheimer disease. The common feature for all tested anti-inflammatory plants extracts was related to downregulation of ALOX12, which was also associated with neuroprotective action of these medicinal plants as well as their potential benefits in neurodegenerative diseases. None of tested anti-inflammatory and adaptogenic plants selectively activated the ALOX15-mediated signaling pathway, which is associated with generation anti-inflammatory lipoxins. Almost all tested plants upregulated the expression of the prostaglandin E receptor 3 gene (PTGER3) suggesting their potential benefits in the treatment of cancer. CONCLUSION: Every single plant tested in this study revealed a specific "signature" on eicosanoid signaling-related gene expression, regardless of their common features as anti-inflammatory or adaptogenic activity. Further studies of the combination of Rhodiola with Withania (Adaptra) for the treatment of Alzheimer disease are required.

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