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Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard in the endoscopic management of biliary disease. An average of 700,000 ERCPs are performed every year, and most are performed using a reusable flexible duodenoscope. The innovation of disposable duodenoscopes has changed the dynamic in the advanced endoscopy field of study to primarily reduce or eliminate the risk of cross-contamination between patients. Many factors affect whether institutions can convert from standard reusable duodenoscopes to single-use duodenoscopes including the cost of the devices, reimbursement from insurance companies for the new devices, and the overall environmental impact. However, the reduction of cross-contamination leading to active infection in patients, environmental waste produced with high-level disinfection procedures, staff and equipment required for reprocessing, and the inability to frequently upgrade duodenoscopes for optimal performance are all factors that favor transitioning to single-use duodenoscopes. As these devices are new to the field of gastroenterology, the purpose of this review is to analyze the advantages and disadvantages of transitioning to single-use devices and a brief mention of alternative options for institutions unable to make this change.
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Filgrastim, a biopharmaceutical listed on WHO model list of essential medicines, was approved in USA in 1991 for patients with non-myeloid malignancies associated with severe neutropenia and fever. Several filgrastim biosimilars have now been approved in USA, Europe and elsewhere since 2008, based on the reference product which has lost patent exclusivity; however their immunogenicity and safety is controversial. We conducted a retrospective, post market study between 1991 and May 2018 using VigiBase®. The study included all adverse events with case reports ≥150. Overall, 11,183 adverse drugs reaction reports were identified during observation period; of which 5764; 51.5% reports concerned to Neupogen®, the originator, and rest consists of Leucostim® (N = 680), Zarzio® (N = 622), Grasin® (N = 545), Nivestim® (N = 359) and Tevagrastim® (N = 152) biosimilars. When compared with the originator, Grasin® was associated with higher reporting of pyrexia (11.5% vs 7.9%, ROR 1.52, IC025 1.12), myalgia (37% vs 2.2%, ROR 25.94, IC025 2.11) and back pain (11.3% vs 4%, ROR 3.09, IC025 2.32). Zarzio® was associated with increased reporting of arthralgia (4.5% vs 2.9%, ROR 1.59, IC025 1.25) and neutropenia (11.4% vs 4%, ROR 2.59, IC025 3.07). Bone pain was reported more often with Nivestim® (14.4% vs 8.3%, ROR 1.87, IC025 5.30). Drug ineffectiveness was reported in cases with Zarzio® (35.9%), Nivestim® (19.4%) and Tevagrastim® (42.2%). Authors observed significant differences among originator and biosimilars in particular to efficacy, adverse events reported and time to onset of occurrences. Large epidemiologic studies are needed to further confirm these finding and provide additional insights.
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Antineoplásicos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Neutropenia Febril/tratamento farmacológico , Filgrastim/efeitos adversos , Fator Estimulador de Colônias de Granulócitos , Adolescente , Adulto , Criança , Pré-Escolar , Aprovação de Drogas , Neutropenia Febril/induzido quimicamente , Feminino , Filgrastim/uso terapêutico , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: To quantitatively and qualitatively evaluate the impingement behavior between structures within the glenohumeral joint under simulated abduction-external rotation (ABER) motion using finite element analysis. METHODS: Computed tomography (CT) scanning of 1 shoulder in a volunteer was performed at 0° and 120° of shoulder abduction with external rotation (ABER position), followed by magnetic resonance imaging at 0° of abduction. The CT and magnetic resonance images were then imported into a customized software program to undergo 3-dimensional reconstruction followed by finite element modeling of the bone and soft tissue including the upper part of the rotator cuff and glenohumeral labral complex. Glenohumeral motion from 0° to the ABER position was simulated by CT images in 2 different humeral positions. On the basis of simulated humeral motion with respect to the scapula, we measured the stress value on the biceps-labral complex and upper part of the rotator cuff as a consequence of their structural deformation. In addition, we intended to design 2 types of labra--a normal stable labrum and an unstable posterosuperior labrum--to evaluate the geometric alteration and resulting stress change on the posterosuperior labrum against a compressive force from the humeral head and rotator cuff. RESULTS: In the ABER position, the posterosuperior labrum was deformed by the humeral head and interposed posterior part of the rotator cuff. When viewed from the rotator cuff, the posterior part of the rotator cuff came into contact with the posterosuperior labrum as external rotation increased. The measured peak contact stress values were 19.7 MPa and 23.5 MPa for the posterosuperior labrum and the upper rotator cuff, respectively. The stress values for both structures decreased to 5.8 MPa and 18.1 MPa, respectively, in the simulated SLAP model. The root of the long head of the biceps became compressed halfway through the range of motion by the humeral head, especially from the part involving horizontal extension and external rotation, resulting in a high stress of 22.4 MPa. CONCLUSIONS: In this simulated SLAP model, the posterosuperior labrum was medially displaced by the humeral head and upper rotator cuff in the ABER position, causing a functional loss of the spacer effect. CLINICAL RELEVANCE: In SLAP lesions, the posterosuperior labrum loses its ability to function as a spacer in certain positions (especially ABER) and may decrease the important spacer effect between the humerus and the rotator cuff; this may lead to posterosuperior subluxation of the humeral head or rotator cuff abnormalities and tears during repetitive ABER tasks.
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Ligamentos Articulares/fisiopatologia , Movimento/fisiologia , Manguito Rotador/fisiopatologia , Articulação do Ombro/fisiopatologia , Estresse Mecânico , Adulto , Análise de Elementos Finitos , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios XRESUMO
Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenic exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20mg/kg body weight, p.o) and curcumin (100mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin.
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Intoxicação por Arsênico/prevenção & controle , Doenças do Sistema Nervoso Autônomo/induzido quimicamente , Doenças do Sistema Nervoso Autônomo/prevenção & controle , Curcumina/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Intoxicação por Arsênico/metabolismo , Doenças do Sistema Nervoso Autônomo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Química Encefálica/efeitos dos fármacos , Química Encefálica/genética , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/ultraestrutura , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/ultraestrutura , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores Muscarínicos/metabolismoRESUMO
Activating V600E in v-Raf murine sarcoma viral oncogene homolog B (BRAF) is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAFV600E has also been implicated in neurodegeneration. The present study aims to characterize BRAFV600E during cell death and proliferation of three major cell types of the central nervous system: neurons, astrocytes, and microglia. Multiple primary cultures (primary cortical mixed culture) and cell lines of glial cells (BV2) and neurons (SH-SY5Y) were employed. BRAFV600E and BRAFWT expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors (extracellular signal-regulated kinase 1/2 and JNK1/2) were achieved by siRNA. In astrocytes and microglia, BRAFV600E induces cell proliferation, and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase, but not c-Jun N-terminal kinase. Conditioned medium from BRAFV600E-expressing microglia induced neuronal death. In neuronal cells, BRAFV600E directly induces neuronal death, through c-Jun N-terminal kinase but not extracellular signal-regulated kinase. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson's disease. Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.
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This technical report serves as a comprehensive guide for conducting a phenome-wide association study (PheWAS) utilizing data extracted from the Nationwide Inpatient Sample 2020. Specifically tailored to individuals diagnosed with pancreatic cysts and lung cancer, the report establishes a step-by-step workflow designed to assist researchers in uncovering potential associations within this specific cohort. The methodology outlined in the report ensures clarity and reproducibility by employing a curated cohort sourced from the GitHub repository and executed using R for robust data analysis. The code encompasses pivotal steps, including the utilization of a QQ plot as a crucial diagnostic tool aimed at identifying systematic biases or associations. Additionally, the report incorporates the creation of a Manhattan plot, delving into essential mathematical considerations to enhance the interpretability of the results. Notably, the report elucidates the handling of the International Classification of Disease version 10 (ICD-10) codes, providing a sample approach for their segmentation to analyze associations by diagnostic categories. The segmentation aligns with the guidelines outlined in the American Medical Association's ICD-10-CM 2022, the Complete Official Codebook with Guidelines (American Medical Association Press, 2021), ensuring a standardized and rigorous analytical process. This comprehensive guide equips researchers with the tools and insights needed to navigate the complexities of PheWAS within the context of pancreatic cysts and lung cancer, fostering transparency, reproducibility, and meaningful scientific exploration.
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Background: Melanocortin 1 receptor (MC1R) is a key pigmentation gene, and loss-of-function of MC1R variants that produce red hair may be associated with Parkinson's disease (PD). We previously reported compromised dopaminergic neuron survival in Mc1r mutant mice and dopaminergic neuroprotective effects of local injection of a MC1R agonist to the brain or a systemically administered MC1R agonist with appreciable CNS permeability. Beyond melanocytes and dopaminergic neurons, MC1R is expressed in other peripheral tissues and cell types, including immune cells. The present study investigates the impact of NDP-MSH, a synthetic melanocortin receptor (MCR) agonist that does not cross BBB, on the immune system and the nigrostriatal dopaminergic system in mouse model of PD. Methods: C57BL/6 mice were treated systemically with MPTP.HCl (20 mg/kg) and LPS (1 mg/kg) from day 1 to day 4 and NDP-MSH (400 µg/kg) or vehicle from day 1 to day 12 following which the mice were sacrificed. Peripheral and CNS immune cells were phenotyped and inflammatory markers were measured. The nigrostriatal dopaminergic system was assessed behaviorally, chemically, immunologically, and pathologically. To understand the role of regulatory T cells (Tregs) in this model, CD25 monoclonal antibody was used to deplete CD25+ Tregs. Results: Systemic NDP-MSH administration significantly attenuated striatal dopamine depletion and nigral dopaminergic neuron loss induced by MPTP+LPS. It improved the behavioral outcomes in the pole test. Mc1r mutant mice injected with NDP-MSH in the MPTP and LPS paradigm showed no changes in striatal dopamine levels suggesting that the NDP-MSH acts through the MC1R pathway. Although no NDP-MSH was detected in the brain, peripheral, NDP-MSH attenuated neuroinflammation as observed by diminished microglial activation in the nigral region, along with reduced TNF-α and IL1ß levels in the ventral midbrain. Depletion of Tregs limited the neuroprotective effects of NDP-MSH. Conclusions: Our study demonstrates that peripherally acting NDP-MSH confers protection on dopaminergic nigrostriatal neurons and reduces hyperactivated microglia. NDP-MSH modulates peripheral immune responses, and Tregs may be involved in the neuroprotective effect of NDP-MSH.
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BACKGROUND: Melanocortin 1 receptor (MC1R) is a key pigmentation gene, and loss-of-function of MC1R variants that produce red hair may be associated with Parkinson's disease (PD). We previously reported compromised dopaminergic neuron survival in Mc1r mutant mice and dopaminergic neuroprotective effects of local injection of a MC1R agonist to the brain or a systemically administered MC1R agonist with appreciable central nervous system (CNS) permeability. Beyond melanocytes and dopaminergic neurons, MC1R is expressed in other peripheral tissues and cell types, including immune cells. The present study investigates the impact of NDP-MSH, a synthetic melanocortin receptor (MCR) agonist that does not cross BBB, on the immune system and the nigrostriatal dopaminergic system in mouse model of PD. METHODS: C57BL/6 mice were treated systemically with MPTP.HCl (20 mg/kg) and LPS (1 mg/kg) from day 1 to day 4 and NDP-MSH (400 µg/kg) or vehicle from day 1 to day 12 following which the mice were sacrificed. Peripheral and CNS immune cells were phenotyped and inflammatory markers were measured. The nigrostriatal dopaminergic system was assessed behaviorally, chemically, immunologically, and pathologically. To understand the role of regulatory T cells (Tregs) in this model, CD25 monoclonal antibody was used to deplete CD25 + Tregs. RESULTS: Systemic NDP-MSH administration significantly attenuated striatal dopamine depletion and nigral dopaminergic neuron loss induced by MPTP + LPS. It improved the behavioral outcomes in the pole test. Mc1r mutant mice injected with NDP-MSH in the MPTP and LPS paradigm showed no changes in striatal dopamine levels suggesting that the NDP-MSH acts through the MC1R pathway. Although no NDP-MSH was detected in the brain, peripheral, NDP-MSH attenuated neuroinflammation as observed by diminished microglial activation in the nigral region, along with reduced TNF-α and IL1ß levels in the ventral midbrain. Depletion of Tregs was associated with diminished neuroprotective effects of NDP-MSH. CONCLUSIONS: Our study demonstrates that peripherally acting NDP-MSH confers protection on dopaminergic nigrostriatal neurons and reduces hyperactivated microglia. NDP-MSH modulates peripheral immune responses, and Tregs may be involved in the neuroprotective effect of NDP-MSH.
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Fármacos Neuroprotetores , Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/tratamento farmacológico , Receptor Tipo 1 de Melanocortina/genética , Receptor Tipo 1 de Melanocortina/metabolismo , Dopamina/farmacologia , Fármacos Neuroprotetores/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Imunidade , Neurônios Dopaminérgicos , Modelos Animais de DoençasRESUMO
Neuromelanin (NM) in dopaminergic neurons of human substantia nigra (SN) has a melanic component that consists of pheomelanin and eumelanin moieties and has been proposed as a key factor contributing to dopaminergic neuron vulnerability in Parkinson's disease (PD). While eumelanin is considered as an antioxidant, pheomelanin and related oxidative stress are associated with compromised drug and metal ion binding and melanoma risk. Using postmortem SN from patients with PD or Alzheimer's disease (AD) and unaffected controls, we identified increased L-3,4-dihydroxyphenylalanine (DOPA) pheomelanin and increased ratios of dopamine (DA) pheomelanin markers to DA in PD SN compared to controls. Eumelanins derived from both DOPA and DA were reduced in PD group. In addition, we report an increase in DOPA pheomelanin relative to DA pheomelanin in PD SN. In AD SN, we observed unaltered melanin markers despite reduced DOPA compared to controls. Furthermore, synthetic DOPA pheomelanin induced neuronal cell death in vitro while synthetic DOPA eumelanin showed no significant effect on cell viability. Our findings provide insights into the different roles of pheomelanin and eumelanin in PD pathophysiology. We anticipate our study will lead to further investigations on pheomelanin and eumelanin individually as biomarkers and possibly therapeutic targets for PD.
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Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , Melaninas/metabolismo , Di-Hidroxifenilalanina/metabolismo , Di-Hidroxifenilalanina/farmacologia , Di-Hidroxifenilalanina/uso terapêutico , Dopamina/metabolismo , Substância Negra/metabolismoRESUMO
Background and Aim: Steroids have long been used in inducing remission of inflammatory bowel disease (IBD). Chronic use, defined as therapy greater than 3 months, has been implicated in complications including increased hospital length of stay (LOS), infections, and even death. In our retrospective study, we aim to identify the complications of chronic steroid use in patients with IBD. Methods: The fourth quarter of 2015-2019 National Inpatient Sample (NIS) was used in this study. International Classification of Diseases (ICD-10) codes were used to identify patients with a diagnosis of IBD and chronic steroid use. Adverse outcomes of chronic steroid use in IBD patients were analyzed, such as osteoporosis, opportunistic infections, mortality rate, and LOS. Cohorts were weighted using an algorithm provided by the NIS allowing for accurate national estimates. Results: A total of 283 970 patients had a diagnosis of IBD. Of those, 18 030 patients had concurrent chronic steroid use. Racial disparities existed, with 77.4% White, 12.7% Black, and 6.0% Hispanic. Patients with a history of IBD and chronic steroid use were found to have higher odds of developing osteoporosis, opportunistic infections, and acute thromboembolic events but did not have higher odds of mortality. Conclusion: There is much controversy about whether IBD patients should be on chronic steroids for maintenance therapy and this study highlights the importance of this decision as patients on chronic steroid use had higher odds of developing adverse effects. These results stress the importance of monitoring patients on steroids and avoiding chronic use.
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BACKGROUND: Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson's disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis. METHODS: Nigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that have an inactivating mutation of MC1R, overexpress its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against αSyn was characterized in vitro. Furthermore, MC1R expression was determined in human postmortem midbrain from patients with PD and unaffected subjects. RESULTS: Targeted expression of αSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against αSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced at the tissue level in PD patients. CONCLUSION: Our study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R possibly through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD.
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Doença de Parkinson , Receptor Tipo 1 de Melanocortina , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Humanos , Camundongos , Doença de Parkinson/metabolismo , Receptor Tipo 1 de Melanocortina/metabolismo , alfa-Sinucleína/metabolismoRESUMO
Depression is a well-known disabling mental illness characterized by sadness, loss of interest in activities, and decreased energy. The symptoms of depression are usually recurrent in vulnerable individuals, and persistence of symptoms significantly impairs individuals' quality of life. The exact pathophysiology of depression remains ambiguous, though many hypotheses have been proposed. Brain-derived neurotrophic factor (BDNF) has recently been reported to play a vital role in the pathophysiology of depression. BDNF is an important neurotrophic factor found in the human brain and is involved in neuronal growth and proliferation, synaptic neurotransmission, and neuroplasticity. The neurotrophic theory of depression proposes that depression results from reduced BDNF levels in the brain, which can be treated with antidepressants to alleviate depressive behavior and increase BDNF levels. The aim of this review is to provide broad insight into the role of BDNF in the pathogenesis of depression and in antidepressant therapy. The studies mentioned in this review article greatly support the role of BDNF in the pathogenesis of depression and treatment of this disorder with antidepressants. Since abnormalities in BDNF levels lead to the production of diverse insults that amplify the development or progression of depression, it is important to study and explore BDNF impairment in relation to depression, neuroplasticity, and neurogenesis, and increasing BDNF levels through antidepressant therapy, showing positive response in the management of depression.
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Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/metabolismo , Animais , Antidepressivos/uso terapêutico , Biomarcadores/metabolismo , Depressão/tratamento farmacológico , HumanosRESUMO
Dysregulation of microRNAs (miRNAs) has been tied to several neurological disorders, including ischemic stroke. It has also been established that social environments can modulate miRNA profiles. We have previously shown that post-stroke social isolation (SI) is linked to poor stroke outcomes and that miR-181c-5p emerged as one of few lead miRNAs that was downregulated in both stroke and SI. Therefore, in this study we examined the potential role of miR-181c-5p mimic in reversing the detrimental effects of post-stroke SI. Two to three-month-old C57BL/6 male mice were pair-housed (PH) for at least two weeks. After two weeks, mice underwent stroke survival surgery using middle cerebral artery occlusion (MCAO) and were randomly assigned to one of two housing conditions: stroke isolation (ST-ISO) or stroke pair-housing with a healthy partner (ST-PH). ST-ISO mice were randomized to receive either miR-181c-5p mimic or a scrambled RNA (7â¯mg/kg i.v./day×drug) control at 24â¯h and 48â¯h after stroke. The effects of miR-181c-5p mimic treatment were evaluated at 1, 3, and 7 days after stroke at histological, behavioral, and biochemical levels. Target genes of miR-181c-5p were then analyzed by qPCR using an RT2 Profiler qPCR Array of pre-coated miR-181c gene targets. Temporal profile expression data suggested that miR-181c-5p was significantly downregulated (pâ¯<â¯0.05 vs ST-PH) up to 7 days after post-stroke SI. MiR-181c-5p mimic treatment significantly increased miR-181c-5p expression in brain tissue and showed partial swift recovery in sensorimotor deficit. Target gene analysis identified downregulation of several calcium signaling-related genes, e.g., Cpne2 and Gria 1 & 2 after miR-181c-5p mimic treatment. In summary, present data suggests that miR-181c-5p is a potential target for post-stroke SI. Data also suggests that genes related to calcium and glutamate signaling might be involved in the beneficial effect of the miR-181c-5p mimic.
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Encéfalo/metabolismo , MicroRNAs/biossíntese , Recuperação de Função Fisiológica/fisiologia , Isolamento Social , Acidente Vascular Cerebral/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Distribuição Aleatória , Isolamento Social/psicologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/psicologiaRESUMO
Stroke remains a leading cause of disability in the United States. Despite recent advances, interventions to reduce damage and enhance recovery after stroke are lacking. P2X4R, a receptor for adenosine triphosphate (ATP), regulates activation of myeloid immune cells (infiltrating monocytes/macrophages and brain-resident microglia) after stroke injury. However, over-stimulation of P2X4Rs due to excessive ATP release from dying or damaged neuronal cells can contribute to ischemic injury. Therefore, we pharmacologically inhibited P2X4R to limit the over-stimulated myeloid cell immune response and improve both acute and chronic stroke recovery. We subjected 8-12-week-old male and female wild type mice to a 60 min right middle cerebral artery occlusion (MCAo) followed by 3 or 30 days of reperfusion. We performed histological, RNA sequencing, behavioral (sensorimotor, anxiety, and depressive), and biochemical (Evans blue dye extravasation, western blot, quantitative PCR, and flow cytometry) analyses to determine the acute (3 days after MCAo) and chronic (30 days after MCAo) effects of P2X4R antagonist 5-BDBD (1 mg/kg P.O. daily x 3 days post 4 h of MCAo) treatment. 5-BDBD treatment significantly (p < .05) reduced infarct volume, neurological deficit (ND) score, levels of cytokine interleukin-1 beta (IL-1ß) and blood brain barrier (BBB) permeability in the 3-day group. Chronically, 5-BDBD treatment also conferred progressive recovery (p < .05) of motor balance and coordination using a rotarod test, as well as reduced anxiety-like behavior over 30 days. Interestingly, depressive-type behavior was not observed in mice treated with 5-BDBD for 3 days. In addition, flow cytometric analysis revealed that 5-BDBD treatment decreased the total number of infiltrated leukocytes, and among those infiltrated leukocytes, pro-inflammatory cells of myeloid origin were specifically reduced. 5-BDBD treatment reduced the cell surface expression of P2X4R in flow cytometry-sorted monocytes and microglia without reducing the total P2X4R level in brain tissue. In summary, acute P2X4R inhibition protects against ischemic injury at both acute and chronic time-points after stroke. Reduced numbers of infiltrating pro-inflammatory myeloid cells, decreased surface P2X4R expression, and reduced BBB disruption are likely its mechanism of neuroprotection and neuro-rehabilitation.
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Benzodiazepinonas/uso terapêutico , AVC Isquêmico/metabolismo , AVC Isquêmico/prevenção & controle , Neuroproteção/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Animais , Benzodiazepinonas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , AVC Isquêmico/reabilitação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X4/metabolismoRESUMO
Stroke is a leading cause of disability worldwide and hence remains a major medical concern. Besides several pathological features, such as excitotoxicity, peri-infarct depolarization, acidosis, reactive oxygen species generation, apoptosis, and necrosis, dysregulation of the immune system severely affects stroke outcomes. After stroke onset, microglia - the brain-resident macrophage immune cells - and peripheral immune cells affect stoke injury/recovery by releasing pro-inflammatory and/or anti-inflammatory cytokines depending on their microenvironment. These pro- or anti-inflammatory cytokines further affect integrity of the blood brain barrier (BBB) and modulate immune infiltration after stroke. Among peripheral immune cells, bone marrow-derived macrophages (BMDMs) play a critical role in stroke pathology which peaks between three and seven days post-stroke. BMDMs have been extensively studied for their role in exacerbation of stroke injury, however they have rarely been studied for their role in tissue repair. Nonetheless, these reparative roles are gaining attention since recent studies have shown either failure or worsening of long-term post-stroke recovery after blockade of peripheral immune infiltration. These diverse but paradoxical effects of infiltrating monocytes/macrophages encouraged us to summarize the latest findings in neuro-immune and immune-vascular interactions. This review highlights the multifaceted role of BMDMs in stroke onset and resolution, and emphasizes the significance of tapping the potential of these cells to gain better insight into disease progression and therapy.
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Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Citocinas/metabolismo , Humanos , Inflamação/patologia , Microglia/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
Earlier, protective role of curcumin in arsenic-induced dopamine (DA)-D2 receptor dysfunctions in corpus striatum has been demonstrated by us. In continuation to that, the present study is focused to decipher the molecular mechanisms associated with alterations in dopaminergic signaling on arsenic exposure in corpus striatum and assess the protective efficacy of curcumin. Exposure to arsenic (20 mg/kg, body weight p.o. for 28 days) in rats resulted to decrease the expression of presynaptic proteins-tyrosine hydroxylase and VMAT2 while no effect was observed on the expression of DAT in comparison to controls. A significant decrease in the expression of DA-D2 receptors associated with alterations in the expression of PKA, pDARPP32 (Thr 34), and PP1 α was clearly evident on arsenic exposure. Expression of BDNF and pGSK3ß in corpus striatum was found decreased in arsenic-exposed rats. Simultaneous treatment with curcumin (100 mg/kg, body weight p.o. for 28 days) resulted to protect arsenic-induced alterations in the expression of DA-D2 receptors, PKA, pDARPP32, pCREB, and pPP1α. Neuroprotective efficacy of curcumin can possibly be attributed to its antioxidant potential which significantly protected arsenic-induced mitochondrial dysfunctions by modulating the ROS generation and apoptosis. Modulation in the expression of BDNF and pGSK3ß in corpus striatum by curcumin exhibits the importance of neuronal survival pathway in arsenic-induced dopaminergic dysfunctions. Interestingly, curcumin was also found to protect arsenic-induced ultrastructural changes in corpus striatum. The results exhibit that curcumin modulates BDNF/DARPP32/CREB in arsenic-induced alterations in dopaminergic signaling in rat corpus striatum.
Assuntos
Arsênio/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/patologia , Curcumina/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Dopamina/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corpo Estriado/ultraestrutura , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores Dopaminérgicos/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Protective efficacy of curcumin in arsenic induced NMDA receptor dysfunctions and PI3K/Akt/ GSK3ß signalling in hippocampus has been investigated in vivo and in vitro. Exposure to sodium arsenite (in vivo - 20â¯mg/kg, body weight p.o. for 28 days; in vitro - 10⯵M for 24â¯h) and curcumin (in vivo - 100â¯mg/kg body weight p.o. for 28 days; in vitro - 20⯵M for 24â¯h) was carried out alone or simultaneously. Treatment with curcumin ameliorated sodium arsenite induced alterations in the levels of NMDA receptors, its receptor subunits and synaptic proteins - pCaMKIIα, PSD-95 and SynGAP both in vivo and in vitro. Decreased levels of BDNF, pAkt, pERK1/2, pGSK3ß and pCREB on sodium arsenite exposure were also protected by curcumin. Curcumin was found to decrease sodium arsenite induced changes in hippocampus by modulating PI3K/Akt/GSK3ß neuronal survival pathway, known to regulate various cellular events. Treatment of hippocampal cultures with pharmacological inhibitors for ERK1/2, GSK3ß and Akt individually inhibited levels of CREB and proteins associated with PI3K/Akt/GSK3ß pathway. Simultaneous treatment with curcumin was found to improve sodium arsenite induced learning and memory deficits in rats assessed by water maze and Y-maze. The results provide evidence that curcumin exercises its neuroprotective effect involving PI3K/Akt pathway which may affect NMDA receptors and downstream signalling through TrKß and BDNF in arsenic induced cognitive deficits in hippocampus.
Assuntos
Arsênio/toxicidade , Curcumina/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem Espacial/fisiologiaRESUMO
Given increasing risk of cadmium-induced neurotoxicity, the study was conducted to delineate the molecular mechanisms associated with cadmium-induced motor dysfunctions and identify targets that govern dopaminergic signaling in the brain involving in vivo, in vitro, and in silico approaches. Selective decrease in dopamine (DA)-D2 receptors on cadmium exposure was evident which affected the post-synaptic PKA/DARPP-32/PP1α and ß-arrestin/Akt/GSK-3ß signaling concurrently in rat corpus striatum and PC12 cells. Pharmacological inhibition of PKA and Akt in vitro demonstrates that both pathways are independently modulated by DA-D2 receptors and associated with cadmium-induced motor deficits. Ultrastructural changes in the corpus striatum demonstrated neuronal degeneration and loss of synapse on cadmium exposure. Further, molecular docking provided interesting evidence that decrease in DA-D2 receptors may be due to direct binding of cadmium at the competitive site of dopamine on DA-D2 receptors. Treatment with quercetin resulted in the alleviation of cadmium-induced behavioral and neurochemical alterations. This is the first report demonstrating that cadmium-induced motor deficits are associated with alteration in postsynaptic dopaminergic signaling due to a decrease in DA-D2 receptors in the corpus striatum. The results further demonstrate that quercetin has the potential to alleviate cadmium-induced dopaminergic dysfunctions.
Assuntos
Antioxidantes/farmacologia , Cádmio/toxicidade , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Dopamina/metabolismo , Transtornos dos Movimentos , Quercetina/farmacologia , Receptores de Dopamina D2/metabolismo , Animais , Antioxidantes/uso terapêutico , Corpo Estriado/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Masculino , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/prevenção & controle , Células PC12 , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/patologia , Transmissão Sináptica/efeitos dos fármacos , beta-Arrestinas/metabolismoRESUMO
The prevalence of lung infection caused by Pseudomonas aeruginosa strains that are classified as multi-drug resistant has increased considerably and is mainly attributed to relative insufficiency of potent chemotherapeutic modalities. The present study was conducted to evaluate the antimicrobial activity of aquo-alcoholic extract of Glycyrrhiza glabra against the P. aeruginosa causing lung infection in Swiss albino mice. The study involves evaluation of lethal dose of P. aeruginosa in Swiss albino mice and analysis of disease manifestation that includes bacteremia, hypothermia, reduction in body weight and other parameters for 48h of infection. Physical manifestations of infected mice showed a significant decline in body temperature that is 29±0.57°C (at 48th h) from 38.81±0.33°C (0h) and 30% weight loss was observed at the end of the study. Further the efficacy of G. glabra extract against lung infection induced with the calculated lethal dose was evaluated by employing bacteremia, histopathology and radiological analysis. Bacterial burden showed that 2.30±0.02 Log10CFU/mL at day 7, a significant decline in the bacterial load as compared to day 1 when the bacterial burden was found to be 3.32±0.1 Log10CFU/mL. Histopathological results showed more diffuse and patchy accumulation of inflammatory cells within the alveolar space also the infiltrates were noted in all the lung section of infected mice. In treated animal group improved lung histology was seen with the exudates were less seen in D1 dose (20mg/kg) and disappeared in D2 dose (80mg/kg). The study clearly declares that the G. glabra extract is effective against lung infection caused by P. aeruginosa at dose of 80mg/kg. The LCMS results revealed that the extract contains Glycyrrhizin, Stigmasterol and Ergosterol, Licochalcone and Glabridin. The current study expected to further exploit the biomedical properties of this extract in the preparation of a potent regimen against such threatening pathogen.