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1.
Mol Ther ; 32(6): 1849-1874, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38584391

RESUMEN

The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (UCAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on hematopoietic stem cells (HSCs), along with an ex vivo, feeder-free HSC differentiation culture. The UCAR-NKT cells are produced with high yield, purity, and robustness, and they display a stable HLA-ablated phenotype that enables resistance to host cell-mediated allorejection. These UCAR-NKT cells exhibit potent antitumor efficacy to blood cancers and solid tumors, both in vitro and in vivo, employing a multifaceted array of tumor-targeting mechanisms. These cells are further capable of altering the tumor microenvironment by selectively depleting immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells. In addition, UCAR-NKT cells demonstrate a favorable safety profile with low risks of graft-versus-host disease and cytokine release syndrome. Collectively, these preclinical studies underscore the feasibility and significant therapeutic potential of UCAR-NKT cell products and lay a foundation for their translational and clinical development.


Asunto(s)
Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Células T Asesinas Naturales , Receptores Quiméricos de Antígenos , Humanos , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Animales , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Inmunoterapia Adoptiva/métodos , Ratones , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Edición Génica , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias/terapia , Neoplasias/inmunología , Línea Celular Tumoral , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología
2.
Diabetes Obes Metab ; 26(7): 2588-2597, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38618974

RESUMEN

AIMS: To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL). RESULTS: A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438). CONCLUSIONS: Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m2) in a subsequent larger study.


Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Persona de Mediana Edad , Femenino , Anciano , Tasa de Filtración Glomerular/efectos de los fármacos , Glucemia/efectos de los fármacos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Glucósidos/farmacocinética , Glucósidos/uso terapéutico , Glucósidos/farmacología , Glucósidos/efectos adversos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Adulto , Nefropatías Diabéticas/tratamiento farmacológico , Hemoglobina Glucada/análisis , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Insuficiencia Renal/metabolismo , Transportador 2 de Sodio-Glucosa , Glucosuria/inducido químicamente , Benzofuranos
3.
Diabetes Obes Metab ; 26(6): 2248-2256, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38456558

RESUMEN

AIM: To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period. RESULTS: Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001). CONCLUSIONS: Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.


Asunto(s)
Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Glucósidos , Hipoglucemiantes , Metformina , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/uso terapéutico , Benzofuranos , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Quimioterapia Combinada , Glucósidos/efectos adversos , Glucósidos/uso terapéutico , Glucósidos/administración & dosificación , Hemoglobina Glucada/análisis , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Metformina/efectos adversos , Metformina/uso terapéutico , Metformina/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Resultado del Tratamiento
4.
Environ Res ; 248: 118242, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38242419

RESUMEN

Exposure to ultrafine particles (UFPs) has been associated with multiple adverse health effects. Inhaled UFPs could reach the gastrointestinal tract and influence the composition of the gut microbiome. We have previously shown that oral ingestion of UFPs alters the gut microbiome and promotes intestinal inflammation in hyperlipidemic Ldlr-/- mice. Particulate matter (PM)2.5 inhalation studies have also demonstrated microbiome shifts in normolipidemic C57BL/6 mice. However, it is not known whether changes in microbiome precede or follow inflammatory effects in the intestinal mucosa. We hypothesized that inhaled UFPs modulate the gut microbiome prior to the development of intestinal inflammation. We studied the effects of UFP inhalation on the gut microbiome and intestinal mucosa in two hyperlipidemic mouse models (ApoE-/- mice and Ldlr-/- mice) and normolipidemic C57BL/6 mice. Mice were exposed to PM in the ultrafine-size range by inhalation for 6 h a day, 3 times a week for 10 weeks at a concentration of 300-350 µg/m3.16S rRNA gene sequencing was performed to characterize sequential changes in the fecal microbiome during exposures, and changes in the intestinal microbiome at the end. PM exposure led to progressive differentiation of the microbiota over time, associated with increased fecal microbial richness and evenness, altered microbial composition, and differentially abundant microbes by week 10 depending on the mouse model. Cross-sectional analysis of the small intestinal microbiome at week 10 showed significant changes in α-diversity, ß-diversity, and abundances of individual microbial taxa in the two hyperlipidemic models. These alterations of the intestinal microbiome were not accompanied, and therefore could not be caused, by increased intestinal inflammation as determined by histological analysis of small and large intestine, cytokine gene expression, and levels of fecal lipocalin. In conclusion, 10-week inhalation exposures to UFPs induced taxonomic changes in the microbiome of various animal models in the absence of intestinal inflammation.


Asunto(s)
Contaminantes Atmosféricos , Microbioma Gastrointestinal , Ratones , Animales , Material Particulado/análisis , Contaminantes Atmosféricos/toxicidad , Exposición por Inhalación/análisis , ARN Ribosómico 16S , Estudios Transversales , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Inflamación/inducido químicamente
5.
Br J Clin Pharmacol ; 89(4): 1462-1470, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36422809

RESUMEN

AIMS: DWP16001 is a novel sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes with selective and sustained sodium-glucose cotransporter 2 inhibition. We aimed to evaluate whether the coadministration of DWP16001 and metformin causes any changes in pharmacokinetics (PK) or pharmacodynamics (PD). METHODS: A randomized, open-label, single- and multiple-dose, 2-sequence, crossover study was conducted in healthy male subjects. Subjects received the following treatments: a single oral dose of DWP16001 (DWP) 2 mg, metformin immediate release 1000 mg (MET) twice daily for 7 days and a single oral dose of DWP and MET at steady-state for metformin (DWP+MET). Serial blood and interval urine were collected for PK and PD analyses. Safety and tolerability profiles were assessed throughout the study. RESULTS: DWP+MET displayed increased peak concentration and area under the concentration-time curve from time 0 to time of the last quantifiable concentration compared with DWP (per standard bioequivalence boundaries, 0.8-1.25); the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were 1.22 (1.13-1.31) and 1.09 (1.05-1.14), respectively. DWP+MET and MET showed similar peak concentration and area under the concentration-time curve within a dosing interval at steady state for metformin; the GMRs and 90% CIs were 0.98 (0.90-1.06) and 1.05 (0.98-1.13), respectively. The amount of urinary glucose excretion from time 0 to 144 h was also comparable between DWP+MET and DWP (GMR and 90% CI; 0.99, 0.94-1.05). CONCLUSION: The results suggest that DWP16001 and metformin could be coadministered without clinically relevant PK and PD interactions.


Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Masculino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Voluntarios Sanos , Estudios Cruzados , Glucosa , Área Bajo la Curva , Sodio , Hipoglucemiantes/efectos adversos
6.
Clin Sci (Lond) ; 135(6): 793-810, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33625485

RESUMEN

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II)-dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.


Asunto(s)
Hipertensión/fisiopatología , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptores de Superficie Celular/metabolismo , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Captopril/farmacología , Dieta Alta en Grasa/efectos adversos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Peróxido de Hidrógeno , Losartán/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad , Sistema Renina-Angiotensina/efectos de los fármacos , Receptor de Prorenina
7.
J Vasc Res ; 57(5): 291-301, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32541137

RESUMEN

INTRODUCTION: Impaired venous reactivity has potential to contribute to clinically significant pathologies such as arteriovenous fistula (AVF) maturation failure. Vascular segments commonly used in murine preclinical models of AVF include the carotid artery and external jugular vein. Detailed descriptions of isometric procedures to evaluate function of murine external jugular vein ex vivo have not been previously published. OBJECTIVE: To establish isometric procedures to measure naive murine external jugular vein reactivity ex vivo. METHODS: Vasomotor responses of external jugular veins and ipsilateral common carotid arteries from C57BL/6 mice were evaluated using isometric tension procedures. RESULTS: External jugular veins developed tension (p < 0.05) to potassium chloride and U-46619, but not to phenylephrine, whereas common carotid arteries responded to all 3 agents (p < 0.05). While maximal responses to acetylcholine (ACh) were similar between the venous and arterial segments, the dose required to achieve this value was lower (p < 0.05) in the artery versus vein. Nitric oxide synthase inhibition attenuated (p < 0.05) but did not abolish ACh-evoked vasorelaxation in both vascular segments, whereas cyclooxygenase blockade had no effect. Endothelium-independent vasorelaxation to sodium nitroprusside was similar in the artery and vein. CONCLUSION: Vasorelaxation and vasocontraction can be reliably assessed in the external jugular vein in C57BL/6 mice using isometric procedures.


Asunto(s)
Arteria Carótida Común/fisiología , Endotelio Vascular/fisiología , Venas Yugulares/fisiología , Músculo Liso Vascular/fisiología , Vasoconstricción , Vasodilatación , Animales , Arteria Carótida Común/efectos de los fármacos , Arteria Carótida Común/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Venas Yugulares/efectos de los fármacos , Venas Yugulares/metabolismo , Masculino , Ratones Endogámicos C57BL , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Miografía , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Prostaglandinas/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología
8.
Eur Radiol ; 30(10): 5317-5326, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32335746

RESUMEN

OBJECTIVES: To determine whether quantification of liver extracellular volume fraction (fECV) using dual-energy CT (DECT) allows prediction of liver-related events (LREs) in cirrhotic patients. METHODS: This retrospective study included 305 cirrhotic patients who underwent dual-source DECT imaging and had serum markers analyzed within 2 weeks of initial CT imaging. The fECV score was measured using an iodine map of equilibrium-phase images obtained 3 min after contrast injection at 100/140 Sn kVp. The association of the fECV score and serum markers with LREs was investigated. A risk model combining the fECV score (< 27 versus ≥ 27%) and serum albumin level (< 4 versus ≥ 4 g/dL) was constructed for LRE prediction. RESULTS: An increased fECV score (odds ratio, 1.27; 95% confidence interval (CI), 1.15, 1.40) was independently associated with decompensated cirrhosis at baseline (n = 85) along with the Model for End-Stage Liver Disease score (odds ratio, 1.32; 95% CI, 1.07, 1.63). Among patients with compensated cirrhosis, 10.5% (23 of 220) experienced LREs during the median follow-up period of 2.0 years (decompensation, n = 14; hepatocellular carcinoma, n = 9). The fECV score (hazard ratio, 1.40; 95% CI, 1.22, 1.62) and serum albumin level (hazard ratio, 0.26; 95% CI, 0.09, 0.73) were independent predictors of LRE. The mean times to LRE among the high (16.5 months, n = 18)-, intermediate (25.6 months, n = 44)-, and low (30.5 months, n = 158)-risk groups were significantly different (p < 0.001). CONCLUSIONS: The fECV score derived from DECT allows prediction of LREs in cirrhotic patients. KEY POINTS: • The extracellular volume fraction (fECV) score derived from the iodine map of dual-energy CT (DECT) was independently associated with the presence of hepatic decompensation. • The fECV score derived from the iodine map of DECT can predict liver-related events (LREs) in patients with cirrhosis. • Equilibrium-phase scanning in dual-energy mode is recommended as part of liver CT in cirrhotic patients because it can provide a prognostic indicator for LRE development.


Asunto(s)
Espacio Extracelular/diagnóstico por imagen , Cirrosis Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Hígado/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Anciano , Medios de Contraste , Femenino , Humanos , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos
9.
Am J Physiol Heart Circ Physiol ; 316(1): H106-H112, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30412436

RESUMEN

Continuous laminar shear stress increases the process of autophagy, activates endothelial nitric oxide (NO) synthase phosphorylation at serine 1177 (p-eNOSS1177), and generates NO in bovine and human arterial endothelial cells (ECs) compared with static controls. However, the translational relevance of these findings has not been explored. In the current study, primary ECs were collected from the radial artery of 7 men using sterile J-wires before (Pre) and after (Post) 60 min of rhythmic handgrip exercise (HG) performed with the same arm. After ECs were identified by positive costaining for vascular endothelial cadherin and 4',6'-diamidino-2-phenylindole, immunofluorescent antibodies were used to assess indices of autophagy, NO generation, and superoxide anion (O2·-) production. Commercially available primary human arterial ECs were stained and processed in parallel to serve as controls. All end points were evaluated using 75 ECs from each subject. Relative to Pre-HG, HG elevated arterial shear rate ( P < 0.05) ~3-fold, whereas heart rate, arterial pressure, and cardiac output were not altered. Compared with values obtained from ECs Pre-HG, Post-HG ECs displayed increased ( P < 0.05) expression of p-eNOSS1177, NO generation, O2·- production, BECLIN1, microtubule-associated proteins 1A/1B light chain 3B, autophagy-related gene 3, and lysosomal-associated membrane protein 2A and decreased ( P < 0.05) expression (i.e., enhanced degradation) of the adaptor protein p62/sequestosome-1. These novel findings provide evidence that elevated arterial shear rate associated with functional hyperemia initiates autophagy, activates p-eNOSS1177, and increases NO and O2·- generation in primary human ECs. NEW & NOTEWORTHY Previously, our group reported in bovine arterial and human arterial endothelial cells (ECs) that shear stress initiates trafficking of the autophagosome to the lysosome and increases endothelial nitric oxide (NO) synthase phosphorylation at serine 1177, NO generation, and O2·- production. Here, the translational relevance of these findings is documented. Specifically, functional hyperemia induced by rhythmic handgrip exercise elevates arterial shear rate to an extent that increases indices of autophagy, NO generation, and O2·- production in primary arterial ECs collected from healthy men.


Asunto(s)
Arterias/metabolismo , Autofagia , Células Endoteliales/metabolismo , Ejercicio Físico , Óxido Nítrico Sintasa de Tipo III/metabolismo , Adulto , Arterias/citología , Arterias/fisiología , Células Cultivadas , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Fuerza de la Mano , Humanos , Masculino , Óxido Nítrico/metabolismo
10.
Arterioscler Thromb Vasc Biol ; 37(9): 1646-1656, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28684613

RESUMEN

OBJECTIVE: Impaired endothelial cell (EC) autophagy compromises shear stress-induced nitric oxide (NO) generation. We determined the responsible mechanism. APPROACH AND RESULTS: On autophagy compromise in bovine aortic ECs exposed to shear stress, a decrease in glucose uptake and EC glycolysis attenuated ATP production. We hypothesized that decreased glycolysis-dependent purinergic signaling via P2Y1 (P2Y purinoceptor 1) receptors, secondary to impaired autophagy in ECs, prevents shear-induced phosphorylation of eNOS (endothelial nitric oxide synthase) at its positive regulatory site S1117 (p-eNOSS1177) and NO generation. Maneuvers that restore glucose transport and glycolysis (eg, overexpression of GLUT1 [glucose transporter 1]) or purinergic signaling (eg, addition of exogenous ADP) rescue shear-induced p-eNOSS1177 and NO production in ECs with impaired autophagy. Conversely, inhibiting glucose transport via GLUT1 small interfering RNA, blocking purinergic signaling via ectonucleotidase-mediated ATP/ADP degradation (eg, apyrase), or inhibiting P2Y1 receptors using pharmacological (eg, MRS2179 [2'-deoxy-N6-methyladenosine 3',5'-bisphosphate tetrasodium salt]) or genetic (eg, P2Y1-receptor small interfering RNA) procedures inhibit shear-induced p-eNOSS1177 and NO generation in ECs with intact autophagy. Supporting a central role for PKCδT505 (protein kinase C delta T505) in relaying the autophagy-dependent purinergic-mediated signal to eNOS, we find that (1) shear stress-induced activating phosphorylation of PKCδT505 is negated by inhibiting autophagy, (2) shear-induced p-eNOSS1177 and NO generation are restored in autophagy-impaired ECs via pharmacological (eg, bryostatin) or genetic (eg, constitutively active PKCδ) activation of PKCδT505, and (3) pharmacological (eg, rottlerin) and genetic (eg, PKCδ small interfering RNA) PKCδ inhibition prevents shear-induced p-eNOSS1177 and NO generation in ECs with intact autophagy. Key nodes of dysregulation in this pathway on autophagy compromise were revealed in human arterial ECs. CONCLUSIONS: Targeted reactivation of purinergic signaling and PKCδ has strategic potential to restore compromised NO generation in pathologies associated with suppressed EC autophagy.


Asunto(s)
Adenosina Trifosfato/metabolismo , Autofagia , Células Endoteliales/enzimología , Glucólisis , Mecanotransducción Celular , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Animales , Autofagia/efectos de los fármacos , Proteínas Relacionadas con la Autofagia/deficiencia , Proteínas Relacionadas con la Autofagia/genética , Bovinos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Mecanotransducción Celular/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/genética , Proteína Quinasa C-delta/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Antagonistas del Receptor Purinérgico P2Y/farmacología , Interferencia de ARN , Especies Reactivas de Oxígeno/metabolismo , Receptores Purinérgicos P2Y1/efectos de los fármacos , Receptores Purinérgicos P2Y1/genética , Serina , Estrés Mecánico , Transfección , Enzimas Ubiquitina-Conjugadoras/deficiencia , Enzimas Ubiquitina-Conjugadoras/genética
11.
Eur J Appl Physiol ; 118(8): 1653-1660, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29846794

RESUMEN

INTRODUCTION: Exercise training is recommended for improving health and protecting against the development of metabolic and cardiovascular pathologies. Combined resistance and aerobic exercise training (CRAE) has been shown to provide unique benefits in older adults with cardiovascular diseases. PURPOSE: We sought to determine the beneficial effects of CRAE in adolescent girls who are obese and hyperinsulinemic. METHODS: Forty adolescent girls who are obese (age 14.7 ± 1 years; BMI 30 ± 2) were randomly assigned to a "no exercise" (CON n = 20) or combined exercise group (EX n = 20). The EX group performed resistance and aerobic exercise for 12 weeks, 5 times per week. Exercise intensity was increased gradually, from 40 to 70% of heart rate reserve (HRR), every 4 weeks. The brachial-ankle pulse wave velocity (BaPWV), blood pressure (BP), heart rate (HR), blood leptin, adiponectin levels, and body composition were measured before and after the 12-week intervention. RESULTS: We observed that CRAE effectively reduced the body fat percentage, body weight, and waist circumference in the EX group (p < 0.05). After 12 weeks of training, subjects in the CRAE group maintained appropriate leptin and adiponectin levels and showed positive improvements of blood insulin, glucose, and insulin resistance parameters relative to baseline and to the CON group (p < 0.05). CONCLUSION: CRAE is a useful therapeutic method to alleviate metabolic risk factors in adolescent girls who are obese and hyperinsulinemic.


Asunto(s)
Adiposidad , Resistencia a la Insulina , Obesidad/terapia , Entrenamiento de Fuerza/métodos , Adiponectina/sangre , Adolescente , Glucemia/metabolismo , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Humanos , Insulina/sangre , Leptina/sangre
12.
Int J Mol Sci ; 19(11)2018 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-30469352

RESUMEN

Glioblastoma, the most common primary brain tumor in adults, is an incurable malignancy with poor short-term survival and is typically treated with radiotherapy along with temozolomide. While the development of tumor-treating fields (TTFields), electric fields with alternating low and intermediate intensity has facilitated glioblastoma treatment, clinical outcomes of TTFields are reportedly inconsistent. However, combinatorial administration of chemotherapy with TTFields has proven effective for glioblastoma patients. Sorafenib, an anti-proliferative and apoptogenic agent, is used as first-line treatment for glioblastoma. This study aimed to investigate the effect of sorafenib on TTFields-induced anti-tumor and anti-angiogenesis responses in glioblastoma cells in vitro and in vivo. Sorafenib sensitized glioblastoma cells to TTFields, as evident from significantly decreased post-TTFields cell viability (p < 0.05), and combinatorial treatment with sorafenib and TTFields accelerated apoptosis via reactive oxygen species (ROS) generation, as evident from Poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, use of sorafenib plus TTFields increased autophagy, as evident from LC3 upregulation and autophagic vacuole formation. Cell cycle markers accumulated, and cells underwent a G2/M arrest, with an increased G0/G1 cell ratio. In addition, the combinatorial treatment significantly inhibited tumor cell motility and invasiveness, and angiogenesis. Our results suggest that combination therapy with sorafenib and TTFields is slightly better than each individual therapy and could potentially be used to treat glioblastoma in clinic, which requires further studies.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Terapia por Estimulación Eléctrica/métodos , Glioblastoma/terapia , Sorafenib/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Autofagia , Neoplasias Encefálicas/tratamiento farmacológico , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Terapia Combinada/métodos , Glioblastoma/tratamiento farmacológico , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sorafenib/administración & dosificación
13.
Eur Radiol ; 27(4): 1517-1526, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27510624

RESUMEN

OBJECTIVE: To evaluate the added value of point shear-wave elastography (pSWE) in the diagnostic performance of conventional US for diagnosis of acute cholecystitis. METHODS: B-mode and colour Doppler US and pSWE were performed prospectively in 216 patients with clinically suspected acute cholecystitis. The morphology and mural vascularity of the gallbladder and median shear wave velocity (SWV) of the right liver were evaluated. Two observers independently reviewed conventional US images and subsequently reviewed combined conventional US and pSWE images. RESULTS: Mean SWVs of the acute cholecystitis group (n = 91) were significantly higher than those of the control group (n = 85) in the right liver within 2 cm lateral to the gallbladder (1.56 versus 1.03 m/s, 1.39 versus 1.04 m/s, P < 0.0001) with a cut-off value of 1.29 or 1.16 m/s. The area under the receiver operating characteristic curve of both observers in the diagnosis of acute cholecystitis improved significantly from 0.790 and 0.777 to 0.963 and 0.962, respectively, after additional review of pSWE images (P < 0.0001). Diagnostic accuracy, sensitivity, specificity, positive and negative predictive values of combined image sets were higher than those of conventional US images alone. CONCLUSION: Adding pSWE to conventional US improves the diagnosis of acute cholecystitis when compared with conventional US alone. KEY POINTS: • In acute cholecystitis, stiffness of the right liver increases adjacent to the gallbladder. • The cut-off value for diagnosing acute cholecystitis was 1.29 or 1.16 m/s. • Adding pSWE to conventional US improves the diagnosis of acute cholecystitis.


Asunto(s)
Colecistitis Aguda/diagnóstico por imagen , Diagnóstico por Imagen de Elasticidad/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hígado/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto Joven
15.
AJR Am J Roentgenol ; 202(2): W169-75, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24450700

RESUMEN

OBJECTIVE: Varying anatomic characteristics and clinical and radiologic manifestations are diagnostic challenges in the evaluation of the cerebral vein and of venous sinus diseases. The purpose of this article is to introduce bone subtraction CT venography and review normal variations and diseases involving the cerebral veins and venous sinuses. CONCLUSION: Knowledge of the normal variations and pathologic findings will be helpful for the accurate diagnosis of diseases involving the cerebral venous system. Bone subtraction CT venography offers complete 3D visualization of the cerebral venous system and can be useful for the evaluation of the cerebral vein and venous sinus diseases.


Asunto(s)
Angiografía Cerebral/métodos , Venas Cerebrales/diagnóstico por imagen , Imagenología Tridimensional , Flebografía/métodos , Tomografía Computarizada por Rayos X/métodos , Venas Cerebrales/patología , Humanos , Cráneo/diagnóstico por imagen , Técnica de Sustracción
16.
Acta Radiol ; 55(1): 8-13, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23884842

RESUMEN

BACKGROUND: Fish bone (FB) is one of the common causes of foreign body impaction in the pharynx and esophagus. PURPOSE: To investigate the efficacy of 64-slice multidetector computed tomography (MDCT) for the evaluation of pharynx and upper esophageal FB foreign bodies. MATERIAL AND METHODS: Sixty-six patients with suspected FB foreign body ingestion were examined by plain radiography (n = 40) and unenhanced MDCT (n = 66). We analyzed the presence, location, size, shape, and lying position of the foreign bodies. RESULTS: On MDCT, 46 foreign bodies were detected. Among them, 45 were confirmed by endoscopy. The sensitivity of MDCT for the detection of foreign bodies was 100%, which was superior to that of the plain radiography (51.7%). The location of the foreign bodies was most common in the upper esophagus (n = 22, 47.8%), followed by pharyngoesophageal junction (n = 10, 21.7%), transjunctional (n = 7, 15.2%), hypopharynx (n = 5, 10.9%), and oropharynx (n = 2, 4.3%). Their longest length was 5.3-40.1 mm (mean, 21.3 mm). Thirty-three FBs (71.7%) were linear and 13 (28.3%) were flat in shape. They showed transverse (n = 23, 50.0%), parallel (n = 13, 28.3%), and oblique positions (n = 10, 21.7%) to the long axis of the pharynx and esophagus, respectively. CONCLUSION: MDCT is useful for the evaluation of the pharynx and upper esophageal FB foreign bodies.


Asunto(s)
Esófago/diagnóstico por imagen , Peces , Cuerpos Extraños/diagnóstico por imagen , Tomografía Computarizada Multidetector/métodos , Faringe/diagnóstico por imagen , Adolescente , Adulto , Anciano , Animales , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad
17.
Front Immunol ; 15: 1418703, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39044831

RESUMEN

Introduction: Salivary gland dysfunction, often resulting from salivary gland obstruction-induced inflammation, is a prevalent condition. Corticosteroid, known for its anti-inflammatory and immunomodulatory properties, is commonly prescribed in clinics. This study investigates the therapeutic implications and potential side effects of dexamethasone on obstructive sialadenitis recovery using duct ligation mice and salivary gland organoid models. Methods: Functional and pathological changes were assessed after administering dexamethasone to the duct following deligation 2 weeks after maintaining ligation of the mouse submandibular duct. Additionally, lipopolysaccharide- and tumor necrosis factor-induced salivary gland organoid inflammation models were established to investigate the effects and underlying mechanisms of action of dexamethasone. Results: Dexamethasone administration facilitated SG function restoration, by increasing salivary gland weight and saliva volume while reducing saliva lag time. Histological evaluation revealed, reduced acinar cell atrophy and fibrosis with dexamethasone treatment. Additionally, dexamethasone suppressed pro-inflammatory cytokines IL-1ß and TNF expression. In a model of inflammation in salivary gland organoids induced by inflammatory substances, dexamethasone restored acinar markers such as AQP5 gene expression levels, while inhibiting pro-inflammatory cytokines TNF and IL6, as well as chemokines CCL2, CXCL5, and CXCL12 induction. Macrophages cultured in inflammatory substance-treated media from salivary gland organoid cultures exhibited pro-inflammatory polarization. However, treatment with dexamethasone shifted them towards an anti-inflammatory phenotype by reducing M1 markers (Tnf, Il6, Il1b, and Cd86) and elevating M2 markers (Ym1, Il10, Cd163, and Klf4). However, high-dose or prolonged dexamethasone treatment induced acino-ductal metaplasia and had side effects in both in vivo and in vitro models. Conclusions: Our findings suggest the effectiveness of corticosteroids in treating obstructive sialadenitis-induced salivary gland dysfunction by regulating pro-inflammatory cytokines.


Asunto(s)
Dexametasona , Factor 4 Similar a Kruppel , Sialadenitis , Animales , Dexametasona/farmacología , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Ratones , Sialadenitis/tratamiento farmacológico , Sialadenitis/patología , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Organoides/efectos de los fármacos , Citocinas/metabolismo , Ratones Endogámicos C57BL , Glándulas Salivales/efectos de los fármacos , Glándulas Salivales/patología , Glándulas Salivales/metabolismo , Glándulas Salivales/inmunología , Acuaporina 5/metabolismo , Acuaporina 5/genética , Masculino , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Células Acinares/efectos de los fármacos , Células Acinares/metabolismo , Células Acinares/patología , Humanos
18.
Food Sci Biotechnol ; 33(1): 129-144, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38186620

RESUMEN

Atopic dermatitis (AD) is an inflammatory skin disease showing skin barrier dysfunction, eczematous lesions, severe itching, and abnormal immune responses. The aim of this study was to determine whether an herb combination of Lithospermum erythrorhizon (LE), Houttuynia cordata (HC), and Spirodela polyrhiza (SP) has a superior anti-AD effect. Forty-two compounds were identified in LE, HC, SP, and a combined herb extract of LE, HC, and SP (LHS) using ultra-high-pressure liquid chromatography (UHPLC)-Orbitrap mass spectrometer (MS). The concentration of flavonoid glycosides including orientin (luteolin-8-C-glucoside), quercetin-3-O-rhamnoside, and luteolin-7-O-glucoside in the LHS was increased than in individual extracts. Furthermore, the treatment of LHS most effectively inhibited the increase of epidermal thickness, the number of mast cells, and the release of immunoglobulin E compared with that with each extract. These results suggest that the potential anti-AD effects of the LHS are due to the changes of bioactive compounds by the combination of herbs. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01329-7.

19.
Adv Sci (Weinh) ; 11(31): e2400596, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38887178

RESUMEN

Early-stage nonalcoholic fatty liver disease (NAFLD) is a silent condition, with most cases going undiagnosed, potentially progressing to liver cirrhosis and cancer. A non-invasive and cost-effective detection method for early-stage NAFLD detection is a public health priority but challenging. In this study, an adhesive, soft on-skin sensor with low electrode-skin contact impedance for early-stage NAFLD detection is fabricated. A method is developed to synthesize platinum nanoparticles and reduced graphene quantum dots onto the on-skin sensor to reduce electrode-skin contact impedance by increasing double-layer capacitance, thereby enhancing detection accuracy. Furthermore, an attention-based deep learning algorithm is introduced to differentiate impedance signals associated with early-stage NAFLD in high-fat-diet-fed low-density lipoprotein receptor knockout (Ldlr-/-) mice compared to healthy controls. The integration of an adhesive, soft on-skin sensor with low electrode-skin contact impedance and the attention-based deep learning algorithm significantly enhances the detection accuracy for early-stage NAFLD, achieving a rate above 97.5% with an area under the receiver operating characteristic curve (AUC) of 1.0. The findings present a non-invasive approach for early-stage NAFLD detection and display a strategy for improved early detection through on-skin electronics and deep learning.


Asunto(s)
Aprendizaje Profundo , Impedancia Eléctrica , Enfermedad del Hígado Graso no Alcohólico , Animales , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Ratones , Modelos Animales de Enfermedad , Diagnóstico Precoz , Ratones Noqueados , Humanos
20.
Sci Adv ; 10(7): eadj7481, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38354249

RESUMEN

Exercise promotes pulsatile shear stress in the arterial circulation and ameliorates cardiometabolic diseases. However, exercise-mediated metabolic transducers for vascular protection remain under-investigated. Untargeted metabolomic analysis demonstrated that wild-type mice undergoing voluntary wheel running exercise expressed increased endothelial stearoyl-CoA desaturase 1 (SCD1) that catalyzes anti-inflammatory lipid metabolites, namely, oleic (OA) and palmitoleic acids (PA), to mitigate NF-κB-mediated inflammatory responses. In silico analysis revealed that exercise augmented time-averaged wall shear stress but mitigated flow recirculation and oscillatory shear index in the lesser curvature of the mouse aortic arch. Following exercise, endothelial Scd1-deleted mice (Ldlr-/- Scd1EC-/-) on high-fat diet developed persistent VCAM1-positive endothelium in the lesser curvature and the descending aorta, whereas SCD1 overexpression via adenovirus transfection mitigated endoplasmic reticulum stress and inflammatory biomarkers. Single-cell transcriptomics of the aorta identified Scd1-positive and Vcam1-negative endothelial subclusters interacting with other candidate genes. Thus, exercise mitigates flow recirculation and activates endothelial SCD1 to catalyze OA and PA for vascular endothelial protection.


Asunto(s)
Aorta , Actividad Motora , Animales , Ratones , Aorta/metabolismo , Dieta Alta en Grasa , Endotelio Vascular/metabolismo , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo
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