RESUMEN
Gambogenic acid is a derivative of gambogic acid, a polyprenylated xanthone isolated from Garcinia hanburyi. Compared with the more widely studied gambogic acid, gambogenic acid has demonstrated advantages such as a more potent antitumor effect and less systemic toxicity than gambogic acid according to early investigations. Therefore, the present review summarizes the effectiveness and mechanisms of gambogenic acid in different cancers and highlights the mechanisms of action. In addition, drug delivery systems to improve the bioavailability of gambogenic acid and its pharmacokinetic profile are included. Gambogenic acid has been applied to treat a wide range of cancers, such as lung, liver, colorectal, breast, gastric, bladder, and prostate cancers. Gambogenic acid exerts its antitumor effects as a novel class of enhancer of zeste homolog 2 inhibitors. It prevents cancer cell proliferation by inducing apoptosis, ferroptosis, and necroptosis and controlling the cell cycle as well as autophagy. Gambogenic acid also hinders tumor cell invasion and metastasis by downregulating metastasis-related proteins. Moreover, gambogenic acid increases the sensitivity of cancer cells to chemotherapy and has shown effects on multidrug resistance in malignancy. This review adds insights for the prevention and treatment of cancers using gambogenic acid.
Asunto(s)
Antineoplásicos , Xantenos , Animales , Apoptosis , Línea Celular Tumoral , Xantenos/farmacología , Xantenos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Helminth infections are an important public health problem in humans and have an even greater impact on domestic animal and livestock welfare. Current readouts for anthelmintic drug screening assays are stage development, migration, or motility that can be subjective, laborious, and low in throughput. The aim of this study was to apply and optimize a fluorometric technique using resazurin for evaluating changes in the metabolic activity of Ascaris suum third-stage larvae (L3), a parasite of high economic relevance in swine. METHODS: Ascaris suum L3 were mechanically hatched from 6- to 8-week embryonated and sucrose-gradient-enriched eggs. Resazurin dye and A. suum L3 were titrated in 96-well microtiter plates, and resazurin reduction activity was assessed by fluorometry after 24 h of incubation. Fluorescence microscopy was used to localize the resazurin reduction site within the larvae. Finally, we exposed A. suum L3 to various stress conditions including heat, methanol, and anthelmintics, and investigated their impact on larval metabolism through resazurin reduction activity. RESULTS: We show that the non-fluorescent dye resazurin is reduced inside vital A. suum L3 to fluorescent resorufin and released into the culture media. Optimal assay parameters are 100-1000 L3 per well, a resazurin concentration of 7.5 µg/ml, and incubation at 37 °C/5% CO2 for 24 h. An intact L2 sheath around the L3 of A. suum completely prevents the uptake of resazurin, while in unsheathed L3, the most intense fluorescence signal is observed along the larval midgut. L3 exposed to methanol or heat show a gradually decreased resazurin reduction activity. In addition, 24 h exposure to ivermectin at 0.625 µM, mebendazole at 5 µM, and thiabendazole from 10 to 100 µM significantly decreased larval metabolic activity by 55%, 73%, and 70% to 89%, respectively. CONCLUSIONS: Together, our results show that both metabolic stressors and anthelmintic drugs significantly and reproducibly reduce the resazurin reduction activity of A. suum L3, making the proposed assay a sensitive and easy-to-use method to evaluate metabolic activity of A. suum L3 in vitro.
Asunto(s)
Antihelmínticos , Ascariasis , Ascaris suum , Humanos , Animales , Porcinos , Metanol/farmacología , Metanol/uso terapéutico , Antihelmínticos/farmacología , Antihelmínticos/uso terapéutico , Xantenos/farmacología , Xantenos/uso terapéutico , Ascariasis/parasitología , LarvaRESUMEN
The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of nosocomial infections, which are becoming increasingly difficult to treat due to antibiotic resistance. Polyphosphate (polyP) plays a key role in P. aeruginosa virulence, stress response, and antibiotic tolerance, suggesting an attractive drug target. Here, we show that the small molecule gallein disrupts polyphosphate homeostasis by inhibiting all members of both polyphosphate kinase (PPK) families (PPK1 and PPK2) encoded by P. aeruginosa, demonstrating dual-specificity PPK inhibition for the first time. Inhibitor treatment phenocopied ppk deletion to reduce cellular polyP accumulation and attenuate biofilm formation, motility, and pyoverdine and pyocyanin production. Most importantly, gallein attenuated P. aeruginosa virulence in a Caenorhabditis elegans infection model and synergized with antibiotics while exhibiting negligible toxicity toward the nematodes or HEK293T cells, suggesting our discovery of dual-specificity PPK inhibitors as a promising starting point for the development of new antivirulence therapeutics. IMPORTANCE Many priority bacterial pathogens such as P. aeruginosa encode both PPK1 and PPK2 enzymes to maintain polyphosphate homeostasis. While PPK1 and PPK2 have distinct structures and catalytic mechanisms, they are both capable of synthesizing and consuming polyphosphate; thus, PPK2 enzymes can compensate for the loss of PPK1 and vice versa. In this study, we identified the small molecule gallein as a dual-specificity inhibitor of both PPK1 and PPK2 enzyme families in P. aeruginosa. Inhibitor treatment reduced cellular polyP in wild-type (WT), Δppk1, and Δppk2 strains to levels that were on par with the Δppk1 Δppk2A Δppk2B Δppk2C knockout control. Treatment also attenuated biofilm formation, motility, toxin production, and virulence to a similar extent, thereby elucidating a hitherto-undocumented role of PPK2 enzymes in P. aeruginosa virulence phenotypes. This work therefore establishes PPK2s, in addition to PPK1, as valuable drug targets in P. aeruginosa and provides a favorable starting molecule for future inhibitor design efforts.
Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Fosfotransferasas (Aceptor del Grupo Fosfato)/antagonistas & inhibidores , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/patogenicidad , Xantenos/farmacología , Animales , Antibacterianos/uso terapéutico , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/microbiología , Inhibidores Enzimáticos/uso terapéutico , Células HEK293 , Humanos , Fenotipo , Fosfotransferasas (Aceptor del Grupo Fosfato)/clasificación , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/enzimología , Virulencia/efectos de los fármacos , Xantenos/uso terapéuticoRESUMEN
Osteoporosis is a chronic disease that has become a serious public health problem due to the associated reduction in quality of life and its increasing financial burden. It is known that inhibiting osteoclast differentiation and promoting osteoblast formation prevents osteoporosis. As there is no drug with this dual activity without clinical side effects, new alternatives are needed. Here, we demonstrate that austalide K, isolated from the marine fungus Penicillium rudallenes, has dual activities in bone remodeling. Austalide K inhibits the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and improves bone morphogenetic protein (BMP)-2-mediated osteoblast differentiation in vitro without cytotoxicity. The nuclear factor of activated T cells c1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), dendritic cell-specific transmembrane protein (DC-STAMP), and cathepsin K (CTSK) osteoclast-formation-related genes were reduced and alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and osteopontin (OPN) (osteoblast activation-related genes) were simultaneously upregulated by treatment with austalide K. Furthermore, austalide K showed good efficacy in an LPS-induced bone loss in vivo model. Bone volume, trabecular separation, trabecular thickness, and bone mineral density were recovered by austalide K. On the basis of these results, austalide K may lead to new drug treatments for bone diseases such as osteoporosis.
Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Resorción Ósea/prevención & control , Osteoblastos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Penicillium/química , Xantenos/uso terapéutico , Animales , Conservadores de la Densidad Ósea/aislamiento & purificación , Conservadores de la Densidad Ósea/farmacología , Resorción Ósea/inducido químicamente , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Sedimentos Geológicos/microbiología , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Factores de Transcripción NFATC/biosíntesis , Factores de Transcripción NFATC/genética , Osteoporosis , Penicillium/aislamiento & purificación , Ligando RANK/farmacología , Fosfatasa Ácida Tartratorresistente/antagonistas & inhibidores , Xantenos/aislamiento & purificación , Xantenos/farmacologíaRESUMEN
Resilience, referring to "achieving a positive outcome in the face of adversity", is a common phenomenon in daily life. Elucidating the mechanisms of stress resilience is instrumental to developing more effective treatments for stress-related psychiatric disorders such as depression. Metabotropic glutamate receptors (mGlu2/3 and mGlu5) within the medial prefrontal cortex (mPFC) have been recently recognized as promising therapeutic targets for rapid-acting antidepressant treatment. In this study, we assessed the functional roles of the mGlu2/3 and mGlu5 within different subregions of the mPFC in modulating stress resilience and vulnerability by using chronic social defeat stress (CSDS) paradigms in mice. Our results showed that approximately 51.6% of the subjects exhibited depression- or anxiety-like behaviors after exposure to CSDS. When a susceptible mouse was confronted with an attacker, c-Fos expression in the prelimbic cortex (PrL) subregion of the mPFC substantially increased. Compared with the resilient and control groups, the expression of mGlu2/3 was elevated in the PrL of the susceptible group. The expression of mGlu5 showed no significant difference among the three groups in the whole mPFC. Finally, we found that the social avoidance symptoms of the susceptible mice were rapidly relieved by intra-PrL administration of LY341495-an mGluR2/3 antagonists. The above results indicate that mGluR2/3 within the PrL may play an important regulatory role in stress-related psychiatric disorders. Our results are meaningful, as they expand our understanding of stress resilience and vulnerability which may open an avenue to develop novel, personalized approaches to mitigate depression and promote stress resilience.
Asunto(s)
Depresión/patología , Corteza Prefrontal/patología , Receptores de Glutamato Metabotrópico/metabolismo , Estrés Psicológico/patología , Aminoácidos/farmacología , Aminoácidos/uso terapéutico , Animales , Depresión/etiología , Depresión/prevención & control , Depresión/psicología , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Resiliencia Psicológica/efectos de los fármacos , Derrota Social , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/etiología , Estrés Psicológico/psicología , Xantenos/farmacología , Xantenos/uso terapéuticoRESUMEN
Cutaneous autoimmune and inflammatory diseases are a major burden of global disease and many lack effective treatments that can derive in different dermatoses like atopic dermatitis. Despite the increase prevalence and the high health-care costs worldwide, the heterogeniety and multifactoriality of these diseases mean that effective treatment options are scarce. Plasma rich in growth factors (PRGF) technology could be an alternative approach that may help in the management of this cutaneous condition. The aim of this study was to assess the effect of two different PRGF formulations (just activated and autologous topical serum (ATS)) for the management of skin inflammation. Additionally, ATS was assessed over two patients suffering from radiotherapy induced dermatitis. Human organotypic skin explant cultures (hOSECs) were used as human skin models. To induce atopic dermatitis-like conditions, skin explants were treated with both interleukin-4 (IL-4) and interleukin-13 (IL-13). PRGF and ATS were intradermally and topically applied, respectively. Metabolic activity, reactive oxigen species (ROS), necrosis and inflammatory cytokine production were determined. Both PRGF formulations increased tissue viability and significantly reduced the excessive free radical accumulation and the cutaneous cytokine production such as TNF-α and IL-1ß. Case reports showed a positive response after ATS treatment in terms of skin quality improvement, local erythema decrease and burning and itching amelioration. The oedema, swelling and desquamation caused by radiation induced dermatitis was also reduced and the patients referred ceased pruritus and pain. This preliminary study suggests that PRGF might aid in the management of inflammatory skin conditions.
Asunto(s)
Antiinflamatorios/análisis , Péptidos y Proteínas de Señalización Intercelular/análisis , Plasma Rico en Plaquetas/fisiología , Piel/efectos de los fármacos , Administración Cutánea , Antiinflamatorios/química , Humanos , Péptidos y Proteínas de Señalización Intercelular/química , Oxazinas/uso terapéutico , Xantenos/uso terapéuticoRESUMEN
Ketamine produces a rapid antidepressant effect, but its use can be associated with serious side effects. Hence, other therapeutic options that will allow us to obtain a quick and safe antidepressant effect by modulating glutamatergic transmission are needed. Antagonists of mGlu2/3 receptors, which share some mechanisms of action with ketamine, may be good candidates to obtain this effect. Here, we show that the metabotropic glutamate (mGlu) 2/3 receptor antagonist LY341495 induced a dose-dependent antidepressant-like effect in the chronic unpredictable mild stress (CUMS) model of depression in C57BL/6J mice after both single and subchronic (three-day) administration. Furthermore, a noneffective dose of LY341495 (0.3 mg/kg) given jointly with a noneffective dose of ketamine (3 mg/kg) reversed the CUMS-induced behavioral effects, indicating that coadministration of ketamine with an mGlu2/3 receptor antagonist might allow its therapeutically effective dose to be lowered. Western blot results indicate that mTOR pathway activation might be involved in the mechanism of action of this drug combination. Moreover, the combined doses of both substances did not produce undesirable behavioral effects characteristic of a higher dose of ketamine (10 mg/kg) commonly used in rodent studies to induce antidepressant effects. Coadministration of low doses of ketamine and LY341495 did not induce the hyperactivity typical of NMDA channel blockers, did not disturb short-term memory in the novel object recognition (NOR) test, and did not disturb motor coordination in the rotarod test. Our research not only confirmed the earlier data on the rapid antidepressant effect of mGlu2/3 receptor antagonists but also indicated that such compounds can safely lower the effective dose of ketamine.
Asunto(s)
Aminoácidos/uso terapéutico , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ketamina/uso terapéutico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Xantenos/uso terapéutico , Aminoácidos/farmacología , Animales , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ketamina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Destreza Motora/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Xantenos/farmacologíaRESUMEN
Melanoma is characterized by high malignancy and early onset of metastasis. Epithelial-to-mesenchymal transition (EMT) is an early event during tumor metastasis. Tumor cells that develop EMT can escape apoptosis, but they are vulnerable to ferroptosis inducers. Gambogenic acid (GNA), a xanthone found in Gamboge, has cytotoxic effects in highly invasive melanoma cells. This study investigated the anti-melanoma effect and mechanism of action of GNA in TGF-ß1-induced EMT melanoma cells. We found that GNA significantly inhibited the invasion, migration and EMT in melanoma cells, and these cells exhibited small mitochondrial wrinkling (an important feature of ferroptosis). An iron chelator, but not an apoptosis inhibitor or a necrosis inhibitor, abolished the inhibitory effects of GNA on proliferation, invasion and migration of TGF-ß1-stimulated melanoma cells. GNA upregulated the expression of p53, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in the model cells, contributing to the mechanisms underlying GNA-induced ferroptosis. Collectively, our findings suggest that GNA induces ferroptosis in TGF-ß1-stimulated melanoma cells via the p53/SLC7A11/GPX4 signaling pathway.
Asunto(s)
Medicamentos Herbarios Chinos/toxicidad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Melanoma/metabolismo , Neoplasias Cutáneas/metabolismo , Xantenos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Medicamentos Herbarios Chinos/uso terapéutico , Transición Epitelial-Mesenquimal/fisiología , Ferroptosis/fisiología , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Xantenos/uso terapéuticoRESUMEN
Photodynamic therapy (PDT) is a modern cancer therapy. But it is still difficult to obtain ideal photosensitizers. We synthesized six new peri-xanthenoxanthene derivatives rapidly and efficiently using solid-phase carbon-bath microwave irradiation technology, and investigated their in vitro photodynamic antitumor activity with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Our results showed that all compounds exhibited extremely low dark cytotoxicity and good phototoxicity against four human cancer cell lines. In particular, compound 3c showed the best in vitro PDT activity against Hela cells and Bel-7402 cells with IC50 values of 91 and 74 nmol/L, respectively. Its value of 1-octanol/water partition coefficient (log Kow) was 0.5309, suggesting that it is a promising photosensitizer for PDT due to its low dark cytotoxicity, high phototoxicity, and potential water solubility.
Asunto(s)
Fármacos Fotosensibilizantes/síntesis química , Xantenos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Concentración 50 Inhibidora , Microondas , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Xantenos/farmacología , Xantenos/uso terapéuticoRESUMEN
Hyperuricaemia, which results from the overproduction and underexcretion of uric acid, has been linked with chronic renal dysfunction, cardiovascular diseases, diabetes and metabolic syndrome. However, available clinical drugs cannot simultaneously target the production and excretion of uric acid. Norathyriol, a natural xanthone, was expected to have the dual actions. We previously reported that norathyriol possessed potent anti-hyperuricaemic activity related to the inhibition of uric acid production. Here, we investigated the uricosuric actions in hyperuricaemic animals and explored the possible molecular mechanisms associated with renal urate transporters and xanthine oxidase (XO). The results showed that norathyriol (0.5-4.0â¯mg/kg) dose- and time-dependently decreased serum urate levels in uric acid-induced hyperuricaemic mice and markedly increased the fractional excretion of urate in oxonate-induced hyperuricaemic rats, demonstrating a promotion of urate excretion in the kidney. Further evidence showed that norathyriol markedly increased renal mRNA and protein expression of the secretory organic anion transporter 1 (OAT1) in hyperuricaemic mice and strengthened its transport function in vitro. Moreover, norathyriol also upregulated the mRNA expression of the secretory transporters OAT3, ATP-binding cassette transporter G2 and multidrug resistance protein 4, but not their protein expression. Changes in the expression of the reabsorptive transporters were not observed. This is the first report that norathyriol has uricosuric effects by targeting OAT1. Moreover, norathyriol significantly inhibited XO activity in an uncompetitive manner. Taken together, these findings suggest that norathyriol has the potential to be developed as a new anti-hyperuricaemic agent with dual actions that activate OAT1 and inhibit XO activity.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hiperuricemia/tratamiento farmacológico , Ácido Úrico/sangre , Ácido Úrico/orina , Xantenos/farmacología , Xantina Oxidasa/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/uso terapéutico , Células HEK293 , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/metabolismo , Xantenos/uso terapéuticoRESUMEN
Gambogenic acid (GNA), which is an important active compound present in gamboge, exerts anticancer activity in various types of tumor cells. However, the effect of GNA on smallcell lung cancer (SCLC) cell lines and the underlying mechanism involved still remain unclear. In the present study, GNA inhibited the proliferation and cell cycle progression of SCLC cells. GNA also promoted the apoptosis of SCLC cells in a dosedependent manner, which is associated with modulating the levels of proteins involved in apoptosis pathways in NCIH446 and NCIH1688 cells. The results demonstrated that GNA increased the level of cleaved caspase3, 8 and 9, and Bax but decreased the expression of antiapoptotic protein, Bcl2. Furthermore, similar results were obtained in a mouse tumor xenograft model. Additionally, GNA exhibit low toxicity in tissues when administered to mice in the SCLC xenograft models. Collectively, our findings demonstrated that GNA significantly inhibited the proliferation of SCLC cells and promoted cell apoptosis via cell cycle arrest and induction of apoptosis.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Xantenos/farmacología , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Garcinia/química , Humanos , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Carcinoma Pulmonar de Células Pequeñas/patología , Xantenos/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The brain renin-angiotensin system (RAS) is considered a crucial regulator for physiological homeostasis and disease progression. We evaluated the protective effects of the angiotensin receptor blocker (ARB) telmisartan and the angiotensin-converting enzyme 2 (ACE2) activator xanthenone on experimental cerebral ischemia/reperfusion (I/R) injury. Rats were divided into a sham control, a cerebral I/R control, a standard treatment (nimodipine, 10 mg/kg/day, 15 days, p.o.), three telmisartan treatments (1, 3, and 10 mg/kg/day, 15 days, p.o.), and three xanthenone treatments (0.5, 1, and 2 mg/kg/day, 15 days, s.c.) groups. One hour after the last dose, all rats except the sham control group were exposed to 30-min cerebral ischemia followed by 24-h reperfusion. Brain ACE and ACE2 activities and the apoptotic marker caspase-3 levels were assessed. Glutathione (GSH), malondialdehyde (MDA), and nitric oxide end products (NOx) as oxidative markers and tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-10 as immunological markers were assessed. Histopathological examination and immunohistochemical evaluation of glial fibrillary acidic protein (GFAP) were performed in cerebral cortex and hippocampus sections. Telmisartan and xanthenone in the higher doses restored MDA, NOx, TNF-α, IL-6, caspase-3, ACE, and GFAP back to normal levels and significantly increased GSH, IL-10, and ACE2 compared to I/R control values. Histopathologically, both agents showed mild degenerative changes and necrosis of neurons in cerebral cortex and hippocampus compared with I/R control group. Modulation of brain RAS, either through suppression of the classic ACE pathway or stimulation of its antagonist pathway ACE2, may be a promising strategy against cerebral I/R damage.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Peptidil-Dipeptidasa A/genética , Daño por Reperfusión/tratamiento farmacológico , Telmisartán/uso terapéutico , Xantenos/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Enzima Convertidora de Angiotensina 2 , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Citocinas/metabolismo , Glutatión/metabolismo , Masculino , Malondialdehído/metabolismo , Óxido Nítrico/metabolismo , ARN Mensajero/metabolismo , Ratas Wistar , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Telmisartán/farmacología , Xantenos/farmacologíaRESUMEN
The cell membrane is a semi-fluid container that defines the boundary of cells, and provides an enclosed environment for vital biological processes. A sound excitable drug (SED) that is non-cytotoxic to cells is developed to disrupt the plasma membrane under gentle ultrasound insonation, 1MHz, 1W/cm2. The frequency and power density of insonation are within the physical therapy and medical imaging windows; thus the applied ultrasound is safe and not harmful to tissues. The insertion of SEDs into the plasma membrane is not toxic to cells; however, the intruding SEDs weaken the membrane's integrity. Under insonation, the ultrasound energy destabilized the SED disrupted membranes, resulting in membrane rupture and eventual cell death. In a xenograft breast tumor model, the SED alone or the ultrasound alone caused little adverse effects to tumor tissue, while the combined treatment triggered necrosis with a brief local insonation of 3min. The described sono-membrane rupture therapy could be a safe alternative to the currently used high-energy tissue ablation technology, which uses X-rays, gamma rays, electron beams, protons, or high-intensity focused ultrasound.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/terapia , Terapia por Ultrasonido/métodos , Xantenos/uso terapéutico , Animales , Antineoplásicos/química , Neoplasias de la Mama/patología , Línea Celular Tumoral , Terapia Combinada/métodos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Rosa Bengala/análogos & derivados , Rosa Bengala/uso terapéutico , Xantenos/químicaRESUMEN
Stress is often a trigger to exacerbate chronic pain including visceral hypersensitivity associated with irritable bowel syndrome, a female predominant functional bowel disorder. Epigenetic mechanisms that mediate stress responses are a potential target to interfere with visceral pain. The purpose of this study was to examine the effect of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid, on visceral hypersensitivity induced by a subchronic stressor in female rats and to investigate the involvement of spinal glutamate receptors. Three daily sessions of forced swim induced visceral hypersensitivity. Intrathecal suberoylanilide hydroxamic acid prevented or reversed the stress-induced visceral hypersensitivity, increased spinal histone 3 acetylation and increased mGluR2 and mGluR3 expression. Chromatin immunoprecipitation (ChIP) analysis revealed enrichment of H3K9Ac and H3K18Ac at several promoter Grm2 and Grm3 regions. The mGluR2/3 antagonist LY341495 reversed the inhibitory effect of suberoylanilide hydroxamic acid on the stress-induced visceral hypersensitivity. In surprising contrast, stress and/or suberoylanilide hydroxamic acid had no effect on spinal NMDA receptor expression or function. These data reveal histone modification modulates mGluR2/3 expression in the spinal cord to attenuate stressinduced visceral hypersensitivity. HDAC inhibitors may provide a potential approach to relieve visceral hypersensitivity associated with irritable bowel syndrome.
Asunto(s)
Histonas/metabolismo , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Médula Espinal/patología , Estrés Psicológico/complicaciones , Vísceras/patología , Acetilación/efectos de los fármacos , Aminoácidos/farmacología , Aminoácidos/uso terapéutico , Animales , Inmunoprecipitación de Cromatina , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Vorinostat , Xantenos/farmacología , Xantenos/uso terapéuticoRESUMEN
OBJECTIVE: Despite considerable advances in the understanding of systemic lupus erythematosus (SLE), there is still an urgent need for new and more targeted treatment approaches. We previously demonstrated that small-molecule blockade of G protein ßγ subunit (Gßγ) signaling inhibits acute inflammation through inhibition of chemokine receptor signal transduction. We undertook this study to determine whether inhibition of Gßγ signaling ameliorates disease in a mouse model of SLE. METHODS: Lupus-prone (NZB × NZW)F1 female mice were prophylactically or therapeutically treated with the small-molecule Gßγ inhibitor gallein. Tissue samples were analyzed by flow cytometry and immunohistochemistry. The development and extent of nephritis were assessed by monitoring proteinuria and by immunohistochemical analysis. Serum immunoglobulin levels were measured by enzyme-linked immunosorbent assay, and total IgG and anti-double-stranded DNA (anti-dsDNA) antibody-secreting cells were measured by enzyme-linked immunospot assay. RESULTS: Gallein inhibited accumulation of T cells and germinal center (GC) B cells in the spleen. Both prophylactic and therapeutic treatment reduced GC size, decreased antibody-secreting cell production in the spleen, and markedly decreased accumulation of autoreactive anti-dsDNA antibody-secreting cells in kidneys. Gallein also reduced immune complex deposition in kidneys. Finally, gallein treatment dramatically inhibited kidney inflammation, prevented glomerular damage, and decreased proteinuria. Mechanistically, gallein inhibited immune cell migration and signaling in response to chemokines in vitro, which suggests that its mechanisms of action in vivo are inhibition of migration of immune cells to sites of inflammation and inhibition of immune cell maturation. CONCLUSION: Overall, these data demonstrate the potential use of gallein or novel inhibitors of Gßγ signaling in SLE treatment.
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Subunidades beta de la Proteína de Unión al GTP/antagonistas & inhibidores , Subunidades gamma de la Proteína de Unión al GTP/antagonistas & inhibidores , Lupus Eritematoso Sistémico/prevención & control , Nefritis/prevención & control , Xantenos/uso terapéutico , Animales , Femenino , Subunidades beta de la Proteína de Unión al GTP/fisiología , Subunidades gamma de la Proteína de Unión al GTP/fisiología , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Endogámicos NZB , Nefritis/inmunología , Transducción de SeñalRESUMEN
Heart failure is a significant global health problem, which is becoming worse as the population ages, and remains one of the biggest burdens on our economy. Despite significant advances in cardiovascular medicine, management and surgery, mortality rates remain high, with almost half of patients with heart failure dying within five years of diagnosis. As a multifactorial clinical syndrome, heart failure still represents an epidemic threat, highlighting the need for deeper insights into disease mechanisms and the development of innovative therapeutic strategies for both treatment and prevention. In this review, we discuss conventional heart failure therapies and highlight new pharmacological agents targeting pathophysiological features of the failing heart, for example, non-coding RNAs, angiotensin receptor-neprilysin inhibitors, cardiac myosin activators, BGP-15 and molecules targeting GRK2 including M119, gallein and paroxetine. Finally, we address the disparity between phase II and phase III clinical trials that prevent the translation of emerging HF therapies into new and approved therapies.
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Antagonistas de Receptores de Angiotensina/uso terapéutico , Ciclohexanos/uso terapéutico , Insuficiencia Cardíaca/terapia , Oximas/uso terapéutico , Paroxetina/uso terapéutico , Piperidinas/uso terapéutico , Xantenos/uso terapéutico , Miosinas Cardíacas/metabolismo , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Quinasa 2 del Receptor Acoplado a Proteína-G/antagonistas & inhibidores , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Humanos , Neprilisina/antagonistas & inhibidores , Neprilisina/metabolismo , ARN no Traducido/metabolismoRESUMEN
BACKGROUND: Emerging research seeking novel analgesic drugs focuses on agents targeting group-II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors). N-Acetylcysteine (NAC) enhances the endogenous activation of mGlu2/3 receptors by activating the glial glutamate:cystine membrane exchanger. Here, we examined whether NAC inhibits nociceptive responses in humans and animals. We tested the effect of oral NAC (1.2 g) on thermal-pain thresholds and laser-evoked potentials in 10 healthy volunteers, according to a crossover, double-blind, placebo-controlled design, and the effect of NAC (100 mg/kg, i.p.) on the tail-flick response evoked by radiant heat stimulation in mice. RESULTS: In healthy subjects, NAC treatment left thermal-pain thresholds unchanged, but significantly reduced pain ratings to laser stimuli and amplitudes of laser-evoked potentials. NAC induced significantly greater changes in these measures than placebo. In the tail-flick test, NAC strongly reduced the nocifensive reflex response to radiant heat. The action of NAC was abolished by the preferential mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). CONCLUSIONS: Our findings show for the first time that NAC inhibits nociceptive transmission in humans, and does the same in mice by activating mGlu2/3 receptors. These data lay the groundwork for investigating the therapeutic potential of NAC in patients with chronic pain.
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Acetilcisteína/uso terapéutico , Analgésicos/uso terapéutico , Dolor/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Adulto , Aminoácidos/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Xantenos/uso terapéutico , Adulto JovenRESUMEN
Resistance to anoikis, enhanced cell motility, and growth in anchorage-independent conditions are hallmarks of highly metastatic cancer cells. The present study demonstrates the anoikis-sensitizing and anti-migration activities of dendrofalconerol A (DF-A), a pure bis(bibenzyl) isolated from the stem of Dendrobium falconeri (Orchidaceae), and its underlying mechanisms in human lung cancer H460 cells. DF-A at non-toxic concentrations significantly increased the anoikis response of the cancer cells, but caused no toxic effect on normal keratinocytes. In addition, DF-A significantly inhibited the growth of lung cancer cells in anchorage-independent conditions. Western blot analysis revealed that the anoikis-sensitizing effect of such a compound involves its ability to suppress survival signals as well as anti-apoptotic proteins, namely, activated protein kinase B (Akt) and Bcl-2. Furthermore, DF-A decreased caveolin-1 (Cav-1), a protein responsible for aggressiveness, while having no effect on Bax, Mcl-1, and activated Erk (p42/44) proteins. In the case of cell motility, DF-A exhibited strong anti-migration activity with the mechanism involving suppression of pFAK and Rho-GTP, but had no effect on Rac-GTP in lung cancer cells. Taken together, DF-A possesses anoikis-sensitizing activity along with anti-migration effects, and may be developed as a novel active compound for cancer treatment.
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Anoicis/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Bibencilos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Dendrobium/química , Neoplasias Pulmonares/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/farmacología , Xantenos/uso terapéutico , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/uso terapéutico , Bibencilos/aislamiento & purificación , Bibencilos/farmacología , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/efectos de los fármacos , Xantenos/aislamiento & purificación , Xantenos/farmacologíaRESUMEN
Heterotrimeric G-proteins play a crucial role in the control of renal epithelial cell function during homeostasis and in response to injury. In this report, G-protein ßγ subunit (Gßγ) dimer activity was evaluated during the process of tubular repair after renal ischemia-reperfusion injury (IRI) in male Sprague Dawley rats. Rats were treated with a small molecule inhibitor of Gßγ activity, gallein (30 or 100 mg/kg), 1 hour after reperfusion and every 24 hours for 3 additional days. After IRI, renal dysfunction was prolonged after the high-dose gallein treatment in comparison with vehicle treatment during the 7-day recovery period. Renal tubular repair in the outer medulla 7 days after IRI was significantly (P < 0.001) attenuated after treatment with high-dose gallein (100 mg/kg) in comparison with low-dose gallein (30 mg/kg), or the vehicle and fluorescein control groups. Gallein treatment significantly reduced (P < 0.05) the number of proliferating cell nuclear antigen-positive tubular epithelial cells at 24 hours after the ischemia-reperfusion phase in vivo. In vitro application of gallein on normal rat kidney (NRK-52E) proximal tubule cells significantly reduced (P < 0.05) S-phase cell cycle entry compared with vehicle-treated cells as determined by 5'-bromo-2'-deoxyuridine incorporation. Taken together, these data suggest that Gßγ signaling contributes to the maintenance and repair of renal tubular epithelium and may be a novel therapeutic target for the development of drugs to treat acute kidney injury.
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Síndrome Cardiorrenal/tratamiento farmacológico , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Riñón/efectos de los fármacos , Daño por Reperfusión/metabolismo , Animales , Síndrome Cardiorrenal/metabolismo , Línea Celular , Movimiento Celular , Proliferación Celular , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/fisiología , Subunidades beta de la Proteína de Unión al GTP/antagonistas & inhibidores , Subunidades gamma de la Proteína de Unión al GTP/antagonistas & inhibidores , Riñón/metabolismo , Riñón/patología , Masculino , Multimerización de Proteína , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Xantenos/farmacología , Xantenos/uso terapéuticoRESUMEN
AIM/HYPOTHESIS: Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling. PTP1B deficiency improves obesity-induced insulin resistance and consequently improves type 2 diabetes in mice. Here, the small molecule norathyriol reversed obesity- and high-fat-diet-induced insulin resistance by inhibiting PTP1B. METHODS: The inhibitory mode of PTP1B was evaluated by using the double-reciprocal substrate in the presence of norathyriol. Primary cultured hepatocytes, myoblasts and white adipocytes were used to investigate the effect of norathyriol on insulin signalling. Glucose homeostasis and insulin sensitivity were characterised by glucose and insulin tolerance tests. RESULTS: Norathyriol was identified as a competitive inhibitor of PTP1B, with an IC50 of 9.59 ± 0.39 µmol/l. In cultured hepatocytes and myoblasts, norathyriol treatment blocked the PTP1B-mediated dephosphorylation of the insulin receptor. Intraperitoneal injection of norathyriol inhibited liver and muscle PTP1B activity in mice, thus contributing to the improved glucose homeostasis and insulin sensitivity. However, these beneficial effects were abolished in PTP1B-deficient mice. Notably, oral administration of norathyriol protected mice from diet-induced obesity and insulin resistance through inhibition of hypothalamic PTP1B activity. CONCLUSIONS/INTERPRETATION: Our results indicate that the small molecule norathyriol is a potent PTP1B inhibitor with good cell permeability and oral availability.