RESUMEN
SEDS family peptidoglycan (PG) glycosyltransferases, RodA and FtsW, require their cognate transpeptidases PBP2 and FtsI (class B penicillin binding proteins) to synthesize PG along the cell cylinder and at the septum, respectively. The activities of these SEDS-bPBPs complexes are tightly regulated to ensure proper cell elongation and division. In Escherichia coli FtsN switches FtsA and FtsQLB to the active forms that synergize to stimulate FtsWI, but the exact mechanism is not well understood. Previously, we isolated an activation mutation in ftsW (M269I) that allows cell division with reduced FtsN function. To try to understand the basis for activation we isolated additional substitutions at this position and found that only the original substitution produced an active mutant whereas drastic changes resulted in an inactive mutant. In another approach we isolated suppressors of an inactive FtsL mutant and obtained FtsWE289G and FtsIK211I and found they bypassed FtsN. Epistatic analysis of these mutations and others confirmed that the FtsN-triggered activation signal goes from FtsQLB to FtsI to FtsW. Mapping these mutations, as well as others affecting the activity of FtsWI, on the RodA-PBP2 structure revealed they are located at the interaction interface between the extracellular loop 4 (ECL4) of FtsW and the pedestal domain of FtsI (PBP3). This supports a model in which the interaction between the ECL4 of SEDS proteins and the pedestal domain of their cognate bPBPs plays a critical role in the activation mechanism.
Asunto(s)
Proteínas Bacterianas/ultraestructura , Proteínas de Escherichia coli/ultraestructura , Proteínas de la Membrana/ultraestructura , Complejos Multiproteicos/ultraestructura , Proteínas de Unión a las Penicilinas/ultraestructura , Peptidoglicano Glicosiltransferasa/ultraestructura , Conformación Proteica , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Modelos Moleculares , Complejos Multiproteicos/química , Complejos Multiproteicos/genética , Proteínas de Unión a las Penicilinas/química , Proteínas de Unión a las Penicilinas/genética , Peptidoglicano/química , Peptidoglicano/genética , Peptidoglicano/ultraestructura , Peptidoglicano Glicosiltransferasa/química , Peptidoglicano Glicosiltransferasa/genética , Peptidil Transferasas/química , Peptidil Transferasas/genética , Peptidil Transferasas/ultraestructuraRESUMEN
Three new flavan derivatives including two methylene-linked flavan-3-ol dimers, bis(8-epiafzelechinyl)methane (1), and 8,8-(epiafzelechin-afzelechin)methane (2), a flavan-3-ol monomer, (-)-3-O-acetyl-epiafzelechin (3) and four known related compounds (4-7) were isolated from the leaves and stems of Cassia nodosa. Their structures were elucidated by extensive spectroscopic analyses and CD data. The isolates were evaluated for their antioxidant, α-glucosidase inhibitory, cytotoxic and neuroinflammatory activities, and compound 3 exhibited remarkable radical scavenging activities in both the DPPH and ABTS models with IC50 values of 2.65±1.25, and 4.78±0.91 µg/mL, respectively.
RESUMEN
Fifteen bibenyls and four fluorenones, including five new bibenzyl-phenylpropane hybrids, were isolated from the aerial part of Dendrobium nobile Lindl. Their structures were determined by spectroscopic methods. Bioassay on the LPS-induced proliferations of mouse splenic B lymphocytes, and Con A-induced T lymphocytes showed that compounds 1, 2, and 14 showed excellent immunosuppressive activities with IC50 values of 1.23, 1.01, and 3.87â µM, respectively, while compoundsâ 3-4, 7, 10, 13, and 15 exhibited moderate immunosuppressive activities with IC50 values ranging from 6.89 to 14.2â µM.
Asunto(s)
Bibencilos , Proliferación Celular , Dendrobium , Inmunosupresores , Dendrobium/química , Animales , Ratones , Inmunosupresores/farmacología , Inmunosupresores/química , Inmunosupresores/aislamiento & purificación , Bibencilos/química , Bibencilos/farmacología , Bibencilos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Concanavalina A/antagonistas & inhibidores , Concanavalina A/farmacologíaRESUMEN
Horsfiequinone G (1), a dimeric diarylpropane featuring an unprecedentedly oxo-6/7/6 fused ring system, a new flavane, horsfielenide F (2), three naturally occurring spirocyclic monomers containing all-carbon quaternary centers, horspirotone A (3), horspirotone B (4), and methyl spirobroussonin B (5), along with horsfiequinone A (6) were isolated from Horsfieldia kingii. Their structures and absolute configurations were determined by the inspection of extensive spectroscopic data and electronic circular dichroism (ECD) calculations. Biological evaluations of these isolates revealed that compounds 1 - 3 and 5 - 6 exhibited specifically immunosuppressive activities against Con A-induced T lymphocytes with IC50 values ranging from 2.07 to 12.34 µM (selectivity indices = 2.3-25.2). Compound 1 also suppressed the secretion of inflammatory factors like IL-1ß and IL-6 in RAW264.7 cells which could present a new class of nonsteroidal anti-inflammatory agent. Finally, the primary structure-activity relationship (SAR) was also discussed.
Asunto(s)
Antiinflamatorios no Esteroideos , Inmunosupresores , Antiinflamatorios no Esteroideos/farmacología , Carbono , Dicroismo Circular , Inmunosupresores/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND: CIC-rearranged sarcomas (CRS) are a group of heterogeneous tumors which mostly occur in the soft tissues of limbs and trunk, and are highly invasive with poor prognosis. Here, we describe a rare case of CRS that occurred in the left kidney with a CIC-LEUTX rearrangement. CASE PRESENTATION: A 45-year-old male was admitted to hospital with a dry cough for more than two months without obvious cause. Physical examination and laboratory tests revealed no notable abnormality. The CT scan demonstrated a mass in the left kidney and multiple nodules in both lungs. The percutaneous core needle biopsy showed similar histomorphology and immunophenotype of small round cell malignant tumors. Genetic test revealed a CIC-LEUTX gene fusion. CONCLUSIONS: We present a rare primary renal CRS with multiple pulmonary metastases, and LEUTX is confirmed as the fusion partner of CIC gene for the first time in a renal case.
Asunto(s)
Neoplasias Pulmonares , Sarcoma de Células Pequeñas , Sarcoma , Masculino , Humanos , Persona de Mediana Edad , Proteínas Represoras/genética , Biomarcadores de Tumor/genética , Sarcoma/complicaciones , Sarcoma/genética , Sarcoma/patología , Sarcoma de Células Pequeñas/diagnóstico , Sarcoma de Células Pequeñas/genética , Sarcoma de Células Pequeñas/patología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/genética , Riñón/patología , Pulmón , Proteínas de Homeodominio/genéticaRESUMEN
Two new bibenzyl-phenylpropane hybrids, dendrophenols A and B (1 and 2), along with nine known bibenzyls, were isolated from the aerial part of Dendrobium devonianum Paxt. Their structures were determined by extensive spectroscopic methods and methylation. Bioassays revealed that compounds 1-9 were specifically immunosuppressive to T lymphocytes with IC50 values ranging from 0.41 to 9.4â µM, of which compounds 1 (IC50 =1.62â µM) and 2 (IC50 =0.41â µM) were promising immunosuppressive agents for T lymphocytes with the selectivity indices of 19.9 and 79.5, respectively.
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Bibencilos , Dendrobium , Bibencilos/farmacología , Bibencilos/química , Dendrobium/química , Depuradores de Radicales Libres/química , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
Seven lignans were isolated from 70 % aqueous acetone extracts of the twigs and leaves of Horsfieldia kingii. Among these, new compounds 1-3 were identified by spectroscopic techniques, with horsfielenigans A and B (1 and 2) being particularly noteworthy for their rare ß-benzylnaphthalene skeleton, where compound 1 contains an oxabicyclo[3,2,1]octane moiety. In vitro evaluation of bioactivity against nitric oxide (NO) production in LPS-activated RAW264.7 macrophages revealed inhibitory effects by 1 (IC50 =7.3â µM) and 2 (IC50 =9.7â µM).
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Lignanos , Myristicaceae , Lignanos/farmacología , Lignanos/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Macrófagos , Análisis Espectral , Óxido Nítrico , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Estructura MolecularRESUMEN
A new phenylpropanoid, myristriol (1), along with 11 known ones were isolated from the seed kernel of Myristica fragrans Houtt. Their chemical structures were clearly elucidated by extensive spectroscopic analysis. In which, the relative configuration of 1 was finally determined as erythro-1 by comparison the NMR data of two synthetic erythro- and threo-diastereoisomers with that of natural 1.
Asunto(s)
Myristica , Fenilpropionatos , Espectroscopía de Resonancia Magnética , Myristica/química , Semillas/química , Fenilpropionatos/químicaRESUMEN
Hypertension has long been recognized as the global health burden. Heavy metal pollution may be one of the environmental risk factors of hypertension. However, the association remains unclear. We studied the levels of aluminum (Al), vanadium (V), manganese (Mn), arsenic (As), selenium (Se), strontium (Sr), barium (Ba), titanium (Ti), lead (Pb) and cobalt (Co) in whole blood, and the relationship between trace element exposure and hypertension in the elderly community-based Chinese population. A total of 1013 participants from the west of Anhui Province in China were consecutively enrolled in this study in 2016. The general sociodemographic characteristics, lifestyles, disease history and physical examination information were collected by face-to-face survey and physical examination. The levels of ten trace elements were determined by inductively coupled plasma mass spectrometry (ICP-MS). Multivariable logistic regression model was used to assess the association of trace element exposure with the risk of hypertension. Results showed that the odds ratio of hypertension in the highest quartile was 1.811 (95% CI 1.175-2.790, P trend = 0.005) and 1.772 (95% CI 1.121-2.800, P trend = 0.022), respectively, after adjusting for potential confounders, as compared with the lowest quartile of blood Pb and Sr levels.
Asunto(s)
Metales Pesados , Oligoelementos , Humanos , Anciano , Oligoelementos/análisis , Plomo , Estroncio , Manganeso/análisisRESUMEN
BACKGROUND: Currently, over 2 billion people worldwide suffer from obesity, which poses a serious health risk. More and more attention is being given to the effects of trace elements on obesity in recent years. Synergistic or antagonistic interactions among these elements can adversely or positively impact human health. However, epidemiological evidence on the relationship between trace element exposure levels and obesity has been inconclusive. METHODS: Baseline data of 994 participants from the Cohort of Elderly Health and Environment Controllable Factors were used in the present study. ICP-MS was used to measure the concentrations of 10 trace elements in the whole blood of the older population. Binary logistic regression, restricted cubic splines (RCS) models, and Bayesian kernel machine regression (BKMR) models were employed to assess single, nonlinear, and mixed relationships between 10 trace element levels and three types of obesity based on body mass index (BMI), waist circumference (WC), and body fat percentage (BFP) in the elderly. RESULTS: Based on BMI, WC and BFP, 51.8% of the included old population were defined as general overweight/obesity, 67.1% as abdominal obesity, and 36.2% as having slightly high/high BFP. After multivariable adjustment, compared with the lowest tertile, the highest tertile of blood selenium (Se) concentration was associated with an increased risk of all three types of obesity. Additionally, compared with the lowest tertile, higher tertiles of strontium (Sr) concentrations were associated with a lower risk of general overweight/obesity and having slightly high/high BFP, and the highest tertile of barium (Ba) was associated with a lower risk of having slightly high BFP, while higher tertiles of arsenic (As) concentrations were associated with an increased risk of having slightly high/high BFP, and the highest tertile of manganese (Mn) was associated with a higher risk of abdominal obesity. BKMR analyses showed a strong linear positive association between Se and three types of obesity. Higher blood levels of trace element mixture were associated with increased obesity risks in a dose-response pattern, with Se having the highest value of the posterior inclusion probability (PIP) within the mixture. CONCLUSIONS: In this study, we found higher Se levels were associated with an elevated risk of obesity and high levels of Ba, Pb and Cr were associated with a decreased risk of obesity. Studies with larger samples are needed to confirm these findings.
Asunto(s)
Selenio , Oligoelementos , Humanos , Anciano , Obesidad Abdominal , Sobrepeso , Teorema de Bayes , Obesidad/epidemiologíaRESUMEN
BACKGROUND: Lp(a) (lipoprotein(a)) contributes to cardiovascular disease mainly through proatherogenic and proinflammatory effects. Here, we aimed to evaluate whether a residual stroke risk of Lp(a) would remain when the LDL-C (low-density lipoprotein cholesterol) and inflammatory levels are maintained low. METHODS: This prospective cohort study included 9899 patients with ischemic stroke or transient ischemic attack from the Third China National Stroke Registry who had measurements of plasma Lp(a) and were followed up for 1 year. Cutoffs were set at the 50 mg/dL for Lp(a). LDL-C was corrected for Lp(a)-derived cholesterol (LDL-Cc [LDL-C corrected]) and cutoffs were set at 55 and 70 mg/dL.The threshold values of IL-6 (interleukin 6) and hsCRP (high-sensitive C-reactive protein) were the median 2.65 ng/L and 2 mg/L. Multivariable-adjusted hazard ratio (HR) were calculated using Cox regression models for each category to investigate the associations of Lp(a) with stroke recurrence within 1 year. RESULTS: Among all patients, those with Lp(a) ≥50 mg/dL were at higher stroke recurrence risk than those with Lp(a) <50 mg/dL (11.5% versus 9.4%; adjusted HR, 1.20 [95% CI, 1.02-1.42]). However, the risk associated with elevated Lp(a) was attenuated in patients with LDL-Cc <55 mg/dL (high Lp(a) versus low Lp(a): 8.9% versus 9.0%; adjusted HR, 0.92 [95% CI, 0.65-1.30]) or IL-6 <2.65 ng/L (9.0% versus 7.8%; adjusted HR, 1.14 [95% CI, 0.87-1.49]). Notably, in the group with both low LDL-Cc and inflammation levels, the rate of patients with high Lp(a) did not significantly different from the rate of patients with low Lp(a; LDL-Cc <55 mg/dL and IL-6 <2.65 ng/L: 6.2% versus 7.1%; adjusted HR, 0.86 [95% CI, 0.46-1.62]; LDL-Cc <55 mg/dL and hsCRP <2 mg/L: 7.7% versus 7.6%; adjusted HR, 0.97 [95% CI, 0.57-1.66]). However, there was no interaction between the LDL-Cc, IL-6, hsCRP, and Lp(a) levels on stroke recurrence risk. CONCLUSIONS: Increased Lp(a) was significantly associated with stroke recurrence risk in patients with ischemic stroke/transient ischemic attack. However, at low LDL-Cc or IL-6 levels, the elevated Lp(a) -associated stroke recurrence risk was attenuated in a secondary prevention setting.
Asunto(s)
Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Biomarcadores , Proteína C-Reactiva , LDL-Colesterol , Humanos , Inflamación , Interleucina-6 , Ataque Isquémico Transitorio/complicaciones , Lipoproteína(a) , Estudios Prospectivos , Factores de Riesgo , Accidente Cerebrovascular/complicacionesRESUMEN
AIMS: Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance. METHODS AND RESULTS: We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe-/- mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD. CONCLUSION: Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α-CREB-OGDH axis in macrophages.
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Aneurisma de la Aorta , Animales , Biomarcadores , Disección , Humanos , Metabolómica , Ratones , Ácido SuccínicoRESUMEN
Two new isopentenyl bibenzyls, denchrysotonols A and B (1-2), along with 26 known phenolic compounds, were isolated from the stems of cultivated Dendrobium chrysotoxum Lindl. Their chemical structures were clearly elucidated by extensive spectroscopic analysis. Biological evaluation of isolated compounds revealed that phenanthrenes (14, 16-17, 20, and 22) and fluorenone 25 exhibited anti-inflammatory activities which inhibited nitric oxide (NO) production in LPS-activated RAW264.7 macrophages with the IC50 values ranging from 9.4 to 32.5â µM. Moreover, bibenzyls (1-2 and 7) showed good anti-proliferative activities against triple-negative breast cancer (TNBC) cells (HCC1806, MDA-MB-231, and MB-MB-468) with the IC50 values ranging from 8.1 to 18.6â µM, of which 1 and 2 seemed preferentially inhibit MDA-MB-231 cells.
Asunto(s)
Bibencilos , Dendrobium , Antiinflamatorios/farmacología , Bibencilos/química , Bibencilos/farmacología , Dendrobium/química , Macrófagos , Estructura Molecular , Fenoles/farmacologíaRESUMEN
Since failed resolution of inflammation is a major contributor to the progression of diabetic nephropathy, identifying endogenously generated molecules that promote the physiological resolution of inflammation may be a promising therapeutic approach for this disease. Annexin A1 (ANXA1), as an endogenous mediator, plays an important role in resolving inflammation. Whether ANXA1 could affect established diabetic nephropathy through modulating inflammatory states remains largely unknown. In the current study, we found that in patients with diabetic nephropathy, the levels of ANXA1 were upregulated in kidneys, and correlated with kidney function as well as kidney outcomes. Therefore, the role of endogenous ANXA1 in mouse models of diabetic nephropathy was further evaluated. ANXA1 deficiency exacerbated kidney injuries, exhibiting more severe albuminuria, mesangial matrix expansion, tubulointerstitial lesions, kidney inflammation and fibrosis in high fat diet/streptozotocin-induced-diabetic mice. Consistently, ANXA1 overexpression ameliorated kidney injuries in mice with diabetic nephropathy. Additionally, we found Ac2-26 (an ANXA1 mimetic peptide) had therapeutic potential for alleviating kidney injuries in db/db mice and diabetic Anxa1 knockout mice. Mechanistic studies demonstrated that intracellular ANXA1 bound to the transcription factor NF-κB p65 subunit, inhibiting its activation thereby modulating the inflammatory state. Thus, our data indicate that ANXA1 may be a promising therapeutic approach to treating and reversing diabetic nephropathy.
Asunto(s)
Anexina A1 , Diabetes Mellitus Experimental , Nefropatías Diabéticas , Animales , Anexina A1/genética , Diabetes Mellitus Experimental/complicaciones , Humanos , Inflamación , Riñón , RatonesRESUMEN
BACKGROUND: Growth hormone inducible transmembrane protein (GHITM) is a highly conserved transmembrane protein. This study was conducted to investigate the role of GHITM gene in the apoptosis and growth of the golden apple snail Pomacea canaliculate. RESULTS: The complete cDNA of this gene was cloned using the rapid amplification of cDNA ends (RACE) method and subjected to bioinformatics analysis. The full-length cDNA was 2242 bp, including an open reading frame of 1021 bp that encoded a protein of 342 amino acid residues. The mRNA expression profiles of GHITM gene in different tissues (liver, kidney, gonad and foot) and different growth phases (6-months old and 2-years old) showed that it was expressed in various tissues and different growth phases. Silencing of the GHITM gene by RNAi (RNA interference) experiments revealed that the GHITM gene possibly plays a role in inhibiting apoptosis through detecting the Caspase (Cysteine-requiring Aspartate Protease)-3 activity. In addition, the aperture width and body whorl length of the snail was significantly affected by RNAi, suggesting that this gene plays a significant role in promoting the growth of the organism. CONCLUSIONS: These results demonstrated that the GHITM gene was involved in apoptosis and growth in golden apple snail.
Asunto(s)
Apoptosis/genética , Proteínas de la Membrana/genética , Sistemas de Lectura Abierta/genética , Caracoles/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , ADN Complementario/genética , Perfilación de la Expresión Génica/métodos , Proteínas de la Membrana/clasificación , Proteínas de la Membrana/metabolismo , Filogenia , Interferencia de ARN , Caracoles/crecimiento & desarrollo , Caracoles/metabolismoRESUMEN
The nuclear factor-κB (NF-κB) signaling pathway plays a crucial role in regulating many physiological processes such as development, inflammation, apoptosis, cell proliferation, differentiation and immune responses. And the NF-κB/Rel family members were considered as the most important transcription factors in the NF-κB signaling pathway. In this study, we cloned a Rel homolog gene (named as CgRel2) from the Pacific oyster, Crassostrea gigas. The 2115-bp open reading frame (ORF) encodes 704 amino acids and CgRel2 possesses a conserved Rel Homology Domain (RHD) at the N-terminus. Phylogenetic analysis revealed that CgRel2 is most closely related to Pinctada fucata dorsal protein. CgRel2 transcripts are widely expressed in all tested tissues, with the highest expression observed in the labial palp and the gill. Moreover, the expression of CgRel2 is significantly upregulated after lipopolysaccharide (LPS), peptidoglycan (PGN), and polyinosinic-polycytidylic acid [poly(I:C)] challenge. CgRel2 transfection into human cell lines activated NF-κB, TNFα and oyster IL-17 (CgIL-17) reporter genes in a dose-dependent manner, while CgRel2 overexpression cannot induce ISRE (Interferon stimulation response element) reporter gene's transcriptional activity. Additionally, the results of co-immunoprecipitation showed that CgRel2 or CgRel1 could interact with oyster IκB1, IκB2 and IκB3 proteins strongly, which may be critical for the immune signaling transduction and the regulation of its immune functions. Together, these results suggest that CgRel2 could respond to pathogenic infection, participate in the immune signal transduction and activate NF-κB, TNFα and CgIL-17 reporter genes. Thus, CgRel2 could play an important role in the oyster immune system.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Inmunidad Innata/genética , Pinctada/genética , Pinctada/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Perfilación de la Expresión Génica , Lipopolisacáridos/administración & dosificación , Peptidoglicano/administración & dosificación , Filogenia , Poli I-C/administración & dosificación , Alineación de Secuencia , Factores de Transcripción/químicaRESUMEN
This study evaluated the relationship between grain consumption and the risk of gastric cancer. A total of 19 studies met the inclusion criteria. For whole grain consumption, there was a 13% reduction in the risk of gastric cancer (p = .003), and a subgroup analysis showed that a large amount of whole grain consumption reduced the risk of gastric cancer by 44% (p < .001). For refined grain consumption, there was a 36% increase in the risk of gastric cancer (p < .001); a subgroup analysis showed that a large and a moderate amount of refined grain consumption increased the risk of gastric cancer by 63% (p < .001) and 28% (p < .001), respectively. A large intake of whole grains might be protective against gastric cancer, whereas the ingestion of refined cereals may be a risk factor for gastric cancer. Moreover, the risk of cancer increases with the increase of refined grain intake.
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Grano Comestible , Neoplasias Gástricas/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Two new phenylpropanoid esters bobulretulates A (1) and B (2), together with eleven known compounds, were isolated from the whole plants of Bulbophyllum retusiusculum. Their structures were elucidated by means of extensive spectroscopic analysis.
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Orchidaceae/química , Fenilpropionatos/aislamiento & purificación , Ésteres/química , Ésteres/aislamiento & purificación , Fenilpropionatos/químicaRESUMEN
Aescin, a natural mixture of triterpene saponins, has been reported to exert anticancer effect. Recent studies show that aescin increases intracellular reactive oxygen species (ROS) levels. However, whether the increased ROS play a role in the anticancer action of aescin remains to be explored. In this study, we demonstrated that aescin (20-80 µg/mL) dose-dependently induced apoptosis and activated mammalian target of rapamycin (mTOR)-independent autophagy in human hepatocellular carcinoma HepG2 cells and colon carcinoma HCT 116 cells. The activation of autophagy favored cancer cell survival in response to aescin, as suppression of autophagy with ATG5 siRNAs or 3-methyladenine (3-MA), a selective inhibitor of autophagy, promoted aescin-induced apoptosis in vitro, and significantly enhanced the anticancer effect of aescin in vivo. Meanwhile, aescin dose-dependently elevated intracellular ROS levels and activated Ataxia-telangiectasia mutated kinase/AMP-activated protein kinase/UNC-51-like kinase-1 (ATM/AMPK/ULK1) pathway. The ROS and ATM/AMPK/ULK1 pathway were upstream modulators of the aescin-induced autophagy, as N-acetyl-L-cysteine (NAC) or ATM kinase inhibitor (KU-55933) remarkably suppressed aescin-induced autophagy and consequently promoted aescin-induced apoptosis, whereas overexpression of ATG5 partly attenuated NAC-induced enhancement in aescin-induced apoptosis. In conclusion, this study provides new insights into the roles of aescin-mediated oxidative stress and autophagy in cancer cell survival. Our results suggest that combined administration of the antioxidants or autophagic inhibitors with aescin might be a potential strategy to enhance the anticancer effect of aescin.
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Antineoplásicos/uso terapéutico , Autofagia/efectos de los fármacos , Escina/uso terapéutico , Neoplasias/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Línea Celular Tumoral , Escina/farmacología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones DesnudosRESUMEN
Phospholipid transfer protein (PLTP) is a widely expressed lipid transfer protein participating in the transport of cholesterol and other lipids in the plasma and peripheral tissues. Recently, elevated amyloid ß (Aß) in young and aged PLTP-deficient brains had been reported. However, the role of PLTP in amyloid precursor protein (APP) processing and Alzheimer's disease (AD) pathology remains elusive. Here we first found that deficiency of PLTP accelerated memory dysfunction in APP/PS1ΔE9 AD model mice at the age of 3 months. Further characterization showed that PLTP deficiency increased soluble Aß peptides, and intracellular accumulation of Aß was illustrated, which might be due to disrupted APP turnover and the enhanced amyloidogenic pathway. Besides, reduced brain-derived neurotrophic factor (BDNF) was found in PLTP-deficient APP/PS1ΔE9 mice, and the BDNF level was negatively correlated with Aß42 content, instead of Aß40 content. In addition, autophagic dysfunction was found in the PLTP-deficient APP/PS1ΔE9 mice. Our data presented a novel model to link phospholipid metabolism to APP processing and also suggested that PLTP played an important role in Aß metabolism and would be useful to further elucidate functions of PLTP in AD susceptibility.