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An ideal tumor treatment strategy involves therapeutic approaches that can enhance the immunogenicity of the tumor microenvironment while simultaneously eliminating the primary tumor. A cholic acid-modified iridium(III) (Ir3) photosensitizer, targeted to the endoplasmic reticulum (ER), has been reported to exhibit potent type I and type II photodynamic therapeutic effects against triple-negative breast cancer (MDA-MB-231). This photosensitizer induces pyroptotic cell death mediated by gasdermin E (GSDME) through photodynamic means and enhances tumor immunotherapy. Mechanistic studies have revealed that complex Ir3 induces characteristics of damage-related molecular patterns (DAMPs) in MDA-MB-231 breast cancer cells under light conditions. These include cell-surface calreticulin (CRT) eversion, extracellular high mobility group box 1 (HMGB1) and ATP release, accompanied by ER stress and increased reactive oxygen species (ROS). Consequently, complex Ir3 promotes dendritic cell maturation and antigen presentation under light conditions, fully activates T cell-dependent immune response in vivo, and ultimately eliminates distant tumors while destroying primary tumors. In conclusion, immune regulation and targeted intervention mediated by metal complexes represent a new and promising approach to tumor therapy. This provides an effective strategy for the development of combined targeted therapy and immunotherapy.
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Miliusanes are a class of anticancer lead molecules belonging to meroterpenoids with an 18-carbon skeleton isolated from Miliusa plants. A phytochemical study of the plant M. sinensis was carried out to discover new miliusanes with diverse structural features in order to better understand their structure-activity relationship. As a result, 20 compounds including 12 new ones (7-14 and 17-20) belonging to two sub-classes of miliusanes were isolated and identified from the twigs and leaves of this plant. Their structures, including absolute configurations, were determined by spectroscopic analyses and electronic circular dichroism. The absolute stereochemistry of miliusane structures has also been confirmed for the first time through the single crystal X-ray diffraction analysis of miliusol (1). Bioactivity evaluation showed that some of the miliusane isolates potently inhibit cell growth of several human derived cancer cell lines with IC50 values ranging from 0.52 to 23.5 µM. Compound 11 demonstrated more potent cytotoxic activity than the known miliusol (1) in stomach cancer cells though its structure contains an unconjugated 1, 4-diketone system, which added a new structure-activity feature to miliusanes. The preliminary mechanism of action studies revealed that they could be a class of dual cell migration inhibitor and senescence inducer.
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Annonaceae , Humanos , Carbono , Ciclo Celular , Línea CelularRESUMEN
The ergosterol pathway is a prime antifungal target as it is required for fungal survival, yet is not involved in human homeostasis. Methods to study the ergosterol pathway, however, are often time-consuming. The minimum inhibitory concentration (MIC) assay is a simple research tool that determines the lowest concentration at which a novel antimicrobial is active in vitro with limited scope to determine the mechanism of action for a drug. In this study, we show that by adding hydrogen peroxide, an oxidative stressor, or glutathione (GSH), an antioxidant, to modify a commonly performed MIC assay allowed us to screen selectively for new antifungal drugs that target ergosterol biosynthesis in fungi. A human pathogen and dermatophyte, Microsporum gypseum, was used as a test organism. When exposed to ergosterol targeting drugs, the hydrogen peroxide treatment significantly decreased fungal survival by reducing ergosterol in the cell wall, whereas GSH increased survival of M. gypseum. Further, by performing a series of experiments with M. gypseum and Trichophyton rubrum, it was determined that the oxidative stress from hydrogen peroxide causes cell death at different developmental stages based on fungal species. These findings allow us to describe a simple, high-throughput method for simultaneously screening new antifungal drugs for activity and effects on the ergosterol pathway. By using this tool, two isoquinoline alkaloids were discovered to be potent inhibitors of ergosterol biosynthesis in vitro by reducing the amount of ergosterol without affecting the expression of 1,3-ß-glucan. Both compounds also significantly reduced the severity of acanthosis, hyperkeratosis, spongiosis and dermal edema in vivo.
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Alcaloides/farmacología , Antifúngicos/farmacología , Ergosterol/biosíntesis , Ensayos Analíticos de Alto Rendimiento/métodos , Isoquinolinas/farmacología , Alcaloides/uso terapéutico , Animales , Antifúngicos/uso terapéutico , Arthrodermataceae/citología , Arthrodermataceae/efectos de los fármacos , Benzofenantridinas/farmacología , Benzofenantridinas/uso terapéutico , Modelos Animales de Enfermedad , Ergosterol/análisis , Femenino , Glutatión/farmacología , Cobayas , Peróxido de Hidrógeno/análisis , Peróxido de Hidrógeno/farmacología , Isoquinolinas/uso terapéutico , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Micelio/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Tiña/tratamiento farmacológico , Tiña/patologíaRESUMEN
PURPOSE: Clinical research suggests that transcranial direct current stimulation (tDCS) at bilateral supraorbital foramen and inferior orbital rim and nose intersections may facilitate rehabilitation after stroke. However, the underlying neurobiological mechanisms of tDCS remain poorly understood, impeding its clinical application. Here, we investigated the effect of tDCS applied after stroke on neural cells. MATERIALS AND METHODS: Middle cerebral arterial occlusion (MCAO) reperfusion was induced in rats. Animals with comparable infarcts were randomly divided into MCAO group and MCAO + tDCS group. Recovery of neurological function was assessed behaviorally by modified neurological severity score (mNSS). Ischemic tissue damage verified histologically by TTC and HE staining. Immunohistochemical staining, real-time qPCR, and western blot were applied to determine the changes of neural cells in ischemic brains. RESULTS: The results reveal that tDCS treated by multilead brain reflex instrument can promote the recovery of neurological function, remarkably reduce cerebral infarct volume, promote brain tissue rehabilitation, and can effectively inhibit astrocytosis and enhance neuronal survival and synaptic function in ischemic brains. CONCULSIONS: Our study suggests that tDCS treated by multilead brain reflex instrument could be prospectively developed into a clinical treatment modality.
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Gliosis/terapia , Infarto de la Arteria Cerebral Media/rehabilitación , Accidente Cerebrovascular Isquémico/rehabilitación , Neuronas , Recuperación de la Función , Rehabilitación de Accidente Cerebrovascular , Estimulación Transcraneal de Corriente Directa , Animales , Supervivencia Celular/fisiología , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/fisiopatología , Accidente Cerebrovascular Isquémico/etiología , Accidente Cerebrovascular Isquémico/patología , Accidente Cerebrovascular Isquémico/fisiopatología , Masculino , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/fisiología , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Apocynum venetum leaves are used as a kind of phytomedicine and the main ingredient in some traditional Chinese medicine products for the relief of colitis. To understand the bioactive constituents of A. venetum L., we did a phytochemistry study and investigated anti-Inflammatory effects of compounds and explored the underlying mechanisms. METHODS: We isolated compounds from ethanol extract of A. venetum L. leaf and detected the most effective compound by NO inhibition assay. We investigated anti-Inflammatory effects on dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The disease activity index was determined by scores of body weight loss, diarrhea and rectal bleeding; histological damage was analyzed by H&E staining; macrophages change in the colon were analyzed by immunohistochemistry (IHC); myeloperoxidase activity was measured by myeloperoxidase assay kits; levels of proinflammatory cytokines were determined by qPCR and ELISA; protein production such as COX-2, iNOS, STAT3 and ERK1/2 were determined by western blotting. RESULTS: We isolated uvaol from ethanol extract of A. venetum L. leaf and found uvaol has excellent potential of inhibiting NO production. We further found uvaol could attenuate disease activity index (DAI), colon shortening, colon injury, and colonic myeloperoxidase activity in DSS-induced colitis mice. Moreover, uvaol significantly reduces mRNA expression and production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß, and MCP-1) and infiltration of macrophages in colonic tissues of colitis mice. Studies on LPS challenged murine macrophage RAW246.7 cells also revealed that uvaol reduces mRNA expression and production of pro-inflammatory cytokines and mediators. Mechanically, uvaol inhibits the pro-inflammatory ERK/STAT3 axis in both inflamed colonic tissues and macrophages. CONCLUSIONS: A. venetum leaf contains uvaol and uvaol has potent anti-inflammatory effects on DSS-induced experimental colitis and LPS-stimulated RAW264.7 macrophage cells. These results suggest uvaol is a prospective anti-inflammatory agent for colonic inflammation.
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Indigo naturalis (also known as Qing-dai, or QD), a traditional Chinese medicine, has been widely used as an anticolitis regimen in the clinical practice of Chinese medicine. However, the precise mechanisms behind its efficacy remain unknown. We investigated the protective effects and associated molecular mechanisms of QD in DSS-induced colitis in mice. We found that QD administration attenuated DSS-induced colon shortening, tissue damage, and the disease activity index during the onset of colitis. Moreover, QD administration significantly suppressed colonic MPO activity and increased the activities of colonic T-SOD, CAT, and GSH-Px, as well the expression of p-AMPK and Nrf-2 in colon tissues of colitic mice. In addition, QD was capable of reducing the colonic Th1 and Th17 cell cytokines, the frequencies of Th1 and Th17 cells, and the phosphorylation of p-STAT1 and p-STAT3 in the mesenteric lymph nodes of colitic mice. An in vitro assay showed that QD significantly suppressed the differentiation of Th1 and Th17 cells. These findings suggest that QD has the potential to alleviate experimental colitis by suppressing colonic oxidative stress and restraining colonic Th1/Th17 responses, which are associated with activating AMPK/Nrf-2 signals and inhibiting STAT1/STAT3 signals, respectively. These findings also support QD as an effective regimen in the treatment of IBD.
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Colitis/tratamiento farmacológico , Colon/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Células TH1/inmunología , Células Th17/inmunología , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Colitis/inducido químicamente , Colon/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Humanos , Inmunidad Celular , Masculino , Medicina Tradicional China , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/metabolismo , Proteínas Quinasas/metabolismo , Transducción de SeñalRESUMEN
We have recently demonstrated that tau hyperphosphorylation causes diabetic synaptic neurodegeneration of retinal ganglion cells (RGCs), which might be the earliest affair during the pathogenesis of diabetic retinopathy (DR). Thus, there is a pressing need to seek therapeutic agents possessing neuroprotective effects against tau hyperphosphorylation in RGCs for arresting the progression of DR. Here, using a well-characterized diabetes model of db/db mouse, we discovered that topical ocular application of 10 mg/kg/day of ginsenoside Rg1 (GRg1), one of the major active ingredients extracted from Panax ginseng and Panax notoginseng, ameliorated hyperphosphorylated tau-triggered RGCs synaptic neurodegeneration in diabetic mice. The neuroprotective effects of GRg1 on diabetic retinae were abrogated when retinal IRS-1 or Akt was suppressed by intravitreal injection with si-IRS-1 or topically coadministered with a specific inhibitor of Akt, respectively. However, selective repression of retinal GSK3ß by intravitreal administration of si-GSK3ß rescued the neuroprotective properties of GRg1 when Akt was inactivated. Therefore, the present study showed for the first time that GRg1 can prevent hyperphosphorylated tau-induced synaptic neurodegeneration of RGCs via activation of IRS-1/Akt/GSK3ß signaling in the early phase of DR. Moreover, our data clarify the potential therapeutic significance of GRg1 for neuroprotective intervention strategies of DR.
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Retinopatía Diabética/tratamiento farmacológico , Ginsenósidos/administración & dosificación , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Ganglionares de la Retina/efectos de los fármacos , Proteínas tau/metabolismo , Animales , Retinopatía Diabética/genética , Retinopatía Diabética/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Humanos , Proteínas Sustrato del Receptor de Insulina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Panax notoginseng/química , Fosforilación , Extractos Vegetales/administración & dosificación , Proteínas Proto-Oncogénicas c-akt/genética , Retina/patología , Células Ganglionares de la Retina/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas tau/genéticaRESUMEN
We previously demonstrated that overexpression of tropomyosin receptor kinase A (TrkA) promotes the survival and Schwann cell-like differentiation of bone marrow stromal stem cells in nerve grafts, thereby enhancing the regeneration and functional recovery of the peripheral nerve. In the present study, we investigated the molecular mechanisms underlying the neuroprotective effects of TrkA in bone marrow stromal stem cells seeded into nerve grafts. Bone marrow stromal stem cells from Sprague-Dawley rats were infected with recombinant lentivirus vector expressing rat TrkA, TrkA-shRNA or the respective control. The cells were then seeded into allogeneic rat acellular nerve allografts for bridging a 1-cm right sciatic nerve defect. Then, 8 weeks after surgery, hematoxylin and eosin staining showed that compared with the control groups, the cells and fibers in the TrkA overexpressing group were more densely and uniformly arranged, whereas they were relatively sparse and arranged in a disordered manner in the TrkA-shRNA group. Western blot assay showed that compared with the control groups, the TrkA overexpressing group had higher expression of the myelin marker, myelin basic protein and the axonal marker neurofilament 200. The TrkA overexpressing group also had higher levels of various signaling molecules, including TrkA, pTrkA (Tyr490), extracellular signal-regulated kinases 1/2 (Erk1/2), pErk1/2 (Thr202/Tyr204), and the anti-apoptotic proteins Bcl-2 and Bcl-xL. In contrast, these proteins were downregulated, while the pro-apoptotic factors Bax and Bad were upregulated, in the TrkA-shRNA group. The levels of the TrkA effectors Akt and pAkt (Ser473) were not different among the groups. These results suggest that TrkA enhances the survival and regenerative capacity of bone marrow stromal stem cells through upregulation of the Erk/Bcl-2 pathway. All procedures were approved by the Animal Ethical and Welfare Committee of Shenzhen University, China in December 2014 (approval No. AEWC-2014-001219).
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The treatment of dermatophytosis has improved considerably over the past several decades following the introduction of the oral antifungals such as azoles and amphotericin B. However, these drugs have had limited success because the treated fungi often develop drug resistance, resulting in recurrence when applied in various topical formulations. Thus, there are constant needs for new topical agents that are effective against dermatophytosis. Dipyrithione is an attractive candidate to become an antifungal agent due to its broad spectrum of antimicrobial activities. In this study, we determined that dipyrithione could potently inhibit the growth of Trichophyton rubrum, which is the most common cause of dermatophytosis. The MIC50 value of dipyrithione against T. rubrum was measured as 6.03 µM, as compared with miconazole (MIC50: 1.38 µM). Additionally, the compound caused morphological changes in the fungi, which was examined using the morphological interference assay. The in vivo experiment further revealed that dipyrithione had a healing effect on the skin of guinea pigs infected with T. rubrum. Our studies have demonstrated that dipyrithione had a potent antifungal activity in vitro and in vivo, suggesting that it could be formulated as a potential antifungal lead compound in search for novel therapeutic agents against dermatophytosis.
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Antifúngicos/farmacología , Piridinas/farmacología , Tiña/tratamiento farmacológico , Trichophyton/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Cobayas , Pruebas de Sensibilidad Microbiana , Piel/efectos de los fármacos , Piel/microbiología , Tiña/microbiologíaRESUMEN
Over the years, various methods have been developed to enhance the solubility of insoluble drugs; however, most of these methods are time-consuming and labor intensive or involve the use of toxic materials. A method that can safely and effectively enhance the solubility of insoluble drugs is lacking. This study adopted baicalin as an insoluble drug model, and used hydroxypropyl-ß-cyclodextrin for the delivery of baicalin via the inclusion complexation by supercritical fluid encapsulation. Different parameters for the complex preparation as well as the physicochemical properties of the complex have been investigated. Our results showed that when compared to the conventional solution mixing approach, supercritical fluid encapsulation enables a more precise control of the properties of the complex, and gives higher loading and encapsulation efficiency. It is anticipated that our reported method can be useful in enhancing the preparation efficiency of inclusion complexes, and can expand the application potential of insoluble herbal ingredients in treatment development and pharmaceutical formulation.
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2-Hidroxipropil-beta-Ciclodextrina , Química Farmacéutica , Portadores de Fármacos , Composición de Medicamentos , Flavonoides/administración & dosificación , Flavonoides/química , 2-Hidroxipropil-beta-Ciclodextrina/química , Portadores de Fármacos/química , Estructura Molecular , Espectroscopía Infrarroja por Transformada de Fourier , Termografía , Difracción de Rayos XRESUMEN
Notoginsenoside R7 was isolated from Panax notoginseng, a plant used commonly in traditional Chinese medicine. We investigated the anti-cancer effects of R7 in HeLa cells in vitro and in vivo, and explored the underlying mechanisms of action. R7 dose-dependently inhibited HeLa cell proliferation and induced apoptosis in vitro, In silico docking-based screening assays showed that R7 can directly bind Akt. Pretreatment with the Akt inhibitor LY294002 synergistically enhanced the R7 anti-proliferation and anti-apoptosis effects in HeLa cells, confirming that R7 acts through the PI3K/Akt pathway. Consistent with the in vitro findings, R7 exerted anti-tumor effects in a mouse xenograft model by targeting PI3K (PTEN) and Akt, activating the pro-apoptotic Bcl-2 family and, subsequently, caspase family members. R7 treatment activated PTEN and downregulated mTOR phosphorylation without affecting mTOR expression, though regulatory-associated protein of mTOR (raptor) expression declined. Our study suggests that R7 is a promising chemotherapeutic agent for the treatment of cervical cancer and other PI3K/PTEN/Akt/mTOR signaling-associated tumors.
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Hydrogels are swellable polymer networks which can imbibe a substantial amount of fluids. Compared to bulk hydrogels, hydrogel nanoparticles exhibit added values in drug delivery because they can be internalized into cells to deliver pharmaceutical agents into the cytosol. Their large surface area also allows for multivalent conjugations, making optimization of the nanoparticles towards in vivo and clinical applications possible. These features, together with the tunable properties and biocompatibility of hydrogels, account for the widespread use of hydrogel-based nanoparticulate systems in drug formulation. From an in vivo perspective, this article presents the latest advances in fabrication and engineering of hydrogel nanoparticles, and illuminates future avenues to enhance the potential of hydrogel-based nanoparticulate systems in treatment development and drug administration.
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Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Nanopartículas , Animales , Química Farmacéutica/métodos , Citosol/metabolismo , Humanos , Hidrogeles , Preparaciones Farmacéuticas/administración & dosificación , Polímeros/químicaRESUMEN
Three new indole alkaloids, named naucleamide G (1), and nauclealomide B and C (5 and 6), were isolated from the n-BuOH-soluble fraction of an EtOH extract of the leaves of Nauclea officinalis, together with three known alkaloids, paratunamide C (2), paratunamide D (3) and paratunamide A (4). The structures with absolute configurations of the new compounds were identified on the basis of 1D and 2D NMR, HRESIMS, acid hydrolysis and quantum chemical circular dichroism (CD) calculation. According to the structures of isolated indole alkaloids, their plausible biosynthetic pathway was deduced.
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Alcaloides/química , Hojas de la Planta/química , Rubiaceae/química , Alcaloides/aislamiento & purificación , Carbolinas/química , Carbolinas/aislamiento & purificación , Dicroismo Circular , Glucósidos/química , Glucósidos/aislamiento & purificación , Glicósidos/química , Glicósidos/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Extractos Vegetales/químicaRESUMEN
There are many herbal teas that are found in nature that may be effective at treating the symptoms and also shortening the duration of viral infections. When combating viral infections, T lymphocytes are an indispensable part of human acquired immunity. However, studies on the use of natural products in stimulating lymphocyte-mediated interferon-gamma (IFN-γ) production are very limited. In this study, we found that acteoside, a natural phenylpropanoid glycoside from Kuding Tea, enhanced IFN-γ production in mouse lymphocytes in a dose-dependent manner, particularly in the CD4+ and CD8+ subsets of T lymphocytes. To this end, we suggest that the antiviral activity of acteoside was highly correlated to its inducing ability of IFN-γ production. Mechanistically, the activation of T-bet enhanced the promoter of IFN-γ and subsequently resulted in an increased IFN-γ production in T cells. Collectively, we have found a natural product with the capacity to selectively enhance mouse T cell IFN-γ production. Given the role of IFN-γ in the immune system, further studies to clarify the role of acteoside in inducing IFN-γ and prevention of viral infection are needed.
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Antivirales/farmacología , Productos Biológicos/farmacología , Glucósidos/farmacología , Interferón gamma/metabolismo , Fenoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta Inmunológica , Glicósidos/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas , Células RAW 264.7 , Proteínas de Dominio T Box/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Tés de Hierbas/análisisRESUMEN
BACKGROUND: Catharanthus roseus (L.) G. Don consists of a range of dimeric indole alkaloids with significant antitumor activities. These alkaloids have been found to possess apoptosis-inducing activity against tumor cells in vitro and in vivo mediated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, in which DNA damage and mitochondrial dysfunction play important roles. In this study, a unique bisindole alkaloid named cathachunine, along with five known dimeric indole alkaloids, was obtained from C. roseus and investigated in vitro. PURPOSE: The aim of this study was to investigate the antitumor activity of isolated alkaloids and the mechanism through which cathachunine exerts its antitumor effect. STUDY DESIGN AND METHODS: Cell growth inhibition was assessed by WST-1 and lactate dehydrogenase (LDH) assays in HL60, K562 leukemia cells and EA.hy926 umbilical vein cells. Induction of apoptosis in HL60 cells was confirmed by observation of nuclear morphology, a caspase-3 activity assay and annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) double staining. The intrinsic apoptotic pathway induced by cathachunine was evidenced by B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) dysregulation, loss of mitochondrial membrane potential, translocation of cytochrome c, and cleavage of caspase-3 and poly-ADP ribose polymerase (PARP). Reactive oxygen species (ROS) production after cathachunine treatment was determined by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Cell cycle arrest of the S phase was also observed in HL60 cells after cathachunine treatment. RESULTS: The WST-1 and LDH assays showed that Catharanthus alkaloids were cytotoxic toward human leukemia cells to a greater extent than toward normal human endothelial cells, and the anti-proliferation and pro-apoptosis abilities of cathachunine were much more potent than other previously reported alkaloids. The induction of apoptosis by cathachunine occurred through an ROS-dependent mitochondria-mediated intrinsic pathway rather than an extrinsic pathway, and was regulated by the Bcl-2 protein family. CONCLUSION: An unprecedented bisindole alkaloid cathachunine which lost C-18' and C-19' was isolated from C. roseus. It exerted a potent antitumor effect toward human leukemia cells through the induction of apoptosis via an intrinsic pathway. Thus, this study provides evidence for a new lead compound from a natural source for anti-cancer investigations.
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Alcaloides/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Leucemia/tratamiento farmacológico , Extractos Vegetales/farmacología , Antineoplásicos/uso terapéutico , Catharanthus/química , China , Humanos , Células K562/efectos de los fármacosRESUMEN
Tuberculosis (TB) is a highly contagious disease mainly caused by Mycobacterium tuberculosis H37 RV . Antitubercular (anti-TB) bioassay-guided isolation of the CHCl3 extract of the leaves and stems of the medicinal plant Ardisia gigantifolia led to the isolation of two anti-TB 5-alkylresorcinols, 5-(8Z-heptadecenyl) resorcinol (1) and 5-(8Z-pentadecenyl) resorcinol (2). We further synthesized 15 derivatives based on these two natural products. These compounds (natural and synthetic) were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37 RV . Resorcinols 1 and 2 exhibited anti-TB activity with MIC values at 34.4 and 79.2 µm in MABA assay, respectively, and 91.7 and 168.3 µm in LORA assay, respectively. Among these derivatives, compound 8 was found to show improved anti-TB activity than its synthetic precursor (2) with MIC values at 42.0 µm in MABA assay and 100.2 µm in LORA assay. The active compounds should be regarded as new hits for further study as a novel class of anti-TB agents. The distinct structure-activity correlations of the parent compound were elucidated based on these derivatives.
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Antituberculosos/química , Antituberculosos/aislamiento & purificación , Ardisia/química , Bioensayo , Extractos Vegetales/farmacología , Resorcinoles/química , Resorcinoles/aislamiento & purificación , Antituberculosos/farmacología , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Resorcinoles/farmacología , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Increased apoptosis of retinal ganglion cells (RGCs) contributes to the gradual loss of retinal neurons at the early phase of diabetic retinopathy (DR). There is an urgent need to search for drugs with neuroprotective effects against apoptosis of RGCs for the early treatment of DR. This study aimed to investigate the neuroprotective effects of saponins extracted from Panax notoginseng, a traditional Chinese medicine, on apoptosis of RGCs stimulated by palmitate, a metabolic factor for the development of diabetes and its complications, and to explore the potential molecular mechanism. We showed that crude saponins of P. notoginseng (CSPN) inhibited the increased apoptosis and loss of postsynaptic protein PSD-95 by palmitate in staurosporine-differentiated RGC-5 cells. Moreover, CSPN suppressed palmitate-induced reactive oxygen species generation and endoplasmic reticulum stress-associated eIF2α/ATF4/CHOP and caspase 12 pathways. Thus, our findings address the potential therapeutic significance of CSPN for the early stage of DR.
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Medicamentos Herbarios Chinos/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Palmitatos/efectos adversos , Panax notoginseng/química , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/efectos de los fármacos , Saponinas/farmacología , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteínas Asociadas a SAP90-PSD95 , Estaurosporina/farmacologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ligustrum purpurascens Y.C. Yang (Oleaceae) is traditionally recorded as "Ku Ding Cha", a kind of functional tea in southern China for about two thousand years, which has been reported with sore throat alleviating and pathogenic heat expelling effects. However, there are no scientific studies demonstrating its antiviral activity. THE AIM OF THE STUDY: This study is aimed at investigating the anti-influenza virus effects of phenylethanoid glycosides isolated from L. purpurascens (LPG) as well as its corresponding mechanisms. MATERIALS AND METHODS: In vitro, hemagglutination assay was employed to detect the influenza virus titer; In vivo, C57BL/6J mice were given oral administration of LPG (100mg/kg, 300mg/kg, 900mg/kg) or ribavirin (100mg/kg) once daily for 5 successive days. Meanwhile, on the second day, mice were infected intranasally (i.n.) with A/FM/1/47 H1N1 virus. Mice survival rate and other clinical index were monitored for 15 days. Infected mice were sacrificed to measure the lung lesion and stained with hematoxylin-eosin. Flow cytometry analyses spleen lymphocytes and interferon-γ (IFN-γ) level. The IFN-γ knockout mice (IFN-γ(-/-) mice, C57BL/6J) which had been verified lacking IFN-γ through Western Blot, were applied in the death-protection test to identify the role of IFN-γ played in LPG antiviral effect. RESULTS: In vitro, LPG at 0.5mg/ml inhibited Influenza A Virus H1N1 type (H1N1) infection of MDCK cells. In vivo, LPG at 300 and 900mg/kg significantly decreased the mouse lung index (p<0.05), alleviated influenza-induced lethality and clinical symptoms, and therefore enhanced mouse survival (p<0.05). More detailed experiments demonstrated that antiviral cytokine IFN-γ was involved in the antiviral effect of LPG. Flow cytometric analysis revealed that LPG (900mg/kg) significantly induced secretion of IFN-γ by splenic CD4(+) and CD8(+) cells (p<0.05). Moreover, LPG (900mg/kg) protected wild-type C57BL/6J mice from H1N1 injury, whereas LPG-mediated survival protection disappeared in IFN-γ(-/-) mice. CONCLUSION: These results suggest that up-regulating endogenous IFN-γ by LPG may represent a novel therapeutic approach for H1N1 infection.
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Antivirales/farmacología , Glicósidos/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Inductores de Interferón/farmacología , Interferón gamma/biosíntesis , Ligustrum/química , Animales , Antivirales/toxicidad , Citocinas/metabolismo , Perros , Femenino , Humanos , Gripe Humana/virología , Interferón gamma/genética , Ligustrum/toxicidad , Pulmón/virología , Recuento de Linfocitos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Edema Pulmonar/tratamiento farmacológico , Edema Pulmonar/patología , Ribavirina/farmacología , Ribavirina/uso terapéutico , Análisis de SupervivenciaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: In Chinese folk medicine, the leaves of Ligustrum robustum Blume (LR) were commonly used in the treatment of obesity and hyperlipidemia. This study aimed to evaluate the anti-obesity effect and mechanisms of total phenylpropanoid glycosides from Ligustrum robustum Blume (LRTPG) in fatty diet-fed C57BL/6J mice. MATERIALS AND METHODS: C57BL/6J mice were divided randomly into 6 groups, i.e., control, model, positive (Orlistat 0.12g/kg), and LRTPG at three dosages (0.3, 0.6 or 1.2g/kg), respectively. Control mice were fed with standard diet; the others were fed with fatty diet. After 4 weeks׳ modeling, therapy mice were intragastrically administrated with positive drug or LRTPG for 5 weeks, respectively. Pharmacodynamic effects including body weight, fat weight, Lee׳s index, serum lipid levels, morphological changes and adipocyte area ratio were evaluated. The mechanisms were explored as the factors related to lipids metabolism in gene expressions by real-time PCR, and assured as the protein level of differential gene by Western blotting. RESULTS: The anti-obesity effects of LRTPG in all treated mice were shown as decreased body weight, fat mass, Lee׳s index, total cholesterol (TC) level, and adipocyte area. The mechanisms were demonstrated as elevated mRNA and protein levels of adipose leptin, and consequently decreasing mRNA of adipose acyl coenzyme A: diacylglycerol acyltransferase (DGAT) with increasing mRNA of hepatic cholesterol 7α-hydroxylase (CYP7A1), which led to inhibition of triglyceride (TG) synthesis and promotion of cholesterol catabolism. CONCLUSIONS: The anti-obesity effect of LRTPG in fatty diet-fed mice was related to the up-regulation of leptin, which may provide scientific evidence supporting the traditional usage of LR on obesity in China.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Glicósidos/uso terapéutico , Leptina/biosíntesis , Ligustrum/química , Fitoterapia/métodos , Extractos Vegetales/uso terapéutico , Acilcoenzima A/biosíntesis , Adipocitos/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/enzimología , Animales , Fármacos Antiobesidad/aislamiento & purificación , Fármacos Antiobesidad/farmacología , Peso Corporal , Colesterol 7-alfa-Hidroxilasa/biosíntesis , Diacilglicerol O-Acetiltransferasa/biosíntesis , Grasas de la Dieta/administración & dosificación , Relación Dosis-Respuesta a Droga , Glicósidos/aislamiento & purificación , Glicósidos/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Obesidad/tratamiento farmacológico , Extractos Vegetales/química , Hojas de la Planta/química , Regulación hacia ArribaRESUMEN
Two new oxindole alkaloid glycosides, nauclealomide A and (3S,7R)-javaniside, were isolated from the leaves of Nauclea officinalis. Their structures and absolute configurations were elucidated by means of NMR, HRESIMS, X-ray diffraction, acid hydrolysis and quantum chemical CD calculation. Nauclealomide A is a novel monoterpenoid oxindole alkaloid possessing a rare tetrahydro-2H-1,3-oxazine ring.