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Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease, affecting the joints with varying severity among patients. The risk factors include age, gender, genetics, and environmental exposure (cigarette smoking, air pollutants, and occupational). Many complications can follow, such as permanent joint damage requiring arthroplasty, rheumatoid vasculitis, and Felty syndrome requiring splenectomy if it remains unaddressed. As there is no cure for RA, the treatment goals are to reduce the pain and stop/slow further damage. Here, we present a brief summary of various past and present treatment modalities to address the complications associated with RA.
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Artrite Reumatoide/tratamento farmacológico , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/cirurgia , Humanos , Imunossupressores/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Leflunomida/uso terapêutico , Modalidades de Fisioterapia , Fatores de Risco , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
Mycotoxins are produced by certain molds that can cause many health effects. We present four human cases of prolonged consistent mycotoxins exposure linked to genetic variations in human leukocyte antigen (HLA) alleles. The HLA-DR/DQ isotype alleles are linked to mycotoxins susceptibility due to the lack of proper immune response; individuals with these alleles are poor eliminators of mycotoxins from their system. Four subjects with variations in their HLA-DR alleles were exposed to mycotoxins from living in mold-infested houses and experienced persistent mold-related symptoms long after moving out from the mold-infested houses and only exposed to the levels of molds found in the ambient air. From one of the subjects, two urine samples were collected ~ 18 months apart after the cessation of exposure. Urinary elimination rate was extremely slow for two of the mycotoxins (ochratoxin A [OTA] and mycophenolic acid [MPA]) detected in both samples. In 18 months, decline in OTA level was only ~ 3-fold (estimated t½ of ~ 311 days) and decline in MPA level was ~ 11-fold (estimated t½ of ~ 160 days), which was ~ 10- and ~ 213-fold slower than expected in individuals without HLA-DR alleles, respectively. We estimated that ~ 4.3 and ~ 2.2 years will be required for OTA and MPA to reach < LLQ in urine, respectively. Three other subjects with variations in HLA-DR alleles were members of a family who lived in a mold-infested house for 4 years. They kept experiencing mold-related issues >2 years after moving to a non-mold-infested house. Consistent exposure was confirmed by the presence of several mycotoxins in urine >2 years after the secession of higher than background (from outdoor ambient air) exposure. This was consistent with the extremely slow elimination of mycotoxins from their system. Variations in HLA-DR alleles can, consequently, make even short periods of exposure to chronic exposure scenarios with related adverse health effects. It is, therefore, important to determine genetic predisposition as a reason for prolonged/lingering mold-related symptoms long after the cessation of higher than background exposure. Increased human exposure to mycotoxins is expected from increased mold infestation that is anticipated due to rising CO2, temperature, and humidity from the climate change with possibly increased adverse health effects, especially in individuals with genetic susceptibility to mold toxicity.
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Micotoxinas , Humanos , Micotoxinas/toxicidade , Micotoxinas/urina , Fungos , Antígenos HLA-DRRESUMO
The effectiveness of messenger RNA (mRNA) vaccines, especially those designed for COVID-19, relies heavily on sophisticated delivery systems that ensure efficient delivery of mRNA to target cells. A variety of nanoscale vaccine delivery systems (VDSs) have been explored for this purpose, including lipid nanoparticles (LNPs), liposomes, and polymeric nanoparticles made from biocompatible polymers such as poly(lactic-co-glycolic acid), as well as viral vectors and lipid-polymer hybrid complexes. Among these, LNPs are particularly notable for their efficiency in encapsulating and protecting mRNA. These nanoscale VDSs can be engineered to enhance stability and facilitate uptake by cells. The choice of delivery system depends on factors like the specific mRNA vaccine, target cell types, stability requirements, and desired immune response. In this review, we shed light on recent advances in delivery mechanisms for self-amplifying RNA (saRNA) vaccines, emphasizing groundbreaking studies on nanoscale delivery systems aimed at improving the efficacy and safety of mRNA/saRNA vaccines.
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Vacinas , Vacinas de mRNA , RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , PolímerosRESUMO
Transport processes are the hallmark of functioning kidney. Various nephrotoxicants disrupt the transport processes to manifest nephrotoxicity. Of several nephrotoxicants, mercuric chloride (HgCl(2)) depletes the reduced glutathione (GSH) in kidney and has been observed to affect the in vitro p-aminohippurate (PAH) transport by basolateral (BL) membrane vesicles. The role of renal nonprotein sulfhydryls such as, reduced GSH has been demonstrated to affect the PAH transport by BL membrane vesicles. The role of protein sulfhydryls in transport process of PAH by BL membrane is not known. Due to mercury mediated effects on sulfhydryls, the effects of protein-sulfhydryls (-SH) modifying reagents in the current study were investigated on PAH transport by BL membrane. It was observed that modification of -SH by p-chloromercuribenzoate sulphate (pCMBS), and mercuric chloride (HgCl(2)) decreased while recovering the protein -SH with dithiothreitol treatment provided protection against the effects of pCMBS, and HgCl(2) on PAH transport by BL membrane vesicles.
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Substâncias Perigosas/toxicidade , Rim/efeitos dos fármacos , Compostos de Sulfidrila/toxicidade , Animais , Transporte Biológico/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Glutationa/metabolismo , Rim/metabolismo , Rim/ultraestrutura , Ratos , Ácido p-Aminoipúrico/metabolismoRESUMO
The mRNA-based vaccines are quality-by-design (QbD) immunotherapies that provide safe, tunable, scalable, streamlined and potent treatment possibilities against different types of diseases. The self-amplifying mRNA (saRNA) vaccines, as a highly advantageous class of mRNA vaccines, are inspired by the intracellular self-multiplication nature of some positive-sense RNA viruses. Such vaccine platforms provide a relatively increased expression level of vaccine antigen(s) together with self-adjuvanticity properties. Lined with the QbD saRNA vaccines, essential optimizations improve the stability, safety, and immunogenicity of the vaccine constructs. Here, we elaborate on the concepts and mode-of-action of mRNA and saRNA vaccines, articulate the potential limitations or technical bottlenecks, and explain possible solutions or optimization methods in the process of their design and development.
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Vacinas , RNA Mensageiro/genéticaRESUMO
The incidence of hypertension with diabetes mellitus (DM) as a co-morbid condition is on the rise worldwide. In 2000, an estimated 972 million adults had hypertension, which is predicted to grow to 1.56 billion by 2025. Hypertension often leads to diabetes mellitus that strongly puts the patients at an increased risk of cardiovascular, kidney, and/or atherosclerotic diseases. Hypertension has been identified as a major risk factor for the development of diabetes; patients with hypertension are at two-to-three-fold higher risk of developing diabetes than patients with normal blood pressure (BP). Causes for the increase in hypertension and diabetes are not well understood, environmental factors (e.g., exposure to environmental toxicants like heavy metals, organic solvents, pesticides, alcohol, and urban lifestyle) have been postulated as one of the reasons contributing to hypertension and cardiovascular diseases (CVD). The mechanism of action(s) of these toxicants in developing hypertension and CVDs is not well defined. Research studies have linked hypertension with the chronic consumption of alcohol and exposure to metals like lead, mercury, and arsenic have also been linked to hypertension and CVD. Workers chronically exposed to styrene have a higher incidence of CVD. Recent studies have demonstrated that exposure to particulate matter (PM) in diesel exhaust and urban air contributes to increased CVD and mortality. In this review, we have imparted the role of environmental toxicants such as heavy metals, organic pollutants, PM, alcohol, and some drugs in hypertension and CVD along with possible mechanisms and limitations in extrapolating animal data to humans.
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Epigenetic regulation involves reversible changes in histones and DNA modifications that can be inherited without any changes in the DNA sequence. Dysregulation of normal epigenetic processes can lead to aberrant gene expression as observed in many diseases, notably cancer. Recent insights into the mechanisms of DNA methylation, histone modifications, and non-coding RNAs involved in altered gene expression profiles of tumor cells have caused a paradigm shift in the diagnostic and therapeutic approaches towards cancer. There has been a surge in search for compounds that could modulate the altered epigenetic landscape of tumor cells, and to exploit their therapeutic potential against cancers. Flavonoids are naturally occurring phenol compounds which are abundantly found among phytochemicals and have potentials to modulate epigenetic processes. Knowledge of the precise flavonoid-mediated epigenetic alterations is needed for the development of epigenetics drugs and combinatorial therapeutic approaches against cancers. This review is aimed to comprehensively explore the epigenetic modulations of flavonoids and their anti-tumor activities.
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The overuse of cisplatin (>50 mg/m2) is limited to nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. The objective of this study was to investigate the nephroprotective effects of Daucus carota and Eclipta prostrata extracts on cisplatin-induced nephrotoxicity in Wistar albino rats. The study involved male Wistar albino rats of 8 weeks weighing 220-270 g. A single injection of 5 mg/kg was injected into the rats for nephrotoxicity. Rats were divided into four groups based on dose conentrations. Blood and urine samples of rats were collected on the 0, 7th, 14th, and 21st days for nephrological analysis. The results showed that Cis + DC/Cis + EP (600 mg/kg) significantly (p < 0.001) increased the body weight and reduced the kidney weight of cisplatin-induced nephrotoxicity in rats (p < 0.001) as compared to Cis group. The results showed that 600 mg/kg administration of Cis + DC/Cis +EP successfully (p < 0.005) improved the urine and plasmin creatinine, Na, and K level compared to the Cis group. Histopathological results confirmed that Cis + EP/Cis + DC effectively improved the renal abnormalities. It is concluded that the co-administration of Cis + EP extract showed exceptional nephroprotective effects at a dose rate of 600 mg/kg.
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Cisplatino/efeitos adversos , Daucus carota/química , Eclipta/química , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/sangue , Nefropatias/urina , Masculino , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Potássio/urina , Substâncias Protetoras/farmacologia , Ratos Wistar , Sódio/urina , Micção/efeitos dos fármacosRESUMO
Organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the world. Poisoning includes acute cholinergic crisis as a result of AChE inhibition, intermediate syndrome (IMS) due to neuromuscular necrosis and organophosphate-induced delayed neuropathy (OPIDN) due to inhibition of neuropathy target esterase (NTE). Standard treatment for acute poisoning involves administration of intravenous atropine, oxime 2-PAM to counter AChE inhibition and diazepam for CNS protection. However clinical trials showed ineffectiveness of the standard therapy regimen. Although new oximes that can reactivate both peripheral and cerebral AChE and other prophylactic agents such as human serum butyrylcholinesterase (Hu BChE), sodium bicarbonate, huperzine A (a reversible ChE inhibitor) with imidazenil (a GABAA receptor modulator) have been proved effective in animal models, systematic clinical trials in patients are warranted. For IMS which is non-responsive to standard therapy, supportive therapy specifically artificial respiration followed by recovery is indicated. For OPIDN which has a different target (NTE) than AChE, standard therapy is ineffective. However neuroprotective drugs such as corticosteroids proved partially effective. Pretreatment with protease inhibitor PMSF has been shown to protect the aging of NTE and prevent the development of delayed symptoms in hens. Since the biology of NTE is being explored, new pharmacological agents should be developed in future. OP pesticide poisoning is a serious condition that needs rapid diagnosis and treatment. Since respiratory failure is the major reason for mortality, artificial respiration, careful monitoring, appropriate treatment and early recognition of OP pesticide poisoning may decrease the mortality rate among these patients.
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Antídotos/uso terapêutico , Intoxicação por Organofosfatos , Praguicidas/intoxicação , Intoxicação/tratamento farmacológico , HumanosRESUMO
Traditionally, toxicity testing is conducted at fixed dose rates (i.e., mg/kg/day) without considering life-changing events, e.g., stress, sickness, aging- and/or pregnancy-related changes in physical, physiological and biochemical parameters. In humans, life-changing events may cause systemic dose non-proportionality requiring modulation of drug dosage; similar changes occur in animals altering systemic dose during chronic/carcinogenic testing leading to "late-occurring" effects in some studies. For example, propylene monomethyl ether, an industrial chemical, initially induced sedation in rats and mice with recovery upon induction of hepatic CYPs after ~1 week. Sedation reappeared in rats but not in mice after ~12 months of exposure due to decreased CYP activity in rats, elderly mice were able to maintain slightly higher CYP activity avoiding recurrence of sedation. The systemic dose of two pharmaceuticals (doxazosin and brimonidine tartrate) increased up to 6-fold in ≥12-month old rats with no toxicity. In a rat reproductive toxicity study, systemic dose of 2,4-D, an herbicide, rapidly increased due to increased consumption of 2,4-D-fortified diet during pregnancy, lactation and neonatal growth, requiring adjustment to maintain the targeted systemic dose. Ideally, toxicological studies should be based on systemic dose with the option of modulating external dose rates to maintain the targeted systemic dose. Systemic dose can easily be monitored in selected core study animals at desired intervals considering recent developments in sampling and analysis at a fraction of the overall cost of a study.
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Envelhecimento/fisiologia , Testes de Toxicidade , Animais , Testes de Carcinogenicidade , Feminino , Masculino , Camundongos , RatosRESUMO
Human immunodeficiency virus type 1 (HIV-1)-infected T cells form a virological synapse with noninfected CD4(+) T cells in order to efficiently transfer HIV-1 virions from cell to cell. The virological synapse is a specialized cellular junction that is similar in some respects to the immunological synapse involved in T-cell activation and effector functions mediated by the T-cell antigen receptor. The immunological synapse stops T-cell migration to allow a sustained interaction between T-cells and antigen-presenting cells. Here, we have asked whether HIV-1 envelope gp120 presented on a surface to mimic an HIV-1-infected cell also delivers a stop signal and if this is sufficient to induce a virological synapse. We demonstrate that HIV-1 gp120-presenting surfaces arrested the migration of primary activated CD4 T cells that occurs spontaneously in the presence of ICAM-1 and induced the formation of a virological synapse, which was characterized by segregated supramolecular structures with a central cluster of envelope surrounded by a ring of ICAM-1. The virological synapse was formed transiently, with the initiation of migration within 30 min. Thus, HIV-1 gp120-presenting surfaces induce a transient stop signal and supramolecular segregation in noninfected CD4(+) T cells.
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Linfócitos T CD4-Positivos/virologia , Proteína gp120 do Envelope de HIV/fisiologia , HIV-1/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Adesão Celular , Movimento Celular , Regulação Viral da Expressão Gênica , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Sistema Imunitário , Molécula 1 de Adesão Intercelular/metabolismo , Leucócitos Mononucleares/virologia , Bicamadas Lipídicas/química , Camundongos , Transdução de SinaisRESUMO
BACKGROUND: The prevalence of NAFLD increases in obese diabetics. Accurate diagnosis of NAFLD requires invasive liver biopsies, which is costly, and time consuming and labor intensive. Currently, there is a lack of non-invasive diagnostic methods to identify those with NASH, in obese Indians. OBJECTIVES: To develop an accurate non-invasive scoring system using clinical and biochemical parameters to predict the risk of developing non-alcoholic steatohepatitis (NASH). METHODS: Clinical and biochemical parameters were recorded pre-operatively from 290 patients who were posted for bariatric/metabolic surgery, between September 2017 and October 2018 and compared with the result of intra-operative liver biopsy NAFLD activity scores (NAS). RESULTS: The mean weight and BMI of the patients were 120.3 ± 24.6 and 45.5 ± 7.8 respectively. In the final histopathological examination, 196/290 (67.6%) had simple steatosis, 92/290 (31.7%) had NASH, and 2/290 (0.007%) had cirrhosis. Binary logistic regression analysis of multiple independent predictors yielded five independent factors that were statistically significant (HbA1c, AST, ALT, liver span on USG, and serum triglycerides). These were used to create a scoring system, with a range of scores from 0 to 6, with maximum predictability at a score of 6. Patients with scores of ⧠3 were at high risk of NASH diagnosis. The sensitivity of this scoring system was 85.87% and diagnostic accuracy was 75.35%. CONCLUSIONS: Our study not only confirms the significant association of NAFLD with obesity but also outlines a simple non-invasive scoring system to identify obese individuals at high risk for NASH.
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Modelos Estatísticos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Obesidade/complicações , Obesidade/diagnóstico , Adulto , Cirurgia Bariátrica , Biópsia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/cirurgia , Feminino , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Cirrose Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/cirurgia , Obesidade/patologia , Obesidade/cirurgia , Obesidade Mórbida/complicações , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/patologia , Obesidade Mórbida/cirurgia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Projetos de PesquisaRESUMO
INTRODUCTION: Obesity is associated with metabolic syndrome, nonalcoholic steatohepatitis, and kidney disease. BMI may not be the ideal measure of obesity when used to assess its effect on kidney disease as it does not discriminate for age, sex, ethnicity, muscle, bone, or fat mass. OBJECTIVES: To assess the prevalence microalbuminuria and identify independent risk factors for development of kidney disease in the obese Indian population. METHODS: Age, weight, BMI, total body fat percentage, waist-to-hip ratio, hypertension, urinary albumin-to-creatinine ratio (UACR), and HbA1c were collected from 568 obese patients, presenting for bariatric surgery. Multivariate binary logistic regression was used to identify independent risk factors for kidney disease. RESULTS: A total of 114 out of 568 (20.07%) obese patients had microalbuminuria (UACR range 30-283 µg/mg). HbA1C levels ≥ 6 (p = 0.01) and hypertension (p = 0.03) were the strongest independent variables for microalbuminuria. 14.67% with a BMI < 35 kg/m2, 21.30% with a BMI 35-50 kg/m2, and 19.44% with a BMI > 50 kg/m2 had microalbuminuria. Increasing BMI however was not statistically significant (p = 0.75). Total body fat percentage (p = 0.51), waist-to-hip ratio (p = 0.96), age (p = 0.30), sex (p = 0.38), and BMI (p = 0.75) were found to be statistically insignificant. CONCLUSIONS: Kidney disease afflicts 1/5th of the obese Indian patients studied. Diabetes and hypertension remained as the most significant risk factors, while age, weight, increasing BMI, waist-to-hip ratio, or increasing body fat were found to be statistically insignificant for development and progression of kidney disease.
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Nefropatias/epidemiologia , Nefropatias/etiologia , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Tecido Adiposo/fisiologia , Adulto , Fatores Etários , Albuminúria/epidemiologia , Albuminúria/etiologia , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Fatores Sexuais , Relação Cintura-QuadrilRESUMO
Chronic alcohol consumption induces multi-organ damage, including alcoholic liver disease (ALD), pancreatitis and hypertension. Ethanol and ethanol metabolic products play a significant role in the manifestation of its toxicity. Ethanol metabolizes to acetaldehyde and produces reduced nicotinamide adenine dinucleotide (NADH) by cytosolic alcohol dehydrogenase. Ethanol metabolism mediated by cytochrome-P450 2E1 causes oxidative stress due to increased production of reactive oxygen species (ROS). Acetaldehyde, increased redox cellular state and ROS activate transcription factors, which in turn activate genes for lipid biosynthesis and offer protection of hepatocytes from alcohol toxicity. Sterol regulatory element binding proteins (SREBPs) and peroxisome proliferator activated-receptors (PPARs) are two key lipogenic transcription factors implicated in the development of fatty liver in alcoholic and non-alcoholic steatohepatitis. SREBP-1 is activated in the livers of chronic ethanol abusers. An increase in ROS activates nuclear factor erythroid-2-related factor-2 (Nrf2) and hypoxia inducible factor (HIF) to provide protection to hepatocytes from ethanol toxicity. Under ethanol exposure, due to increased gut permeability, there is release of gram-negative bacteria-derived lipopolysaccharide (LPS) from intestine causing activation of immune response. In addition, the metabolic product, acetaldehyde, modifies the proteins in hepatocyte, which become antigens inviting auto-immune response. LPS activates macrophages, especially the liver resident macrophages, Kupffer cells. These Kupffer cells and circulating macrophages secrete various cytokines. The level of tumor necrosis factor-α (TNFα), interleukin-1beta (IL-1ß), IL-6, IL-8 and IL-12 have been found elevated among chronic alcoholics. In addition to elevation of these cytokines, the peripheral iron (Fe(2+)) is also mobilized. An increased level of hepatic iron has been observed among alcoholics. Increased ROS, IL-1ß, acetaldehyde, and increased hepatic iron, all activate nuclear factor-kappa B (NF-κB) transcription factor. Resolution of increased reactive oxygen species requires increased expression of genes responsible for dismutation of increased ROS which is partially achieved by IL-6 mediated activation of signal transducers and activators of transcription 3 (STAT3). In addition to these transcription factors, activator protein-1 may also be activated in hepatocytes due to its association with resolution of increased ROS. These transcription factors are central to alcohol-mediated hepatotoxicity.
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Consumo de Bebidas Alcoólicas/metabolismo , Fígado Gorduroso/metabolismo , Hipertensão/metabolismo , Fatores de Transcrição/metabolismo , Animais , Etanol/farmacocinética , Etanol/toxicidade , Fígado Gorduroso/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Estresse OxidativoRESUMO
Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin II (Ang II) and a decrease in nitric oxide. The renin-angiotensin system (RAS), and its primary mediator Ang II, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors (angiotensin-converting enzyme inhibitors)], Ang II receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in ApoE-deficient atherosclerotic mice.
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Epidemiological, preclinical and clinical studies established the association between high alcohol consumption and hypertension. However the mechanism through which alcohol raises blood pressure remains elusive. Several possible mechanisms have been proposed such as an imbalance of the central nervous system, impairment of the baroreceptors, enhanced sympathetic activity, stimulation of the renin-angiotensin-aldosterone system, increased cortisol levels, increased vascular reactivity due to increase in intracellular calcium levels, stimulation of the endothelium to release vasoconstrictors and loss of relaxation due to inflammation and oxidative injury of the endothelium leading to inhibition of endothelium-dependent nitric oxide production. Loss of relaxation due to inflammation and oxidative injury of the endothelium by angiotensin II leading to inhibition of endothelium-dependent nitric oxide production is the major contributors of the alcohol-induced hypertension. For the prevention of alcohol-induced hypertension is to reduce the amount of alcohol intake. Physical conditioning/exercise training is one of the most important strategies to prevent/treat chronic alcohol-induced hypertension on physiological basis. The efficacious pharmacologic treatment includes the angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs) which have antioxidant activity and calcium channel blockers. The most effective prevention and treatment of alcohol-induced hypertension is physical exercise and the use of ACE inhibitors or ARBs in the clinic.
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The study aim was to investigate the relationship of chronic ethanol-induced inflammation leading to vascular endothelial injury and elevation of blood pressure (BP) in a rat model. Male Fisher rats were divided into two groups of six animals each and treated as follows: (1) Control (5% sucrose, orally) daily for 12 weeks and (2) 20% ethanol (4 g kg(-1), orally) daily for 12 weeks. The mean arterial blood pressure was recorded every week. The animals were anesthetized with pentobarbital after 12 weeks; thoracic aorta were isolated and analyzed for aortic reactivity response, inflammatory mediators, oxidant/antioxidant enzyme protein expression and endothelial nitric oxide-generating system. The results show that the mean BP was significantly elevated 12 weeks after ethanol ingestion. The increased BP was related to increased aortic inflammation (tumor necrosis factor [TNF]-α; nitric oxide synthase [iNOS], COX-2 and MCP-1 protein expression) and elevated angiotensin II levels in alcohol-treated group compared to control. Aortic Nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity, membrane and cytosolic subunits p22(phox) and p47(phox) expression and Mn-SOD activity and protein expression significantly increased, whereas nitric oxide (NO), endothelial NO synthase (eNOS), vascular endothelial growth factor (VEGF)-A and CuZn-SOD activity and protein expression significantly decreased in alcohol-treated group compared to control. The acetylcholine-mediated vasorelaxation response was depressed in the aorta of ethanol-treated rats compared to control. In conclusion, chronic ethanol-induced elevation in BP is related to increased aortic inflammation, elevated angiotensin II levels, induction of NADPH oxidase causing endothelial injury, depletion of CuZn-SOD, down-regulation of endothelial NO generating system and impaired vascular relaxation in rats.
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Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Etanol/toxicidade , Hipertensão/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Animais , Aorta Torácica/enzimologia , Aorta Torácica/imunologia , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/enzimologia , Endotélio Vascular/imunologia , Glutationa/metabolismo , Hipertensão/imunologia , Hipertensão/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Endogâmicos F344 , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vasodilatação/efeitos dos fármacosRESUMO
The link between chronic alcohol consumption and cardiovascular injury including hypertension is well known. However, molecular mediators implicated with alcohol-induced elevation in blood pressure (BP) remain elusive. The aim of this study was to investigate the relationship of chronic ethanol-induced endothelial injury and elevation in BP with angiotensin II levels in rats. Male Fisher rats were divided into two groups of seven animals each and treated as follows: (1) Control (5% sucrose, orally) daily for 12 weeks and (2) ethanol (4 g kg(-1), orally) daily for 12 weeks. The BP (systolic, diastolic, and mean) was recorded every week. The animals were anesthetized with pentobarbital after 12 weeks; blood and thoracic aorta were isolated and analyzed for aortic reactivity response, angiotensin II levels, and oxidative endothelial injury. The results show that the systolic, diastolic, and mean BP were significantly elevated 12 weeks after ethanol ingestion. The increased BP was related to elevated angiotensin II levels in the plasma and aorta of alcohol treated group compared to control. The aortic NADPH oxidase activity, ratio of oxidized to reduced glutathione (GSSG/GSH) and lipid peroxidation significantly increased, whereas nitric oxide (NO), endothelial NO synthase (eNOS), and vascular endothelial growth factor (VEGF) protein expressions were depressed in alcohol group compared to control. The phenylephrine-mediated vasoconstriction response was not altered, while acetylcholine-mediated vasorelaxation response was depressed in the aorta of ethanol treated rats compared to control. It is concluded that chronic ethanol ingestion induces hypertension which is correlated with elevated tissue angiotensin II levels, activation of NADPH oxidase activity causing endothelial injury, depletion of endothelial NO generating system, and impaired vascular relaxation in rats.
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Angiotensina II/sangue , Angiotensina II/metabolismo , Endotélio Vascular/efeitos dos fármacos , Etanol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/metabolismo , Glutationa/sangue , Glutationa/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Masculino , Malondialdeído/sangue , NADPH Oxidases/metabolismo , Óxido Nítrico , Óxido Nítrico Sintase Tipo III/metabolismo , Oxirredução , Ratos , Ratos Endogâmicos F344 , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Human immunodeficiency virus type 1 (HIV-1) transmembrane glycoprotein gp41 is targeted by broadly-reactive neutralizing antibodies 2F5 and 4E10, making it an attractive target for vaccine development. To better assess immunogenic properties of gp41, we generated five soluble glutathione S-transferase fusion proteins encompassing C-terminal 30, 64, 100, 142, or 172 (full-length) amino acids of gp41 ectodomain from M group consensus envelope sequence. Antibody responses in HIV-1-infected patients were evaluated using these proteins and overlapping peptides. We found (i) antibody responses against different regions of gp41 varied tremendously among individual patients, (ii) patients with stronger antibody responses against membrane-proximal external region exhibit broader and more potent neutralizing activity, and (iii) several patients mounted antibodies against epitopes that are near, or overlap with, those targeted by 2F5 or 4E10. These soluble gp41 fusion proteins could be an important source of antigens for future vaccine development efforts.