RESUMEN
C-peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C-peptide serves an anti-inflammatory and anti-atherogenic role in type 1 diabetes mellitus (T1DM) and early T2DM. C-peptide protects endothelial cells by activating AMP-activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia-induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase-3 activity and promoting expression of B-cell lymphoma-2. Additionally, C-peptide suppresses platelet-derived growth factor (PDGF)-beta receptor and p44/p42 mitogen-activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF-kB) signaling, a major pro-inflammatory cascade. Consequently, it is envisaged that supplementation of C-peptide in T1DM might ameliorate or even prevent end-organ damage. In marked contrast, C-peptide increases monocyte recruitment and migration through phosphoinositide 3-kinase (PI-3 kinase)-mediated pathways, induces lipid accumulation via peroxisome proliferator-activated receptor γ upregulation, and stimulates VSMC proliferation and CD4+ lymphocyte migration through Src-kinase and PI-3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C-peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C-peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications.
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Péptido C , Humanos , Péptido C/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Transducción de SeñalRESUMEN
The cardiovascular and renovascular complications of metabolic deterioration are associated with localized adipose tissue dysfunction. We have previously demonstrated that metabolic impairment delineated the heightened vulnerability of both the perivascular (PVAT) and perirenal adipose tissue (PRAT) depots to hypoxia and inflammation, predisposing to cardioautonomic, vascular and renal deterioration. Interventions either addressing underlying metabolic disturbances or halting adipose tissue dysfunction rescued the observed pathological and functional manifestations. Several lines of evidence implicate adipose tissue thromboinflammation, which entails the activation of the proinflammatory properties of the blood clotting cascade, in the pathogenesis of metabolic and cardiovascular diseases. Despite offering valuable tools to interrupt the thromboinflammatory cycle, there exists a significant knowledge gap regarding the potential pleiotropic effects of anticoagulant drugs on adipose inflammation and cardiovascular function. As such, a systemic investigation of the consequences of PVAT and PRAT thromboinflammation and its interruption in the context of metabolic disease has not been attempted. Here, using an established prediabetic rat model, we demonstrate that metabolic disturbances are associated with PVAT and PRAT thromboinflammation in addition to cardioautonomic, vascular and renal functional decline. Administration of rivaroxaban, a FXa inhibitor, reduced PVAT and PRAT thromboinflammation and ameliorated the cardioautonomic, vascular and renal deterioration associated with prediabetes. Our present work outlines the involvement of PVAT and PRAT thromboinflammation during early metabolic derangement and offers novel perspectives into targeting adipose tissue thrombo-inflammatory pathways for the management its complications in future translational efforts.
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Estado Prediabético , Trombosis , Enfermedades Vasculares , Ratas , Animales , Tromboinflamación , Inflamación/patología , Trombosis/metabolismo , Enfermedades Vasculares/metabolismo , Tejido Adiposo/metabolismoRESUMEN
As a new approach to the management of inflammatory disorders, a series of chromone-based derivatives containing a (carbamate)hydrazone moiety was designed and synthesized. The compounds were assessed for their ability to inhibit COX-1/2, 15-LOX, and mPGES-1, as a combination that should effectively impede the arachidonate pathway. Results revealed that the benzylcarbazates (2a-c) demonstrated two-digit nanomolar COX-2 inhibitory activities with reasonable selectivity indices. They also showed appreciable 15-LOX inhibition, in comparison to quercetin. Further testing of these compounds for mPGES-1 inhibition displayed promising activities. Intriguingly, compounds 2a-c were capable of suppressing edema in the formalin-induced rat paw edema assay. They exhibited an acceptable gastrointestinal safety profile regarding ulcerogenic liabilities in gross and histopathological examinations. Additionally, upon treatment with the test compounds, the expression of the anti-inflammatory cytokine IL-10 was elevated, whereas that of TNF-α, iNOS, IL-1ß, and COX-2 were downregulated in LPS-challenged RAW264.7 macrophages. Docking experiments into the three enzymes showed interesting binding profiles and affinities, further substantiating their biological activities. Their in silico physicochemical and pharmacokinetic parameters were advantageous.
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Antiinflamatorios , Inhibidores de la Lipooxigenasa , Ratas , Animales , Ciclooxigenasa 2/metabolismo , Inhibidores de la Lipooxigenasa/química , Ciclooxigenasa 1/metabolismo , Antiinflamatorios/farmacología , Ácidos Araquidónicos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Araquidonato 5-Lipooxigenasa/metabolismo , Relación Estructura-ActividadRESUMEN
AIMS: Prostate cancer is among the highest incidence malignancies in men with a prevalence rate increasing in parallel to the rising global trends in metabolic disorders. Whereas a sizeable body of evidence links metabolic impairment to negative prognosis of prostate cancer, the molecular mechanism underlying this connection has not been thoroughly examined. Our previous work showed that localized adipose tissue inflammation occurring in select adipose depots in early metabolic derangement instigated significant molecular, structural, and functional alterations in neighboring tissues underlying the complications observed at this stage. In this context, the periprostatic adipose tissue (PPAT) constitutes an understudied microenvironment with potential influence on the prostatic milieu. MAIN METHODS AND RESULTS: We show that PPAT inflammation occurs in early prediabetes with signs of increased thrombogenic activity including enhanced expression and function of Factor X. This was mirrored by early neoplastic alterations in the prostate with fibrosis, increased epithelial thickness with marked luminal cellular proliferation and enhanced formation of intraepithelial neoplasia. Significantly, interruption of the procoagulant state in PPAT by a 10-day anticoagulant rivaroxaban treatment not only mitigated PPAT inflammation, but also reduced signs of prostatic neoplastic changes. Moreover, rivaroxaban decreased the murine PLum-AD epithelial prostatic cell viability, proliferation, migration, and colony forming capacity, while increasing oxidative stress. A protease-activated receptor-2 agonist reversed some of these effects. SIGNIFICANCE: We provide some evidence of a molecular framework for the crosstalk between PPAT and prostatic tissue leading to early neoplastic changes in metabolic impairment mediated by upregulation of PPAT thromboinflammation.
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Neoplasias de la Próstata , Trombosis , Masculino , Humanos , Animales , Ratones , Rivaroxabán/farmacología , Rivaroxabán/metabolismo , Tromboinflamación , Inflamación/patología , Trombosis/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Tejido Adiposo/metabolismo , Microambiente TumoralRESUMEN
ABSTRACT: Raynaud's phenomenon, which results from exaggerated cold-induced vasoconstriction, is more prevalent in females than males. We previously showed that estrogen increases the expression of alpha 2C-adrenoceptors (α 2C -AR), the sole mediator of cold-induced vasoconstriction. This effect of estrogen is reproduced by the cell-impermeable form of the hormone (E 2 :bovine serum albumin [BSA]), suggesting a role of the membrane estrogen receptor, G-protein-coupled estrogen receptor [GPER], in E 2 -induced α 2C -AR expression. We also previously reported that E 2 upregulates α 2C -AR in microvascular smooth muscle cells (VSMCs) via the cAMP/Epac/Rap/JNK/AP-1 pathway, and that E 2 :BSA elevates cAMP levels. We, therefore, hypothesized that E 2 uses GPER to upregulate α 2C -AR through the cAMP/Epac/JNK/AP-1 pathway. Our results show that G15, a selective GPER antagonist, attenuates the E 2 -induced increase in α 2C -AR transcription. G-1, a selective GPER agonist, induced α 2C -AR transcription, which was concomitant with elevated cAMP levels and JNK activation. Pretreatment with ESI09, an Epac inhibitor, abolished G-1-induced α 2C -AR upregulation and JNK activation. Moreover, pretreatment with SP600125, a JNK-specific inhibitor, but not H89, a PKA-specific inhibitor, abolished G-1-induced α 2C -AR upregulation. In addition, transient transfection of an Epac dominant negative mutant (Epac-DN) attenuated G-1-induced activation of the α 2C -AR promoter. This inhibitory effect of Epac-DN on the α 2C -AR promoter was overridden by the cotransfection of constitutively active JNK mutant. Furthermore, mutation of AP-1 site in the α 2C -AR promoter abrogated G1-induced expression. Collectively, these results indicate that GPER upregulates α 2C -AR through the cAMP/EPAC/JNK/AP-1 pathway. These findings unravel GPER as a new mediator of cold-induced vasoconstriction, and present it as a potential target for treating Raynaud's phenomenon in estrogen-replete females.
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Transducción de Señal , Humanos , AMP Cíclico/metabolismo , Estrógenos/farmacología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Factores de Intercambio de Guanina Nucleótido/farmacología , Miocitos del Músculo Liso/metabolismo , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Adrenérgicos/metabolismoRESUMEN
Cardiovascular complications of diabetes and obesity remain a major cause for morbidity and mortality worldwide. Despite significant advances in the pharmacotherapy of metabolic disease, the available approaches do not prevent or slow the progression of complications. Moreover, a majority of patients present with significant vascular involvement at early stages of dysfunction prior to overt metabolic changes. The lack of disease-modifying therapies affects millions of patients globally, causing a massive economic burden due to these complications. Significantly, adipose tissue inflammation was implicated in the pathogenesis of metabolic syndrome, diabetes, and obesity. Specifically, perivascular adipose tissue (PVAT) and perirenal adipose tissue (PRAT) depots influence cardiovascular and renal structure and function. Accumulating evidence implicates localized PVAT/PRAT inflammation as the earliest response to metabolic impairment leading to cardiorenal dysfunction. Increased mitochondrial uncoupling protein 1 (UCP1) expression and function lead to PVAT/PRAT hypoxia and inflammation as well as vascular, cardiac, and renal dysfunction. As UCP1 function remains an undruggable target so far, modulation of the augmented UCP1-mediated PVAT/PRAT thermogenesis constitutes a lucrative target for drug development to mitigate early cardiorenal involvement. This can be achieved either by subtle targeted reduction in UCP-1 expression using innovative proteolysis activating chimeric molecules (PROTACs) or by supplementation with cyclocreatine phosphate, which augments the mitochondrial futile creatine cycling and thus decreases UCP1 activity, enhances the efficiency of oxygen use, and reduces hypoxia. Once developed, these molecules will be first-in-class therapeutic tools to directly interfere with and reverse the earliest pathology underlying cardiac, vascular, and renal dysfunction accompanying the early metabolic deterioration. SIGNIFICANCE STATEMENT: Adipose tissue dysfunction plays a major role in the pathogenesis of metabolic diseases and their complications. Although mitochondrial alterations are common in metabolic impairment, it was only recently shown that the early stages of metabolic challenge involve inflammatory changes in select adipose depots associated with increased uncoupling protein 1 thermogenesis and hypoxia. Manipulating this mode of thermogenesis can help mitigate the early inflammation and the consequent cardiorenal complications.
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Tejido Adiposo Pardo , Enfermedades Renales , Humanos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/patología , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Obesidad/complicaciones , Obesidad/metabolismo , Termogénesis , Inflamación/complicaciones , Inflamación/metabolismo , Hipoxia/metabolismo , Hipoxia/patología , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Proteína Desacopladora 1/metabolismoRESUMEN
Pomegranate juice concentrate (PJC) is a rich source of polyphenols, which exhibit significant antioxidant activity and potential health benefits for disease prevention and therapy. In this study, the polyphenolic profile of PJC was investigated for the first time, and it was found that PJC can inhibit oxidative damage to bovine serum albumin (BSA) and deoxyribonucleic acid (DNA), as well as acetylcholinesterase, α-amylase, and tyrosinase activities. The primary polyphenols identified in PJC were 4-Hydroxy-3-Methoxybenzoate, epicatechin, catechin, rutin, ferulic acid, P-coumaric acid, and cinnamic acid. Additionally, PJC demonstrated potent antibacterial effects against human pathogens such as Streptococcus mutans and Aeromonas hydrophila and dose-dependently reduced the proliferation of colorectal, breast, and hepatic cancer cells via apoptosis. Furthermore, PJC blocked B-cell lymphoma 2 (BCl-2) and the expression of a potent cyclin-dependent kinase inhibitor (P21) and enhanced tumor protein (P53) expression, compared to both untreated cells and cells treated with fluoropyrimidine 5-fluorouracil (5-FU). As a result, PJC may be a beneficial ingredient in the formulation of emerging natural-compound-based chemotherapy and functional foods and could be utilized by the food, nutraceutical, and pharmaceutical industries.
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Antiinfecciosos , Granada (Fruta) , Humanos , Antioxidantes/farmacología , Acetilcolinesterasa , Polifenoles/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , AntiinflamatoriosRESUMEN
Palm fruit pollen extract (PFPE) is a natural source of bioactive polyphenols. The primary aim of the study was to determine the antioxidant, antimicrobial, anticancer, enzyme inhibition, bovine serum albumin (BSA), and DNA-protective properties of PFPE and identify and quantify the phenolic compounds present in PFPE. The results demonstrated that PFPE exhibited potent antioxidant activity in various radical-scavenging assays, including (2,2-diphenyl-1-picrylhydrazyl) (DPPHâ¢), 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTSâ¢), nitric oxide (NO), ferric-reducing/antioxidant power (FRAP), and total antioxidant capacity (TAC). PFPE also displayed antimicrobial activity against several pathogenic bacteria. Similarly, PFPE reduced acetylcholinesterase, tyrosinase, and α-amylase activities. PFPE has been proven to have an anticancer effect against colon carcinoma (Caco-2), hepatoma (HepG-2), and breast carcinoma (MDA) cancer cells. Apoptosis occurred in PFPE-treated cells in a dose-dependent manner, and cell cycle arrest was observed. Furthermore, in breast cancer cells, PFPE down-regulated Bcl-2 and p21 and up-regulated p53 and Caspase-9. These results show that PFPE constitutes a potential source of polyphenols for pharmaceutical, nutraceutical, and functional food applications.
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Neoplasias , Phoeniceae , Humanos , Antioxidantes/farmacología , Frutas/química , Acetilcolinesterasa , Células CACO-2 , Extractos Vegetales/farmacología , Polifenoles/farmacología , Polifenoles/análisis , ADN , Neoplasias/tratamiento farmacológicoRESUMEN
Structural modifications of the antibacterial drug nitrofurantoin were envisioned, employing drug repurposing and biology-oriented drug synthesis, to serve as possible anticancer agents. Eleven compounds showed superior safety in non-cancerous human cells. Their antitumor efficacy was assessed on colorectal, breast, cervical, and liver cancer cells. Three compounds induced oxidative DNA damage in cancer cells with subsequent cellular apoptosis. They also upregulated the expression of Bax while downregulated that of Bcl-2 along with activating caspase 3/7. The DNA damage induced by these compounds, demonstrated by pATM nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53 mutant) cell lines. Mechanistic studies confirmed the dependence of these compounds on p53-mediated pathways as they suppressed the p53-MDM2 interaction. Indeed, exposure of radiosensitive prostatic cancer cells to low non-cytotoxic concentrations of compound 1 enhanced the cytotoxic response to radiation indicating a possible synergistic effect. In vivo antitumor activity was verified in an MCF7-xenograft animal model.
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Antineoplásicos , Neoplasias de la Mama , Animales , Humanos , Femenino , Nitrofurantoína/farmacología , Proteína p53 Supresora de Tumor/genética , Reposicionamiento de Medicamentos , Proliferación Celular , Apoptosis , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Biología , Línea Celular TumoralRESUMEN
Background: Little research addressed deprescribing-focused medication optimization interventions while utilizing implementation science. This study aimed to develop a pharmacist-led medication review service with a deprescribing focus in a care facility serving patients of low income receiving medications for free in Lebanon followed by an assessment of the recommendations' acceptance by prescribing physicians. As a secondary aim, the study evaluates the impact of this intervention on satisfaction compared to satisfaction associated with receiving routine care. Methods: The Consolidated Framework for Implementation Research (CFIR) was used to address implementation barriers and facilitators by mapping its constructs to the intervention implementation determinants at the study site. After filling medications and receiving routine pharmacy service at the facility, patients 65 years or older and taking 5 or more medications, were assigned into two groups. Both groups of patients received the intervention. Patient satisfaction was assessed right after receiving the intervention (intervention group) or just before the intervention (control group). The intervention consisted of an assessment of patient medication profiles before addressing recommendations with attending physicians at the facility. Patient satisfaction with the service was assessed using a validated translated version of the Medication Management Patient Satisfaction Survey (MMPSS). Descriptive statistics provided data on drug-related problems, the nature and the number of recommendations as well as physicians' responses to recommendations. Independent sample t-tests were used to assess the intervention's impact on patient satisfaction. Results: Of 157 patients meeting the inclusion criteria, 143 patients were enrolled: 72 in the control group and 71 in the experimental group. Of 143 patients, 83% presented drug-related problems (DRPs). Further, 66% of the screened DRPs met the STOPP/START criteria (77%, and 23% respectively). The intervention pharmacist provided 221 recommendations to physicians, of which 52% were to discontinue one or more medications. Patients in the intervention group showed significantly higher satisfaction compared to the ones in the control group (p < 0.001, effect size = 1.75). Of those recommendations, 30% were accepted by the physicians. Conclusion: Patients showed significantly higher satisfaction with the intervention they received compared to routine care. Future work should assess how specific CFIR constructs contribute to the outcomes of deprescribing-focused interventions.
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AIMS: Traumatic brain injury (TBI) constitutes a serious public health concern. Although TBI targets the brain, it can exert several systemic effects which can worsen the complications observed in TBI subjects. Currently, there is no FDA-approved therapy available for its treatment. Thus, there has been an increasing need to understand other factors that could modulate TBI outcomes. Among the factors involved are diet and lifestyle. High-fat diets (HFD), rich in saturated fat, have been associated with adverse effects on brain health. MAIN METHODS: To study this phenomenon, an experimental mouse model of open head injury, induced by the controlled cortical impact was used along with high-fat feeding to evaluate the impact of HFD on brain injury outcomes. Mice were fed HFD for a period of two months where several neurological, behavioral, and molecular outcomes were assessed to investigate the impact on chronic consequences of the injury 30 days post-TBI. KEY FINDINGS: Two months of HFD feeding, together with TBI, led to a notable metabolic, neurological, and behavioral impairment. HFD was associated with increased blood glucose and fat-to-lean ratio. Spatial learning and memory, as well as motor coordination, were all significantly impaired. Notably, HFD aggravated neuroinflammation, oxidative stress, and neurodegeneration. Also, cell proliferation post-TBI was repressed by HFD, which was accompanied by an increased lesion volume. SIGNIFICANCE: Our research indicated that chronic HFD feeding can worsen functional outcomes, predispose to neurodegeneration, and decrease brain recovery post-TBI. This sheds light on the clinical impact of HFD on TBI pathophysiology and rehabilitation as well.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Lesiones Traumáticas del Encéfalo/complicaciones , Encéfalo/metabolismo , Lesiones Encefálicas/complicaciones , Ratones Endogámicos C57BLRESUMEN
Cardiometabolic diseases present an escalating global health and economic burden. Such a surge is driven by epidemic prevalence rates of metabolic disorders, such as obesity and type 2 diabetes, and their associated cardiovascular complications, majorly contributing to morbidity and mortality. A fundamental challenge impeding the effective management and therapy of these complications is a lack of clear understanding of the molecular mechanisms underpinning disease initiation and progression. Over the past decade, a role for metabolic disease-associated adipose tissue dysfunction and inflammation in evoking cardiovascular and renal deterioration emerged, together with a growing recognition of the positive impact of pharmacological tools modulating adipose tissue function. Adipose tissue is a plastic endocrine organ whose homeostasis is essentially dependent on the intercellular communication of its comprising cellular components. Yet, despite being a principal regulator of adipose tissue metabolic activity, changes in aspects of adipose tissue mitochondrial biogenesis, dynamics, and bioenergetics in the context of cardiometabolic disorders have not garnered the necessary attention. Here, we gather the available evidence on the contribution of mitochondrial dysfunction to that of the adipose tissue in metabolic diseases, and to the ensuing cardiovascular deterioration. The involved molecular pathways are highlighted together with potential targets for intervention. The effects of several drug classes with known beneficial impact on adipose tissue remodeling and mitochondrial dysfunction in such a context are discussed. Finally, future research aspects in this domain are explored.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Tejido Adiposo/metabolismo , Obesidad/metabolismo , Enfermedades Cardiovasculares/metabolismo , Mitocondrias/metabolismoRESUMEN
Sodium-glucose transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 (GLP-1) receptor agonists are newer antidiabetic drug classes, which were recently shown to decrease cardiovascular (CV) morbidity and mortality in diabetic patients. CV benefits of these drugs could not be directly attributed to their blood glucose lowering capacity possibly implicating a pleotropic effect as a mediator of their impact on cardiovascular disease (CVD). Particularly, preclinical and clinical studies indicate that SGLT-2i(s) and GLP-1 receptor agonists are capable of differentially modulating distinct adipose pools reducing the accumulation of fat in some depots, promoting the healthy expansion of others, and/or enhancing their browning, leading to the suppression of the metabolically induced inflammatory processes. These changes are accompanied with improvements in markers of cardiac structure and injury, coronary and vascular endothelial healing and function, vascular remodeling, as well as reduction of atherogenesis. Here, through a summary of the available evidence, we bring forth our view that the observed CV benefit in response to SGLT-2i or GLP-1 agonists therapy might be driven by their ameliorative impact on adipose tissue inflammation.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Enfermedades Metabólicas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/efectos adversos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/complicaciones , Enfermedades Metabólicas/tratamiento farmacológico , Tejido Adiposo/metabolismo , Péptido 1 Similar al GlucagónRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is an important health threat that is strongly linked to components of metabolic syndrome, particularly the low-grade inflammatory changes. Significantly, several of the available anti-diabetic drug classes demonstrate a considerable anti-inflammatory effect, and hence might be of benefit for NAFLD patients. In this study, we used a rat model of diet-induced NAFLD to examine the potential effect of metformin, pioglitazone, dapagliflozin and their combinations on NAFLD manifestations. Rats were fed an atherogenic diet containing 1.25 % cholesterol, 0.5 % cholic acid and 60 % cocoa butter for 6 weeks causing a number of metabolic and hepatic alterations including insulin resistance, dyslipidemia, systemic inflammation, increased hepatic oxidative stress and lipid peroxidation, hepatic steatosis, lobular inflammation, as well as increased markers of liver inflammation and hepatocyte apoptosis. Drug treatment, which started at the third week of NAFLD induction and continued for three weeks, not only ameliorated the observed metabolic impairment, but also functional and structural manifestations of NAFLD. Specifically, anti-diabetic drug treatment reversed markers of systemic and hepatic inflammation, oxidative stress, hepatic fibrosis, and hepatocyte apoptosis. Our findings propose that anti-diabetic drugs with a potential anti-inflammatory effect can ameliorate the manifestations of NAFLD, and thus may provide a therapeutic option for such a condition that is closely associated with metabolic diseases. The detailed pharmacology of these classes in aspects linked to the observed impact on NAFLD requires to be further investigated and translated into clinical studies for tailored therapy specifically targeting NAFLD.
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Resistencia a la Insulina , Metformina , Enfermedad del Hígado Graso no Alcohólico , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/metabolismo , Antioxidantes/farmacología , Compuestos de Bencidrilo , Biomarcadores/metabolismo , Colesterol/metabolismo , Ácido Cólico/metabolismo , Ácido Cólico/farmacología , Dieta Alta en Grasa/efectos adversos , Fibrosis , Glucósidos , Inflamación/metabolismo , Hígado/metabolismo , Metformina/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Pioglitazona/metabolismo , Pioglitazona/farmacología , RatasRESUMEN
Cardiovascular disease (CVD) continues to be the primary cause of global mortality. Vascular smooth muscle cells (VSMCs) are integral components of vascular structure and function, evident by their vital roles in modulating blood flow and pressure. Such roles exist due to the differentiated contractile phenotype of VSMCs. However, VSMCs may switch to a dedifferentiated, proliferative synthetic phenotype in a phenomenon known as phenotypic switching. This switch involves dramatic changes in VSMC migration, proliferation, gene expression programs, differentiation, cellular stiffness and extracellular matrix (ECM) deposition. In this review, we explore the role of the small GTPase Rho and its effector, Rho-associated kinase (ROCK), in phenotypic switching as well as apoptotic pathways in VSMCs. We critically dissect how RhoA promotes cell migration and proliferation as well as its role in modulating the expression of a battery of VSMC marker proteins. We also discuss how RhoA modulates apoptosis, induces dedifferentiation, increases vascular stiffness, or modifies ECM accumulation. These alterations in VSMC phenotypes contribute to multiple vascular dysfunctions, including hypertension and atherosclerosis. Understanding the molecular underpinnings and the signaling pathways involved in these altered phenotypes may provide novel avenues of drug design and other therapeutic interventions for the management of CVDs.
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Músculo Liso Vascular , Quinasas Asociadas a rho , Proliferación Celular , Células Cultivadas , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Fenotipo , Quinasas Asociadas a rho/metabolismoRESUMEN
Diabetic patients present established cardiovascular disease at the onset of diagnostic metabolic symptoms. While premature autonomic and vascular deterioration considered risk factors for major cardiovascular complications of diabetes, present in initial stages of metabolic impairment, their early detection remains a significant challenge impeding timely intervention. In the present study, we examine the utility of beat-to-beat blood pressure variability (BPV) parameters in capturing subtle changes in cardiac autonomic and vascular control distinguishing between various risk categories, independent of the average BP. A rat model of mild hypercaloric (HC) intake was used to represent the insidious cardiovascular changes associated with early metabolic impairment. Invasive hemodynamics were used to collect beat-to-beat BP time series in rats of either sex with different durations of exposure to the HC diet. Linear (standard deviation and coefficient of variation) and nonlinear (approximate entropy, ApEn, and self-correlation of detrended fluctuation analysis, α) BPV parameters were calculated to assess the impact of early metabolic impairment across sexes and feeding durations. HC-fed male, but not female, rats developed increased fat:lean ratio as well as hyperinsulinemia. Unlike linear parameters, multivariate analysis showed that HC-fed rats possessed lower ApEn and higher α, consistent with early changes in heart rate variability and blunting of parasympathetic baroreceptor sensitivity, particularly in males. Moreover, logistic regression demonstrated the superiority of nonlinear parameters of diastolic BPV in predicting a prediabetic disease state. Our findings support the use of nonlinear beat-to-beat BPV for early detection of cardiovascular derangements in the initial stages of metabolic impairment.
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The use of complementary medicine (CMD) for liver support in Hepatitis C virus (HCV) patients sometimes coincides with the administration of oral antiviral drugs to eradicate the virus. This calls for a deep investigation of CMD effects on the pharmacokinetic parameters of these drugs to ensure their safety and efficacy. Silymarin (SLY), as a CMD, was selected to be given orally to healthy male rats with sofosbuvir (SFB) and ledipasvir (LED), a common regimen in HCV treatment. A new and sensitive LC-MS method was validated for the bioassay of SLY, LED, SFB and its inactive metabolite, GS-331007, in spiked plasma with lower limits of quantitation of 10, 1, 4 and 10 ng/ml, respectively. Moreover, the method was further applied to conduct a full pharmacokinetic profile of SFB, GS-331007 and ledipasvir with and without SLY. It was found that co-administration of SLY may expose the patient to unplanned high serum concentrations of SFB and LED. This could be accompanied by a decrease in SFB efficacy, potentially leading to therapeutic failure and the emergence of viral resistance.
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Hepatitis C , Silimarina , Animales , Antivirales/farmacocinética , Bencimidazoles , Cromatografía Liquida , Quimioterapia Combinada , Fluorenos , Hepacivirus , Hepatitis C/tratamiento farmacológico , Masculino , Ratas , Silimarina/farmacología , Sofosbuvir , Espectrometría de Masas en TándemRESUMEN
The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.