RESUMEN
Terpenoids are the largest class of natural products, most of which are derived from plants. Amongst their numerous biological properties, their anti-tumor effects are of interest for they are extremely diverse which include anti-proliferative, apoptotic, anti-angiogenic, and anti-metastatic activities. Recently, several in vitro and in vivo studies have been dedicated to understanding the 'terpenoid induced autophagy' phenomenon in cancer cells. Light has already been shed on the intricacy of apoptosis and autophagy relationship. This latter crosstalk is driven by the delicate balance between activating or silencing of certain proteins whereby the outcome is expressed via interrelated signaling pathways. In this review, we focus on nine of the most studied terpenoids and on their cell death and autophagic activity. These terpenoids are grouped in three classes: sesquiterpenoid (artemisinin, parthenolide), diterpenoids (oridonin, triptolide), and triterpenoids (alisol, betulinic acid, oleanolic acid, platycodin D, and ursolic acid). We have selected these nine terpenoids among others as they belong to the different major classes of terpenoids and our extensive search of the literature indicated that they were the most studied in terms of autophagy in cancer. These terpenoids alone demonstrate the complexity by which these secondary metabolites induce autophagy via complex signaling pathways such as MAPK/ERK/JNK, PI3K/AKT/mTOR, AMPK, NF-kB, and reactive oxygen species. Moreover, induction of autophagy can be either destructive or protective in tumor cells. Nevertheless, should this phenomenon be well understood, we ought to be able to exploit it to create novel therapies and design more effective regimens in the management and treatment of cancer.
Asunto(s)
Apoptosis , Fosfatidilinositol 3-Quinasas , Autofagia , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-akt , Terpenos/farmacologíaRESUMEN
Oxidative damage by reactive oxygen species (ROS) is one of the main contributors to cell injury and tissue damage in thalassemia patients. Recent studies suggest that ROS generation in non-transfusion-dependent (NTDT) patients occurs as a result of iron overload. Among the different sources of ROS, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes and cytochrome P450 (CYP450) have been proposed to be major contributors for oxidative stress in several diseases. However, the sources of ROS in patients with NTDT remain poorly understood. In this study, Hbbth3/+ mice, a mouse model for ß-thalassemia, were used. These mice exhibit an unchanged or decreased expression of the major NOX isoforms, NOX1, NOX2 and NOX4, when compared to their C57BL/6 control littermates. However, a significant increase in the protein synthesis of CYP4A and CYP4F was observed in the Hbbth3/+ mice when compared to the C57BL/6 control mice. These changes were paralleled by an increased production of 20-hydroxyeicosatetraenoic acid (20-HETE), a CYP4A and CYP4F metabolite. Furthermore, these changes corroborate with onset of ROS production concomitant with liver injury. To our knowledge, this is the first report indicating that CYP450 4A and 4F-induced 20-HETE production mediates reactive oxygen species overgeneration in Hbbth3/+ mice through an NADPH-dependent pathway.
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Familia 4 del Citocromo P450/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Talasemia beta/metabolismo , Animales , Modelos Animales de Enfermedad , Hepatitis/etiología , Hepatitis/patología , Hierro/metabolismo , Isoenzimas/metabolismo , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasas/metabolismo , Talasemia beta/complicaciones , Talasemia beta/patologíaRESUMEN
Diabetic kidney disease is one of the most serious complications of diabetes worldwide and is the leading cause of end-stage renal disease. While research has primarily focused on hyperglycemia as a key player in the pathophysiology of diabetic complications, recently, increasing evidence have underlined the role of adipose inflammation in modulating the development and/or progression of diabetic kidney disease. This review focuses on how adipose inflammation contribute to diabetic kidney disease. Furthermore, it discusses in detail the underlying mechanisms of adipose inflammation, including pro-inflammatory cytokines, oxidative stress, and AMPK/mTOR signaling pathway and critically describes their role in diabetic kidney disease. This in-depth understanding of adipose inflammation and its impact on diabetic kidney disease highlights the need for novel interventions in the treatment of diabetic complications.
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Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo/patología , Inflamación/patología , Riñón/lesiones , NADPH Oxidasa 4/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , HumanosRESUMEN
Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic interventions. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a promising class of drugs, with evidence demonstrating that they can improve renal outcomes in people with diabetes. However, the exact mechanism by which SGLT2i exert their renoprotective effects is not yet fully understood. This study demonstrates that dapagliflozin treatment attenuates renal injury observed in type 2 diabetic mice. This is evidenced by the reduction in renal hypertrophy and proteinuria. Furthermore, dapagliflozin decreases tubulointerstitial fibrosis and glomerulosclerosis by mitigating the generation of reactive oxygen species and inflammation, which are activated through the production of CYP4A-induced 20-HETE. Our findings provide insights onto a novel mechanistic pathway by which SGLT2i exerts their renoprotective effects. Overall, and to our knowledge, the study provides critical insights into the pathophysiology of DKD and represents an important step towards improving outcomes for people with this devastating condition.
RESUMEN
Diabetes is associated with decreased epoxyeicosatrienoic acid (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of the VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the cross talk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of the VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced reactive oxygen species production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4. ARTICLE HIGHLIGHTS: Diabetes is associated with an alteration in cytochrome P450 2C11 (CYP2C11)-derived epoxyeicosatrienoic acid (EET) bioavailability. Decreased CYP2C11-derived EET bioavailability mediates hyperglycemia-induced glomerular injury. Decreased CYP2C11-derived EET bioavailability is associated with increased reactive oxygen species production, NADPH oxidase activity, and Nox4 expression in type 1 diabetes. Decreased CYP2C11-derived EET formation mediates hyperglycemia-induced glomerular injury through the activation of the vascular endothelial growth factor A (VEGF-A) signaling pathway. Inhibiting VEGF signaling using anti-VEGF or SU5416 attenuates type 1 diabetes-induced glomerular injury by decreasing NADPH oxidase activity and NOX4 expression.
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Diabetes Mellitus Tipo 1 , Nefropatías Diabéticas , Hiperglucemia , Ratas , Animales , Humanos , Factor A de Crecimiento Endotelial Vascular , Especies Reactivas de Oxígeno/metabolismo , Sistema Enzimático del Citocromo P-450 , NADPH Oxidasa 4/genéticaRESUMEN
This work introduces novel body-matched, vasculature-inspired, quasi-antenna-arrays that act as electromagnetic sensors to instantaneously, continuously, and wirelessly sense glucose variations in the bloodstream. The proposed sensors are personalized, leverage electromagnetic waves, and are coupled with a custom machine-learning-based signal-processing module. These sensors are flexible, and embedded in wearable garments such as socks, which provide conformity to curved skin surfaces and movement resilience. The entire wearable system is calibrated against temperature, humidity, and movement resulting in high accuracy in glucose variations tracking. In-Vivo experiments on diabetic rats and pigs exhibit a 100% diagnostic accuracy over a wide range of glucose variations. Human trials on patients with diabetes and healthy individuals reveal a clinical accuracy of continuous glucose monitoring of 99.01% in twenty-eight subjects who underwent Oral Glucose Tolerance Tests. Hence, our approach ensures the continuous tracking of glucose variations from hypo-to-hyper glycemic levels with great fidelity.
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Diabetes Mellitus Experimental , Dispositivos Electrónicos Vestibles , Animales , Glucemia , Automonitorización de la Glucosa Sanguínea , Fenómenos Electromagnéticos , Glucosa , Humanos , Monitoreo Fisiológico/métodos , Ratas , PorcinosRESUMEN
Diabetic cardiomyopathy (DCM) is a well-established complication of type 1 and type 2 diabetes associated with a high rate of morbidity and mortality. DCM is diagnosed at advanced and irreversible stages. Therefore, it is of utmost need to identify novel mechanistic pathways involved at early stages to prevent or reverse the development of DCM. In vivo experiments were performed on type 1 diabetic rats (T1DM). Functional and structural studies of the heart were executed and correlated with mechanistic assessments exploring the role of cytochromes P450 metabolites, the 20-hydroxyeicosatetraenoic acids (20-HETEs) and epoxyeicosatrienoic acids (EETs), and their crosstalk with other homeostatic signaling molecules. Our data displays that hyperglycemia results in CYP4A upregulation and CYP2C11 downregulation in the left ventricles (LV) of T1DM rats, paralleled by a differential alteration in their metabolites 20-HETEs (increased) and EETs (decreased). These changes are concomitant with reductions in cardiac outputs, LV hypertrophy, fibrosis, and increased activation of cardiac fetal and hypertrophic genes. Besides, pro-fibrotic cytokine TGF-ß overexpression and NADPH (Nox4) dependent-ROS overproduction are also correlated with the observed cardiac functional and structural modifications. Of interest, these observations are attenuated when T1DM rats are treated with 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA), which blocks EETs metabolism, or N-hydroxy-N'-(4-butyl-2-methylphenol)Formamidine (HET0016), which inhibits 20-HETEs formation. Taken together, our findings confer pioneering evidence about a potential interplay between CYP450-derived metabolites and Nox4/TGF-ß axis leading to DCM. Pharmacologic interventions targeting the inhibition of 20-HETEs synthesis or the activation of EETs synthesis may offer novel therapeutic approaches to treat DCM.
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Ácido Araquidónico/metabolismo , Cardiomiopatías/etiología , Sistema Enzimático del Citocromo P-450/fisiología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Ácidos Hidroxieicosatetraenoicos/fisiología , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animales , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/metabolismo , Ácidos Hidroxieicosatetraenoicos/antagonistas & inhibidores , Masculino , NADPH Oxidasa 4/fisiología , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , EstreptozocinaRESUMEN
Clinical studies showed that dextran sulfate sodium (DSS) alleviates stroke, diabetic retinopathy and hypercholesterolemia, yet its mechanism of action was unrevealed. This study show that DSS reduces hyperglycemia, plasma insulin and enhances glucose utilization by attenuating ROS production, suggesting a novel therapeutic use of DSS in diabetes and its complication.
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Sulfato de Dextran/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Animales , Sulfato de Dextran/farmacología , Humanos , Hipoglucemiantes/farmacología , Masculino , RatonesRESUMEN
Painless, needle-free, and continuous glucose monitoring sensors are needed to enhance the life quality of diabetic patients. To that extent, we propose a first-of-its-kind, highly sensitive, noninvasive continuous glycemic monitoring wearable multisensor system. The proposed sensors are validated on serum, animal tissues, and animal models of diabetes and in a clinical setting. The noninvasive measurement results during human trials reported high correlation (>0.9) between the system's physical parameters and blood glucose levels, without any time lag. The accurate real-time responses of the sensors are attributed to their unique vasculature anatomy-inspired tunable electromagnetic topologies. These wearable apparels wirelessly sense hypo- to hyperglycemic variations with high fidelity. These components are designed to simultaneously target multiple body locations, which opens the door for the development of a closed-loop artificial pancreas.
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Diabetes Mellitus , Dispositivos Electrónicos Vestibles , Animales , Glucemia , Automonitorización de la Glucosa Sanguínea/métodos , Diabetes Mellitus/diagnóstico , Humanos , Monitoreo FisiológicoRESUMEN
Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.
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Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Neuropatías Diabéticas/metabolismo , Receptores X del Hígado/metabolismo , NADPH Oxidasa 4/metabolismo , Células de Schwann/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Neuropatías Diabéticas/etiología , Femenino , Humanos , Hidrocarburos Fluorados/farmacología , Receptores X del Hígado/agonistas , Masculino , Ratones , Proteínas de la Mielina/genética , NADPH Oxidasa 4/antagonistas & inhibidores , Pirazoles/farmacología , Pirazolonas , Piridinas/farmacología , Piridonas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Sulfonamidas/farmacologíaRESUMEN
Traumatic brain injury is a detrimental medical condition particularly when accompanied by diabetes. There are several comorbidities going along with diabetes including, but not limited to, kidney failure, obesity, coronary artery disease, peripheral vascular disease, hypertension, stroke, neuropathies and amputations. Unlike diabetes type 1, diabetes type 2 is more common in adults who simultaneously suffer from other comorbid conditions making them susceptible to repetitive fall incidents and sustaining head trauma. The resulting brain insult exacerbates current psychiatric disorders such as depression and anxiety, which, in turn, increases the risk of sustaining further brain traumas. The relationship between diabetes, traumatic brain injury and psychiatric health constitutes a triad forming a non-reversible vicious cycle. At the proteomic and psychiatric levels, cellular, molecular and behavioral alterations have been reported with the induction of non-traumatic brain injury in diabetic models such as stroke. However, research into traumatic brain injury has not been systematically investigated. Thus, in cases of diabetic neuropathy complicated with traumatic brain injury, utilizing fine structural and analytical techniques allows the identification of key biological markers that can then be used as innovative diagnostics as well as novel therapeutic targets in an attempt to treat diabetes and its sequelae especially those arising from repetitive mild brain trauma.