RESUMEN
Scutellaria baicalensis Georgi (SBG), an herbal medicine with various biological activities, including anti-inflammatory, anticancer, antiviral, antibacterial, and antioxidant activities, is effective in treatment of colitis, hepatitis, pneumonia, respiratory infections, and allergic diseases. This herbal medicine consists of major active substances, such as baicalin, baicalein, wogonoside, and wogonin. Inflammatory bowel disease (IBD) comprises a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis being the main types. IBD can lead to serious complications, such as increased risk of colorectal cancer (CRC), one of the most common cancers worldwide. Currently, there is no cure for IBD, and its incidence has been increasing over the past few decades. This review comprehensively summarizes the efficacy of SBG in IBD and CRC and may serve as a reference for future research and development of drugs for IBD and cancer treatment.
Asunto(s)
Neoplasias Colorrectales , Enfermedades Inflamatorias del Intestino , Plantas Medicinales , Humanos , Scutellaria baicalensis , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Flavonoides , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológicoRESUMEN
DNA topoisomerases are important enzymes that stabilize DNA supercoiling and resolve entanglements. There are two main types of topoisomerases in all cells: type I, which causes single-stranded DNA breaks, and type II, which cuts double-stranded DNA. Topoisomerase activity is particularly increased in rapidly dividing cells, such as cancer cells. Topoisomerase inhibitors have been an effective chemotherapeutic option for the treatment of several cancers. In addition, combination cancer therapy with topoisomerase inhibitors may increase therapeutic efficacy and decrease resistance or side effects. Topoisomerase inhibitors are currently being used worldwide, including in the United States, and clinical trials on the combination of topoisomerase inhibitors with other drugs are currently underway. The primary objective of this review was to comprehensively analyze the current clinical landscape concerning the combined application of irinotecan, an extensively investigated type I topoisomerase inhibitor for colorectal cancer, and doxorubicin, an extensively researched type II topoisomerase inhibitor for breast cancer, while presenting a novel approach for cancer therapy.
Asunto(s)
Neoplasias de la Mama , Neoplasias Colorrectales , Humanos , Femenino , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/uso terapéutico , Quimioterapia Combinada , Neoplasias Colorrectales/tratamiento farmacológico , ADN-Topoisomerasas de Tipo II/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismoRESUMEN
Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a polyphenol found in grapes, red wine, peanuts, and apples, has been reported to exhibit a wide range of biological and pharmacological properties. In addition, resveratrol has been reported to intervene in multiple stages of carcinogenesis. It has also been known to kill several human cancer cells through programmed cell death (PCD) mechanisms such as apoptosis, autophagy, and necroptosis. However, resveratrol has limitations in its use as an anticancer agent because it is susceptible to photoisomerization owing to its unstable double bond, short half-life, and is rapidly metabolized and eliminated. Trans-(E)-resveratrol is nontoxic, and has several biological and pharmacological activities. However, little is known about the pharmacological properties of the photoisomerized cis-(Z)-resveratrol. Therefore, many studies on resveratrol derivatives and analogues that can overcome the shortcomings of resveratrol and increase its anticancer activity are underway. This review comprehensively summarizes the literature related to resveratrol-induced PCD, such as apoptosis, autophagy, necroptosis, and the development status of synthetic resveratrol derivatives and analogues as novel anticancer drugs.
Asunto(s)
Antineoplásicos , Neoplasias , Estilbenos , Humanos , Resveratrol/farmacología , Neoplasias/tratamiento farmacológico , Apoptosis , Estilbenos/farmacología , Estilbenos/uso terapéutico , Estilbenos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Descubrimiento de DrogasRESUMEN
The flavonoid apigenin (4',5,7-trihydroxyflavone), which is one of the most widely distributed phytochemicals in the plant kingdom, is one of the most thoroughly investigated phenolic components. Previous studies have attributed the physiological effects of apigenin to its anti-allergic, antibacterial, antidiabetic, anti-inflammatory, antioxidant, antiviral, and blood-pressure-lowering properties, and its documented anticancer properties have been attributed to the induction of apoptosis and autophagy, the inhibition of inflammation, angiogenesis, and cell proliferation, and the regulation of cellular responses to oxidative stress and DNA damage. The most well-known mechanism for the compound's anticancer effects in human cancer cell lines is apoptosis, followed by autophagy, and studies have also reported that apigenin induces novel cell death mechanisms, such as necroptosis and ferroptosis. Therefore, the aim of this paper is to review the therapeutic potential of apigenin as a chemopreventive agent, as well as the roles of programmed cell death mechanisms in the compound's chemopreventive properties.
Asunto(s)
Apigenina , Apoptosis , Apigenina/farmacología , Apigenina/uso terapéutico , Autofagia , Línea Celular Tumoral , Proliferación Celular , Daño del ADN , HumanosRESUMEN
Bile acids are major signaling molecules that play a significant role as emulsifiers in the digestion and absorption of dietary lipids. Bile acids are amphiphilic molecules produced by the reaction of enzymes with cholesterol as a substrate, and they are the primary metabolites of cholesterol in the body. Bile acids were initially considered as tumor promoters, but many studies have deemed them to be tumor suppressors. The tumor-suppressive effect of bile acids is associated with programmed cell death. Moreover, based on this fact, several synthetic bile acid derivatives have also been used to induce programmed cell death in several types of human cancers. This review comprehensively summarizes the literature related to bile acid-induced programmed cell death, such as apoptosis, autophagy, and necroptosis, and the status of drug development using synthetic bile acid derivatives against human cancers. We hope that this review will provide a reference for the future research and development of drugs against cancer.
Asunto(s)
Ácidos y Sales Biliares , Neoplasias , Apoptosis , Ácidos y Sales Biliares/farmacología , Colesterol/metabolismo , Descubrimiento de Drogas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patologíaRESUMEN
Sirtuins (SIRTs), which are nicotinamide adenine dinucleotide-dependent class III histone deacetylases, regulate cell division, survival, and senescence. Although sirtinol, a synthetic SIRT inhibitor, is known to exhibit antitumor effects, its mechanism of action is not well understood. Therefore, we aimed to assess the anticancer effects and underlying mechanism of MHY2245, a derivative of sirtinol, in HCT116 human colorectal cancer cells in vitro. Treatment with MHY2245 decreased SIRT1 activity and caused DNA damage, leading to the upregulation of p53 acetylation, and increased levels of p53, phosphorylation of H2A histone family member X, ataxia telangiectasia and Rad3-related kinase, checkpoint kinase 1 (Chk1), and Chk2. The level of the breast cancer type 1 susceptibility protein was also found to decrease. MHY2245 induced G2/M phase cell cycle arrest via the downregulation of cyclin B1, cell division cycle protein 2 (Cdc2), and Cdc25c. Further, MHY2245 induced HCT116 cell death via apoptosis, which was accompanied by internucleosomal DNA fragmentation, decreased B-cell lymphoma 2 (Bcl-2) levels, increased Bcl-2-asscociated X protein levels, cleavage of poly(ADP-ribose) polymerase, and activation of caspases -3, -8, and -9. Overall, MHY2245 induces cell cycle arrest, triggers apoptosis through caspase activation, and exhibits DNA damage response-associated anticancer effects.
Asunto(s)
Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Naftalenos/farmacología , Sirtuinas/antagonistas & inhibidores , Apoptosis , Benzamidas/química , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Células HT29 , Humanos , Naftalenos/química , Naftoles/químicaRESUMEN
BACKGROUND/AIMS: Pyruvate kinase M2 (PKM2) is essential for aerobic glycolysis. Although high PKM2 expression is observed in various cancer tissues, its functional role in cancer metabolism is unclear. Here, we investigated the role of PKM2 in regulating autophagy and its associated pathways in prostate cancer cells. METHODS: Immunohistochemistry was performed to compare the expression level of PKM2 in prostate cancer patients and normal human, whereas expression of PKM2 in several cell lines was also examined by using western blot. PKM2 expression was silenced using various small interfering RNAs (siRNAs). Cell viability was examined using IncuCyte ZOOM™ live cell imaging system. Western blotting and immunofluorescence were performed to investigate the PKM2 knockdown on other cellular signaling molecules. Acridine orange and Monodansylcadaverine staining was performed to check effect of PKM2 knockdown on autophagy induction. High performance thin layer chromatography was carried out to quantify the level of different cellular metabolites (pyruvate and lactate). Colony formation assay was performed to determine the ability of a cells to form large colonies. RESULTS: PKM2 was highly expressed in prostate cancer patients as compared to normal human. PKM2 siRNA-transfected prostate cancer cells showed significantly reduced viability. Acridine orange, Monodansylcadaverine staining and western blotting analysis showed that PKM2 downregulation markedly increased autophagic cell death. Results of western blotting analysis showed that PKM2 knockdown affected protein kinase B/mechanistic target of rapamycin 1 pathway, which consequently downregulated the expression of glycolytic enzymes lactate dehydrogenase A and glucose transporter 1. Knockdown of PKM2 also reduced the colony formation ability of human prostate cancer cell DU145. CONCLUSION: To the best of our knowledge, this is the first study to show that PKM2 inhibition alters prostate cancer cell metabolism and induces autophagy, thus providing new perspectives for developing PKM2-targeting anticancer therapies for treating prostate cancer.
Asunto(s)
Autofagia , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piruvato Quinasa/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Línea Celular Tumoral , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Lactato Deshidrogenasa 5 , Masculino , Neoplasias de la Próstata/metabolismo , Piruvato Quinasa/antagonistas & inhibidores , Piruvato Quinasa/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de SeñalRESUMEN
Evidence suggests that auranofin (AF) exhibits anticancer activity by inhibiting thioredoxin reductase (TrxR). Here, in this study, we have investigated the synergistic effects of AF and morin and their mechanism for the anticancer effects focusing on apoptosis in Hep3B human hepatocellular carcinoma cells. We assessed the anticancer activities by annexin V/PI double staining, caspase, and TrxR activity assay. Morin enhances the inhibitory effects on TrxR activity of AF as well as reducing cell viability. Annexin V/PI double staining revealed that morin/AF cotreatment induced apoptotic cell death. Morin enhances AF-induced mitochondrial membrane potential (ΔΨm) loss and cytochrome c release. Further, morin/AF cotreatment upregulated death receptor DR4/DR5, modulated Bcl-2 family members (upregulation of Bax and downregulation of Bcl-2), and activated caspase-3, -8, and -9. Morin also enhances AF-induced reactive oxygen species (ROS) generation. The anticancer effects results from caspase-dependent apoptosis, which was triggered via extrinsic pathway by upregulating TRAIL receptors (DR4/DR5) and enhanced via intrinsic pathway by modulating Bcl-2 and inhibitor of apoptosis protein family members. These are related to ROS generation. In conclusion, this study provides evidence that morin can enhance the anticancer activity of AF in Hep3B human hepatocellular carcinoma cells, indicating that its combination could be an alternative treatment strategy for the hepatocellular carcinoma.
Asunto(s)
Auranofina/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Flavonoides/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Caspasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocromos c/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Neoplasias Hepáticas/patología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
We investigated the antitumor activity and action mechanism of MHY440 in AGS human gastric cancer cells. MHY440 inhibited topoisomerase (Topo) Ι activity and was associated with a DNA damage response signaling pathway. It exhibited a stronger anti-proliferative effect on AGS cells relative to Hs27 human foreskin fibroblast cells, and this effect was both time- and concentration-dependent. MHY440 also increased cell arrest in the G2/M phase by decreasing cyclin B1, Cdc2, and Cdc25c, and upregulating p53 and p73. MHY440 induced AGS cell apoptosis through the upregulation of Fas-L, Fas, and Bax as well as the proteolysis of BH3 interacting-domain death agonist and poly(ADP-ribose) polymerase. It also contributed to the loss of mitochondrial membrane potential. The apoptotic cell death induced by MHY440 was inhibited by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor, indicating that apoptosis was caspase-dependent. Moreover, the apoptotic effect of MHY440 was reactive oxygen species (ROS)-dependent, as evidenced by the inhibition of MHY440-induced PARP cleavage and ROS generation via N-acetylcysteine-induced ROS scavenging. Taken together, MHY440 showed anticancer effects by inhibiting Topo I, regulating the cell cycle, inducing apoptosis through caspase activation, and generating ROS, suggesting that MHY440 has considerable potential as a therapeutic agent for human gastric cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Daño del ADN , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Inhibidores de Topoisomerasa I/farmacología , Caspasas/metabolismo , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Unión Proteica , Neoplasias Gástricas/metabolismo , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/químicaRESUMEN
Identifying novel biomarkers to detect nephrotoxicity is clinically important. Here, we attempted to identify new biomarkers for mercury-induced nephrotoxicity and compared their sensitivity to that of traditional biomarkers in animal models. Comparative proteomics analysis was performed in kidney tissues of Sprague-Dawley rats after oral treatment with HgCl2 (0.1, 1, or 5 mg/kg/day) for 21 days. Kidney cortex tissues were analyzed by two-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization, and differentially expressed proteins were identified. The corresponding spots were quantitated by RT-PCR. Selenium-binding protein 1 (SBP1) was found to be the most markedly upregulated protein in the kidney cortex of rats after HgCl2 administration. However, blood urea nitrogen, serum creatinine, and glucose levels increased significantly only in the 1 or 5 mg/kg HgCl2-treated groups. A number of urinary excretion proteins, including kidney injury molecule-1, clusterin, monocyte chemoattractant protein-1, and ß-microglobulin, increased dose-dependently. Histopathological examination revealed severe proximal tubular damage in high-dose (5 mg/kg) HgCl2-exposed groups. In addition, urinary excretion of SBP1 significantly increased in a dose-dependent manner. To confirm the critical role of SBP1 as a biomarker for nephrotoxicity, normal kidney proximal tubular cells were treated with HgCl2, CdCl2, or cisplatin for 24 h. SBP1 levels significantly increased in conditioned media exposed to nephrotoxicants, but decreased in cell lysates. Our investigations suggest that SBP1 may play a critical role in the pathological processes underlying chemical-induced nephrotoxicity. Thus, urinary excretion of SBP1 might be a sensitive and specific biomarker to detect early stages of kidney injury.
Asunto(s)
Cloruro de Cadmio/toxicidad , Enfermedades Renales/inducido químicamente , Cloruro de Mercurio/toxicidad , Proteínas de Unión al Selenio/metabolismo , Animales , Biomarcadores/metabolismo , Nitrógeno de la Urea Sanguínea , Cloruro de Cadmio/administración & dosificación , Cisplatino/administración & dosificación , Cisplatino/toxicidad , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Electroforesis en Gel Bidimensional , Corteza Renal/efectos de los fármacos , Corteza Renal/patología , Enfermedades Renales/patología , Masculino , Cloruro de Mercurio/administración & dosificación , Metales Pesados/administración & dosificación , Metales Pesados/toxicidad , Proteínas/efectos de los fármacos , Proteínas/metabolismo , Proteómica/métodos , Ratas , Ratas Sprague-Dawley , Sensibilidad y Especificidad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Paecilocin A, a phthalide derivative isolated from the jellyfish-derived fungus Paecilomyces variotii, activates PPAR-γ (Peroxisome proliferator-activated receptor gamma) in rat liver Ac2F cells. Based on a SAR (Structure-activity relationships) study and in silico analysis of paecilocin A-mimetic derivatives, additional N-substituted phthalimide derivatives were synthesized and evaluated for PPAR-γ agonistic activity in both murine liver Ac2F cells and in human liver HepG2 cells by luciferase assay, and for adipogenic activity in 3T3-L1 cells. Docking simulation indicated PD6 was likely to bind most strongly to the ligand binding domain of PPAR-γ by establishing crucial H-bonds with key amino acid residues. However, in in vitro assays, PD1 and PD2 consistently displayed significant PPAR-γ activation in Ac2F and HepG2 cells, and adipogenic activity in 3T3-L1 preadipocytes.
Asunto(s)
PPAR gamma/metabolismo , Ftalimidas/química , Ftalimidas/farmacología , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Animales , Benzofuranos/farmacología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Células Cultivadas , Células Hep G2 , Humanos , Ligandos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , RatasRESUMEN
Baicalein is one of the main bioactive flavonoids found in the roots of Scutellaria baicalensis Georgi. Here, we report that baicalein-induced growth inhibition was associated with the induction of apoptosis in human lung carcinoma A549 cells. Baicalein stimulated the expression of DR5, FasL, and FADD, and activated caspase-8 by reducing the levels of FLIPs (FLICE-inhibitory proteins). The apoptotic cell death was also connected with an activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase; however, a blockage of caspase activation abolished baicalein-induced apoptotic potentials. Additionally, baicalein caused a mitochondrial membrane potential (MMP), the truncation of Bid, and the translocation of pro-apoptotic Bax to the mitochondria, thereby inducing the release of cytochrome c into the cytosol. In turn, baicalein increased the generation of reactive oxygen species (ROS); however, an ROS scavenger, N-acetylcysteine, notably attenuated baicalein-mediated loss of MMP and activation of caspases. Furthermore, baicalein activated the AMP-activated protein kinase (AMPK) signaling pathway. Consequently, baicalein-triggered cell death was attenuated by an AMPK inhibitor, but increased by an AMPK activator, compound C. Overall, the results suggest that the apoptotic activity of baicalein may be associated with caspase-dependent cascade through the activation of both intrinsic and extrinsic signaling pathways connected with ROS generation and AMPK activation.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos/farmacología , Caspasas/metabolismo , Flavanonas/farmacología , Neoplasias Pulmonares/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Muscle aging is closely related to unhealthy late-life and organismal aging. Recently, the state of differentiated cells was shown to be critical to tissue homeostasis. Thus, understanding how fully differentiated muscle cells age is required for ensuring healthy aging. Adult Drosophila muscle is a useful model for exploring the aging process of fully differentiated cells. In this study, we investigated age-related changes of γH2AX, an indicator of DNA strand breaks, in adult Drosophila muscle to document whether its changes are correlated with muscle degeneration and lifespan. The results demonstrate that γH2AX accumulation increases in adult Drosophila thoracic and leg muscles with age. Analyses of short-, normal-, and long-lived strains indicate that the age-related increase of γH2AX is closely associated with the extent of muscle degeneration, cleaved caspase-3 and poly-ubiquitin aggregates, and longevity. Further analysis of muscle-specific knockdown of heterochromatin protein 1a revealed that the excessive γH2AX accumulation in thoracic and leg muscles induces accelerated degeneration and decreases longevity. These data suggest a strong correlation between age-related muscle damage and lifespan in Drosophila. Our findings indicate that γH2AX may be a reliable biomarker for assessing muscle aging in Drosophila.
Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Histonas/metabolismo , Longevidad , Músculos/metabolismo , Factores de Edad , Animales , Biomarcadores/metabolismo , Caspasa 3/metabolismo , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Roturas del ADN de Doble Cadena , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Femenino , Genotipo , Músculos/patología , Fenotipo , Fosforilación , Poliubiquitina/metabolismo , Agregado de ProteínasRESUMEN
FoxO activity and modifications, such as its phosphorylation, acetylation, and methylation, may help drive the expression of genes involved in combating oxidative stress by causing the epigenetic modifications, and thus, preserve cellular function during aging and age-related diseases, such as diabetes, cancer, and Alzheimer disease. Insulin signaling has been postulated to influence the aging process by increasing resistance to oxidative stress, and slowing the accumulation of oxidative damage. Some antioxidative effects are mediated by a conserved family of forkhead box transcription factors (FoxOs), which in the absence of insulin signaling freely bind to promoters of antioxidant enzymes, superoxide dismutase, and catalase. On the other hand, calorie restriction (CR) extends the lifespans of several species via the insulin pathway, and extends longevity and healthspan in diverse species via a conserved mechanism. CR enhances adaptive stress responses at the cellular and organism levels and extends lifespan in a FoxO-independent manner. Thus, increased modification of FoxO is modulated via the hyperinsulinemia-induced PI3K/Akt pathway during aging, and CR reverses this process. Accordingly, FoxO plays an important role in maintenance of metabolic homeostasis and removal of oxidative stress in the aging process and in the effect of CR on lifespan.
Asunto(s)
Envejecimiento/fisiología , Restricción Calórica , Factores de Transcripción Forkhead/fisiología , Homeostasis/fisiología , Humanos , Insulina/fisiología , Estrés Oxidativo/fisiología , Transducción de Señal/fisiologíaRESUMEN
This study investigated the agonistic activity of magnesium lithospermate B (1), isolated from Salvia miltiorrhiza, on peroxisome proliferator-activated receptor (PPARß/δ) and the expressions of collagen genes (COL1A1 and COL3A1) and transforming growth factor-ß1 (TGF-ß1) in models of skin aging. The action of compound 1 as a PPARß/δ agonist was determined by reporter gene assay, immunostaining, and Western blotting. To determine the antiaging effects of compound 1 on skin, aged Sprague-Dawley rat skin and ultraviolet B (UVB)-irradiated human skin fibroblasts were used. The results show that 1 presented a marked enhancement of both nuclear protein levels and activity of PPARß/δ in fibroblasts. In addition, 1 prevented downregulation of PPARß/δ activity in aged rat skin and UVB-induced fibroblasts. Furthermore, 1 increased the expressions of COL1A1, COL3A1, and TGF-ß1 in vivo and in a cell culture system. Therefore, the present study shows that compound 1 prevents collagen degradation in aged rat skin and UVB-exposed fibroblasts through PPARß/δ activation. The therapeutic and cosmetic applications of compound 1 need further investigation.
Asunto(s)
Colágeno/metabolismo , PPAR delta/metabolismo , PPAR-beta/metabolismo , Salvia miltiorrhiza/química , Piel/efectos de los fármacos , Anciano , Animales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/metabolismo , Fibroblastos/efectos de los fármacos , Humanos , Magnesio/metabolismo , Masculino , Estructura Molecular , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Activación Transcripcional , Regulación hacia ArribaRESUMEN
To address the challenge of solid tumor targeting in CAR-T therapy, we utilized the A56 antigen, which is uniquely expressed on a diverse range of cancer cells following the systemic administration of an oncolytic vaccinia virus (OVV). Immunohistochemical assays precisely confirmed exclusive localization of A56 to tumor tissues. In vitro studies demonstrated a distinct superiority of A56-dependent CAR-T cytotoxicity across multiple cancer cell lines. Building on these in vitro observations, we strategically administered A56 CAR-T cells, OVV, and hydroxyurea (HU) combination in HCT-116 tumor-bearing non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, leading to a significant reduction in tumor size and an extended time to progression. Consequently, A56-targeting combinatorial immunotherapy provides the benefit of reducing inadvertent CAR-T effects on normal cells while preserving its effectiveness against cancer cells. Furthermore, our approach of implanting A56 via OVV on tumors facilitates a wide therapeutic application of CAR-T cells across various solid tumors.
RESUMEN
We studied the roles of JMJD1A and its target gene ADM in the growth of hepatocellular carcinomas (HCCs) and breast cancer cells under hypoxic conditions. Hypoxia stimulated HepG2 and Hep3B cell proliferation but had no effect on MDA-MB-231 cell proliferation. Interestingly, the JMJD1A and ADM expressions were enhanced by hypoxia only in HepG2 and Hep3B cells. Our ChIP results showed that hypoxia-induced HepG2 and Hep3B cell proliferation is mediated by JMJD1A upregulation and subsequent decrease in methylation in the ADM promoter region. Furthermore, JMJD1A gene silencing abrogated the hypoxia-induced ADM expression and inhibited HepG2 and Hep3B cell growth. These data suggest that JMJD1A might function as a proliferation regulator in some cancer cell types.
Asunto(s)
Adrenomedulina/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas con Dominio de Jumonji/genética , Adrenomedulina/metabolismo , Animales , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Hipoxia de la Célula , Línea Celular Tumoral , Metilación de ADN , Femenino , Células Hep G2 , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Regiones Promotoras Genéticas/genética , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The present study investigated possible mechanisms of apoptosis induction of U937 human leukemic cells by 7,8-dihydroxyflavone hydrate (7,8-DHF), a member of the flavonoid family and a recently identified tyrosine kinase receptor B (TrkB) agonist. 7,8-DHF treatment of U937 cells resulted in inhibition of growth and induction of apoptosis as measured by MTT assay, fluorescence microscopy, DNA fragmentation, and flow cytometry analysis. 7,8-DHF-induced apoptosis in U937 cells was correlated with the up-regulation of death receptor related protein levels and down-regulation of anti-apoptotic IAP family proteins. The increase in apoptosis was also associated with proteolytic activation of caspases, Bid cleavage, insertion of pro-apoptotic Bax into the mitochondria and release of cytochrome c from mitochondria to cytosol. Furthermore, it was found that Bcl-2 overexpression markedly protected U937 cells from 7,8-DHF-induced apoptosis by restoring activation of caspases. In addition, 7,8-DHF treatment effectively activated the mitogen-activated protein kinases (MAPK), and inhibitors of extracellular-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p38 MAPK, which significantly reduced 7,8-DHF-induced apoptosis. Taken together, our results indicate that the JNK and ERK pathways, and modulation of Bcl-2 family proteins were key regulators of apoptosis in response to 7,8-DHF in U937 cells.
Asunto(s)
Flavonas/farmacología , Leucemia/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptor trkB/agonistas , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Citocromos c , Humanos , Leucemia/metabolismo , Receptores de Muerte Celular/metabolismo , Transducción de Señal , Células U937RESUMEN
The present study investigated possible mechanisms on the apoptosis induction of human leukemic cells by fucoidan, a sulfated polysaccharide found in marine algae. Fucoidan treatment of cells resulted in inhibition of growth and induction of apoptosis, as measured by 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyl-tetrazolium (MTT) assay, fluorescence microscopy, DNA fragmentation, and flow cytometry analysis. The increase in apoptosis was associated with the proteolytic activation of caspases, Bid cleavage, insertion of pro-apoptotic Bax into the mitochondria, release of cytochrome c from mitochondria to cytosol, and loss of mitochondria membrane potential (MMP) in U937 cells. However, apoptosis induced by fucoidan was attenuated by caspase inhibitors, indicating that fucoidan-induced apoptosis was dependent on the activation of caspases. Furthermore, fucoidan treatment effectively activated the p38 mitogen-activated protein kinase (MAPK) and p38 MAPK inhibitor, SB203580, and significantly reduced fucoidan-induced apoptosis through inhibition of Bax translocation and caspases activation, suggesting that the activation of p38 MAPK may play a key role in fucoidan-induced apoptosis. In addition, the authors found fucoidan-induced significantly attenuated in Bcl-2 overexpressing U937 cells, and pretreatment with fucoidan and HA 14-1, a small-molecule Bcl-2 inhibitor, markedly increased fucoidan-mediated apoptosis in Bcl-2 overexpressing U937 cells. Our findings imply that we may attribute some of the biological functions of p38 MAPK and Bcl-2 to their ability to inhibit fucoidan-induced apoptosis.
Asunto(s)
Apoptosis/efectos de los fármacos , Leucemia/tratamiento farmacológico , Polisacáridos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Apoptosis/genética , Caspasas/genética , Caspasas/metabolismo , Línea Celular Tumoral , Citocromos c/genética , Citocromos c/metabolismo , Citosol/efectos de los fármacos , Citosol/metabolismo , Células HL-60 , Humanos , Células K562 , Leucemia/genética , Leucemia/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Células U937 , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Sarcopenia refers to the loss of muscle strength and mass in older individuals and is a major determinant of fall risk and impaired ability to perform activities of daily living, often leading to disability, loss of independence, and death. Owing to its impact on morbidity, mortality, and healthcare expenditure, sarcopenia in the elderly has become a major focus of research and public policy debates worldwide. Despite its clinical importance, sarcopenia remains under-recognized and poorly managed in routine clinical practice, partly owing to the lack of available diagnostic testing and uniform diagnostic criteria. Since the World Health Organization and the United States assigned a disease code for sarcopenia in 2016, countries worldwide have assigned their own disease codes for sarcopenia. However, there are currently no approved pharmacological agents for the treatment of sarcopenia; therefore, interventions for sarcopenia primarily focus on physical therapy for muscle strengthening and gait training as well as adequate protein intake. In this review, we aimed to examine the latest information on the epidemiology, molecular mechanisms, interventions, and possible treatments with new drugs for sarcopenia.