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BACKGROUND: The epidemiological burden of chronic diseases and their risk factors is increasing all over the world, especially in developing and low-income countries. Inflammatory bowel disease (IBD) is one of the chronic diseases which has imposed a great financial burden on individuals and the society. OBJECTIVES: The current study aimed at estimating the economic burden of IBD among 90 patients with IBD who referred to Namazi hospital and Motahari clinic of Shiraz in 2019. The costs to patients were monitored for a year to detect their expenses. METHODS: This study is descriptive cross-sectional and from a social perspective. The cost-of-illness method, based on the human capital theory, has been used. Both direct and indirect costs have been estimated using a prevalence approach and bottom-up method. Hospital costs were extracted from patients' records and the accounting system of Namazi Hospital. Outpatient expenses were obtained according to the number of outpatient visits and the average cost of visit were obtained by interviewing patients. Socio-economic status, medical expenses and number of days absent from work were determined using a valid and reliable questionnaire. Assessment of the cost of hospital care was made on the basis of the average daily. Non-medical direct costs such as transportation and residence, etc. were also calculated. RESULTS: The total annual economic costs of IBD per patient were estimated at 1229.74 USD. Finally, increased use of health care as well as lost productivity leads to increased disease costs. CONCLUSION: IBD imposes a substantial economic burden on patients, families and the society. Establishing a correct diagnosis early, management of IBD worsening, and appropriate treatment can reduce the costs of treatment and lost production to some extent. Therefore, policymakers should take this into consideration and according to available health resources, provide services and facilities for the prevention and treatment of the disease.
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Custos de Cuidados de Saúde , Doenças Inflamatórias Intestinais , Humanos , Estresse Financeiro , Irã (Geográfico)/epidemiologia , Estudos Transversais , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/terapia , Efeitos Psicossociais da DoençaRESUMO
The endothelial glycocalyx is an extracellular matrix that coats the endothelium and extends into the lumen of blood vessels, acting as a barrier between the vascular wall and blood flowing through the vessel. This positioning of the glycocalyx permits a variety of its constituents, including the major endothelial proteoglycans glypican-1 and syndecan-1, as well as the major glycosaminoglycans heparan sulfate and hyaluronic acid, to contribute to the processes of mechanosensation and subsequent mechanotransduction following such stimuli as elevated shear stress. To coordinate the vast array of processes that occur in response to physical force, the glycocalyx interacts with a plethora of membrane and cytoskeletal proteins to carry out specific signaling pathways resulting in a variety of responses of endothelial cells and, ultimately, blood vessels to mechanical force. This review focuses on proposed glycocalyx-protein relationships whereby the endothelial glycocalyx interacts with a variety of membrane and cytoskeletal proteins to transduce force into a myriad of chemical signaling pathways. The established and proposed interactions at the molecular level are discussed in context of how the glycocalyx regulates membrane/cytoskeletal protein function in the many processes of endothelial mechanotransduction.
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Proteínas do Citoesqueleto , Mecanotransdução Celular , Mecanotransdução Celular/fisiologia , Proteínas do Citoesqueleto/metabolismo , Células Endoteliais/metabolismo , Glicocálix/metabolismo , Glicosaminoglicanos/metabolismoRESUMO
OBJECTIVE: To explore the relationship between metabolic syndrome and its components with nephrolithiasis. METHODS: In current study, 4,901 individuals from the PERSIAN (Prospective Epidemiological Research Studies in IrAN) Kavar cohort study were included. Metabolic syndrome was defined according to the ATP III criteria (2005 revision). The nephrolithiasis was assessed using a structured questionnaire, and ultrasound findings were reviewed in subjects who reported positive history of nephrolithiasis. We applied logistic regression to estimate the odds ratio (OR) and 95% confidence interval (CI). RESULTS: The prevalence of nephrolithiasis and metabolic syndrome was 28.5% and 40.91%, respectively. Almost 31% of the patients with metabolic syndrome had a history of nephrolithiasis. Multivariable logistic regression analysis revealed a positive association between metabolic syndrome and nephrolithiasis (OR= 1.30, 95% CI: 1.14-1.49, P<.001) after adjustment age, sex, ethnicity, physical activity, smoking status, and alcohol intake. Furthermore, the relation was higher for elders aged 50 years or more (P for interaction= .016) and Turk Nomad participants (P for interaction= 0.044) than the others. There was also a positive independent association between hypertension (OR=1.29, 95% CI: 1.12-1.48, P<.001) and hypertriglyceridemia (OR= 1.15, 95% CI: 1.01-1.31, P=.033) with nephrolithiasis. CONCLUSION: In this large sample study, we demonstrate a weak positive association between metabolic syndrome, hypertension, and hypertriglyceridemia with nephrolithiasis.
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Hipertensão , Hipertrigliceridemia , Cálculos Renais , Síndrome Metabólica , Humanos , Idoso , Estudos de Coortes , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Estudos Prospectivos , Estudos Transversais , Hipertensão/epidemiologia , Fatores de Risco , PrevalênciaRESUMO
The human microbiome comprises the genomes of the microbiota that live on and within humans, such as protozoa, archaea, eukaryotes, viruses, and most bacteria. Gastrointestinal disorders such as inflammatory bowel disease, colon cancer, celiac disease, and irritable bowel syndrome can all be triggered by a change in gut flora. The alteration of the gut microbiota (also known as "gut dysbiosis") is affected by host genetics, nutrition, antibiotics, and inflammation, and it is associated with the development of inflammatory bowel disease (IBD). Also, intestinal epithelial dysfunction, altered autophagy, and immune hyperactivation are frequently detected in individuals with severe IBD, which may be attributed to impaired miRNA expression functions. While the exact mechanisms of how Gut Microbiota may cause IBD and intestinal epithelial dysfunction are still debated, recent data point toward the possibility that hormones, gender and miRNAs expression are modifiable contributors to IBD. This review summarizes the current evidence for an association between hormones, gender and miRNAs and Gut Microbiota in IBD and discusses potential mechanisms by which gut microbiota may impact IBD. The study also outlines critical unanswered topics that need to be solved to enhance IBD prevention and treatment in people with gut dysbiosis.
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Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , MicroRNAs , Humanos , Disbiose/complicações , Disbiose/microbiologia , Inflamação/complicações , MicroRNAs/genéticaRESUMO
Efferocytosis (clearance of apoptotic cells by phagocytosis without inducing inflammation and autoimmunity) is an important mechanism in the resolution of inflammatory processes. Efficient efferocytosis inhibits the accumulation of apoptotic cells/debris and maintains homeostasis before the onset of necrosis (secondary necrosis), which promotes inflammation or injury. Moreover, the detection and clearance of apoptotic cells can promote anti-inflammatory responses. Defective efferocytosis is involved in the pathogenesis of several diseases, such as atherosclerosis, chronic inflammation, autoimmunity and cancer. Statins are 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors which exert cholesterol-lowering effects plus multiple pleiotropic properties, such as inhibition of inflammation and macrophage proliferation. Statins exhibit anti-inflammatory properties by reducing both the prenylation of signaling molecules with downregulation of gene expression and the expression of adhesion molecules, as well as the levels of cytokines and chemokines. Additionally, statins suppress the prenylation of GTPases, such as Rac-1, as a positive regulator of efferocytosis, and RhoA, as a negative regulator of efferocytosis. However, statins alter the membrane balance of Rho GTPases in efferocytosis toward Rac-1. Efferocytosis has modifiable targets, which can be exploited for the treatment of several diseases, although limited attention has been given to the mechanisms by which statins regulate efferocytosis and the resulting therapeutic implications. In this review, we will elaborate on the mechanisms underlying the modulation of apoptotic cell clearance by statins, which, in turn, inhibits uncontrolled inflammation and ensuing diseases.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Apoptose , Colesterol , Coenzima A/farmacologia , Citocinas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Necrose/tratamento farmacológico , Oxirredutases , Fagocitose/fisiologia , Proteínas rho de Ligação ao GTPRESUMO
BACKGROUND: MicroRNAs (miRNAs) are non-coding, endogenous, single-stranded, small (21-25 nucleotides) RNAs. Various target genes at the post-transcriptional stage are modulated by miRNAs that are involved in the regulation of a variety of biological processes such as embryonic development, differentiation, proliferation, apoptosis, inflammation, and metabolic homeostasis. Abnormal miRNA expression is strongly associated with the pathogenesis of multiple common human diseases including cardiovascular diseases, cancer, hepatitis, and metabolic diseases. METHODS AND RESULTS: Various signaling pathways including transforming growth factor-ß, apoptosis, and Wnt signaling pathways have also been characterized to play an essential role in kidney diseases. Most importantly, miRNA-targeted pharmaceutical manipulation has represented a promising new therapeutic approach against kidney diseases. Furthermore, miRNAs such as miR-30e-5p, miR-98-5p, miR-30d-5p, miR-30a-5p, miR-194-5p, and miR-192-5p may be potentially employed as biomarkers for various human kidney diseases. CONCLUSIONS: A significant correlation has also been found between some miRNAs and the clinical markers of renal function like baseline estimated glomerular filtration rate (eGFR). Classification of miRNAs in different genetic renal disorders may promote discoveries in developing innovative therapeutic interventions and treatment tools. Herein, the recent advances in miRNAs associated with renal pathogenesis, emphasizing genetic kidney diseases and development, have been summarized.
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Nefropatias , MicroRNAs , Biomarcadores , Perfilação da Expressão Gênica , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Nefropatias/genética , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
K-Ras activating mutations are significantly associated with tumor progression and aggressive metastatic behavior in various human cancers including pancreatic cancer. So far, despite a large number of concerted efforts, targeting of mutant-type K-Ras has not been successful. In this regard, we aimed to target this oncogene by a combinational approach consisting of small peptide and small molecule inhibitors. Based on a comprehensive analysis of structural and physicochemical properties of predominantly K-Ras mutants, an anti-cancer peptide library and a small molecule library were screened to simultaneously target oncogenic mutations and functional domains of mutant-type K-Ras located in the P-loop, switch I, and switch II regions. The selected peptide and small molecule showed notable binding affinities to their corresponding binding sites, and hindered the growth of tumor cells carrying K-RasG12D and K-RasG12C mutations. Of note, the expression of K-Ras downstream genes (i.e., CTNNB1, CCND1) was diminished in the treated Kras-positive cells. In conclusion, our combinational platform signifies a new potential for blockade of oncogenic K-Ras and thereby prevention of tumor progression and metastasis. However, further validations are still required regarding the in vitro and in vivo efficacy and safety of this approach.
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Inibidores Enzimáticos , Genes ras , Mutação , Neoplasias Pancreáticas , Peptídeos , Proteínas Proto-Oncogênicas p21(ras) , Bibliotecas de Moléculas Pequenas , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Peptídeos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Cholangiocarcinoma (CCA) is a type of cancer with increasing prevalence around the world that originates from cholangiocytes, the epithelial cells of the bile duct. The tumor begins insidiously and is distinguished by high grade neoplasm, poor outcome, and high risk for recurrence. Liver transplantation has become broadly accepted as a treatment option for CCA. Liver transplantation is expected to play a crucial role as palliative and curative therapy for unresectable hilar CCA and intrahepatic CCA. The purpose of this study was to determine which cases with CCA should be subjected to liver transplantation instead of resection, although reported post-transplant recurrence rate averages approximately 20%. This review also aims to highlight the molecular current frontiers of CCA and directions of liver transplantation for CCA.
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Brucellosis is considered as the most common bacterial zoonosis in the world. Although the laboratory findings are the most reliable diagnosis today, the current laboratory methods have many limitations. This research aimed to design and evaluate the performance of a novel technique based on the localized surface plasmon resonance (LSPR) to eliminate or reduce existing shortcomings. For this purpose, smooth lipopolysaccharides were extracted from Brucella melitensis and Brucella abortus and fixed on the surface of the gold nanoparticles through covalent interactions. After some optimizing processes, dynamic light scattering was used to characterize the probe. The detection of captured anti-Brucella antibody was performed by measuring the redshift on LSPR peak followed by the determination of cutoff value, which indicated a significant difference between controls and true positive patients (P value < 0.01). Furthermore, 40 sera from true negative samples and positive patients were used to evaluate the performance of this method by comparing its outcomes with the gold standard (culture), standard tube agglutination test, and anti-brucellosis IgM and IgG levels (ELISA). The sensitivity, specificity, positive predictive value, and negative predictive value showed an appropriate performance of the LSPR-based method (85%, 100%, 100%, and 86%, respectively). The current research results provide a promising fast, convenient, and inexpensive method for detecting the anti-Brucella antibodies in human sera, which can be widely used in medical laboratories to diagnose brucellosis quickly and effectively.
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It is hypothesized that liver impairment caused by coronavirus disease 2019 (COVID-19) infection might play a central role in severe clinical presentations. Liver injury is closely associated with severe disease and, even with antiviral drugs, have a poor prognosis in COVID-19 patients. In addition to the common hepatobiliary disorders caused by COVID-19, patients with pre-existing liver diseases demand special considerations during the current pandemic. Thus, it is vital that upon clinical presentation, patients with concurrent pre-existing liver disease associated with metabolic dysfunction and COVID-19 be managed properly to prevent liver failure. Careful monitoring and early detection of liver damage through biomarkers after hospitalization for COVID-19 is underscored in all cases, particularly in those with pre-existing metabolic liver injury. The purpose of this study was to determine most recent evidence regarding causality, potential risk factors, and challenges, therapeutic options, and management of COVID-19 infection in vulnerable patients with pre-existing liver injury. This review aims to highlight the current frontier of COVID-19 infection and liver injury and the direction of liver injury in these patients.
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Several studies have tried to find an efficient agent to prevent or reverse gentamicin (Gm) induced acute kidney injury (AKI). In this study, we assessed the potential renal protective effects of Descurainia sophia (L.) Webb ex Prantl against Gm-induced nephrotoxicity in rats. Thirty-five male Wistar rats were categorized in five groups (n = 7 per group). Control group was treated with normal saline. In four experimental groups, the rats were initially treated with normal saline (A), 800 (B), 1600 (C) and 2400 (D) mg/kg Descurainia sophia respectively for 28 days. After that, the rats of experimental groups were treated with Gm (80 mg/Kg) for 7 consecutive days. Blood and urine markers, as well as apoptosis and histological features were determined. Serum BUN, creatinine, cholesterol, and triglycerides level, as well as urinary excretion of Na+ significantly increased in group A. Furthermore, Gm induced inflammatory cells infiltration, apoptosis, and renal cells injuries in rats were pretreated with normal saline (group A). However, in the rats pretreated with Descurainia sophia extract (groups B, C, and D, there were significant and dose-dependent reductions in serum BUN, creatinine, cholesterol and triglyceride, urinary Na+ excretion, apoptosis rate, and inflammatory cells infiltration in renal tissues. Overall, Descurainia sophia showed significant protective effects against Gm-induced AKI by alleviating biochemical and histological markers of renal toxicity.
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CD47, a member of the immunoglobulin superfamily, is an important "Don't Eat-Me" signal in phagocytosis process [clearance of apoptotic cells] as well as a regulator of the adaptive immune response. The lower level of CD47 on the cell surface leads to the clearance of apoptotic cells. Dysregulation of CD47 plays a critical role in the development of disorders, particularly cancers. In cancers, recognition of CD47 overexpression on the surface of cancer cells by its receptor, SIRPα on the phagocytic cells, inhibits phagocytosis of cancer cells. Thus, blocking of CD47-SIRPα signaling axis might be as a promising therapeutic target, which promotes phagocytosis of cancer cells, antigen-presenting cell function as well as adaptive T cell-mediated anti-cancer immunity. In this respect, it has been reported that CD47 expression can be regulated by microRNAs (miRNAs). MiRNAs can regulate phagocytosis of macrophages apoptotic process, drug resistance, relapse of disease, radio-sensitivity, and suppress cell proliferation, migration, and invasion through post-transcriptional regulation of CD47-SIRPα signaling axis. Moreover, the regulation of CD47 expression by miRNAs and combination with conventional cytotoxic drugs together with the help of nano-delivery represent a valuable opportunity for effective cancer treatment. In this review, we review studies that evaluate the role of miRNAs in the regulation of CD47-SIRPα in disorders to achieve a novel preventive, diagnostic, and therapeutic strategy.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct. Confirmed.Journal standard instruction requires a structured abstract; however, none was provided. Please supply an Abstract with subsections..Not confirmed. This is a review article. According to submission guidelines: "The abstract should be presented divided into subheadings (unless it is a mini or full review article)". Kindly check and confirm whether the corresponding authors and mail ID are correctly identified. Confirmed.
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Antígenos de Diferenciação/metabolismo , Antineoplásicos/farmacologia , Antígeno CD47/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Interferência de RNA , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antígenos de Diferenciação/genética , Antineoplásicos/administração & dosagem , Antígeno CD47/genética , Gerenciamento Clínico , Suscetibilidade a Doenças , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Especificidade de Órgãos , Fagocitose/efeitos dos fármacos , Receptores Imunológicos/genéticaRESUMO
Recently, the novel coronavirus disease 2019 (COVID-19), has attracted the attention of scientists where it has a high mortality rate among older adults and individuals suffering from chronic diseases, such as chronic kidney diseases (CKD). It is important to elucidate molecular mechanisms by which COVID-19 affects the kidneys and accordingly develop proper nutritional and pharmacological strategies. Although numerous studies have recently recommended several approaches for the management of COVID-19 in CKD, its impact on patients with renal diseases remains the biggest challenge worldwide. In this paper, we review the most recent evidence regarding causality, potential nutritional supplements, therapeutic options, and management of COVID-19 infection in vulnerable individuals and patients with CKD. To date, there is no effective treatment for COVID-19-induced kidney dysfunction, and current treatments are yet limited to anti-inflammatory (e.g. ibuprofen) and anti-viral medications (e.g. Remdesivir, and Chloroquine/Hydroxychloroquine) that may increase the chance of treatment. In conclusion, the knowledge about kidney damage in COVID-19 is very limited, and this review improves our ability to introduce novel approaches for future clinical trials for this contiguous disease.
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P-Coumaric acid (p-CA) is a hydroxycinnamic acid, an organic compound that is a hydroxyl derivative of cinnamic acid. P-CA is the most abundant isomer in nature and can be found in a wide variety of edible plants such as fungi, peanuts, navy beans, tomatoes, carrots, basil, and garlic. Recently, the therapeutic properties of p-CA have received a great deal of attention from scientific society. Here, we described the medicinal effects of p-CA on various pathological conditions. This review was performed via evaluating PubMed reported studies from January 2010 to January 2020. Also, reference lists were checked to find additional studies. All intermediation or complementarity of animal models, case-control and cohort studies, in vitro studies, and controlled trials (CTs) on p-CA were acceptable. However plant extract studies without indication of main active substances were excluded due to the considerable diversities and heterogeneities. According to recent evidence regarding the beneficial effects of p-CA, numerous diseases such as nephropathies, cardiovascular diseases, neuroinflammatory diseases, liver diseases, cancers, and some metabolic disorders could potentially be controlled by this natural herb. Interestingly, autophagy is a novel molecular mechanism involved in the crosstalk between classic effects of p-CA and introduces alternative therapeutic pathways for this compound. Much work remains in clarifying the main therapeutic properties among the various p-CA effects; these will be the subject of forthcoming work, resulting in presenting further mechanism of action.
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Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Ácidos Cumáricos/uso terapêutico , Animais , HumanosRESUMO
OBJECTIVES: Post-dural Puncture Headache (PDPH) is prevalent among individuals undergoing lumbar punctures. The non-invasive effect of some drugs, such as aminophylline on PDPH has been investigated in several clinical studies. As there is no comprehensive systematic review and meta-analysis about the preventive and therapeutic effects of aminophylline on PDPH in the literature, the clinical effectiveness of this drug on the prevention and/or treatment of PDPH will be assessed in this study. METHODS: PubMed/MEDLINE, Embase, WoS (Clarivate Analytics), the Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL Complete, Scopus, and Google Scholar as electronic databases will be precisely searched for clinical studies that assessed the effect of aminophylline on PDPH. Studies between 01-01-1980 and 30-06-2020 will be evaluated in this study, and there will not be any language restrictions. Contradictions between the reviewers within any phase of the study (screening, selecting, quality assessment, and data extraction) will be resolved by consensus; in case of unsolved disagreements, a third reviewer will eventually decide. The combination method will be applied according to the methodological resemblance in the selected articles using the Random Effect Model or the Fixed Effect Model. Also, for the included articles, forest plots will be drawn. For assessing statistical heterogeneity, the I2 statistic and the Q-statistic test will be applied. In addition, funnel plots will be used for assessing non-significant study effects and potential reporting bias. Furthermore, Egger's and Begg's tests will be done, and publication bias will be indicated by significant findings (P < 0.05). CONCLUSIONS: It is expected that the results of this study will be of benefit to researchers and clinicians for managing PDPH, and will be reported in conferences and publications.
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Immunotherapy approaches consisting of genetically modified immune cells have become a promising platform for cancer treatment. Such 'living' therapies targeting tumor antigens have shown success in many cancer patients in the form of durable responses in a growing number of clinical studies. Besides, a large number of ongoing studies have been designed to introduce reliable methods for identification of tumor antigens. In addition, technical and biotechnological developments are being applied to the generation and expansion of genetically modified immune cells. In this review, we summarize and discuss the latest progress and current challenges in the tumor antigen landscape and in the generation of genetically modified immune cells in view of their clinical efficacy, either as monotherapy or combinational therapy.
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Antígenos de Neoplasias/metabolismo , Células Dendríticas/transplante , Terapia Genética , Imunoterapia Adotiva , Subpopulações de Linfócitos/transplante , Macrófagos/transplante , Neoplasias/terapia , Receptores de Antígenos Quiméricos/genética , Animais , Antígenos de Neoplasias/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/transplante , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/transplante , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Resultado do Tratamento , Microambiente TumoralRESUMO
Chimeric antigen receptor (CAR) T-cells represent a paradigm shift in cancer immunotherapy and a new milestone in the history of oncology. In 2017, the Food and Drug Administration approved two CD19-targeted CAR T-cell therapies (Kymriah™, Novartis, and Yescarta™, Kite Pharma/Gilead Sciences) that have remarkable efficacy in some B-cell malignancies. The CAR approach is currently being evaluated in multiple pivotal trials designed for the immunotherapy of hematological malignancies as well as solid tumors. To generate CAR T-cells ex vivo, lentiviral vectors (LVs) are particularly appealing due to their ability to stably integrate relatively large DNA inserts, and to efficiently transduce both dividing and nondividing cells. This review discusses the latest advances and challenges in the design and production of CAR T-cells, and the good manufacturing practices (GMP)-grade production process of LVs used as a gene transfer vehicle. New developments in the application of CAR T-cell therapy are also outlined with particular emphasis on next-generation allogeneic CAR T-cells.
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Vetores Genéticos/metabolismo , Imunoterapia Adotiva , Lentivirus/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Animais , Ensaios Clínicos como Assunto , Humanos , Neoplasias/imunologia , Neoplasias/terapiaRESUMO
The interplay between H2 S and nitric oxide (NO) is thought to contribute to renal functions. The current study was designed to assess the role of NO in mediating the renoprotective effects of hydrogen sulfide in the 5/6 nephrectomy (5/6 Nx) animal model. Forty rats were randomly assigned to 5 experimental groups: (a) Sham; (b) 5/6 Nx; (c) 5/6Nx+sodium hydrosulfide-a donor of H 2 S, (5/6Nx+sodium hydrosulfide [NaHS]); (d) 5/6Nx+NaHS+ L-NAME (a nonspecific nitric oxide synthase [NOS] inhibitor); (e) 5/6Nx+NaHS+aminoguanidine (a selective inhibitor of inducible NOS [iNOS]). Twelve weeks after 5/6 Nx, we assessed the expressions of iNOS and endothelial NOS (eNOS), oxidative/antioxidant status, renal fibrosis, urine N-acetyl-b-glucosaminidase (NAG) activity as the markers of kidney injury and various markers of apoptosis, inflammation, remodeling, and autophagy. NaHS treatment protected the animals against chronic kidney injury as depicted by improved oxidative/antioxidant status, reduced apoptosis, and autophagy and attenuated messenger RNA (mRNA) expression of genes associated with inflammation, remodeling, and NAG activity. Eight weeks Nω-nitro-l-arginine methyl ester ( L-NAME) administration reduced the protective effects of hydrogen sulfide. In contrast, aminoguanidine augmented the beneficial effects of hydrogen sulfide. Our finding revealed some fascinating interactions between NO and H 2 S in the kidney. Moreover, the study suggests that NO, in an isoform-dependent manner, can exert renoprotective effects in 5/6 Nx model of CKD.
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Autofagia/fisiologia , Sulfeto de Hidrogênio/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Insuficiência Renal Crônica/tratamento farmacológico , Sulfetos/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Guanidinas/administração & dosagem , Guanidinas/farmacologia , Rim/enzimologia , Rim/patologia , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , NG-Nitroarginina Metil Éster/farmacologia , Tamanho do Órgão , Distribuição Aleatória , Ratos , Ratos Wistar , Insuficiência Renal Crônica/patologia , Sulfetos/administração & dosagemRESUMO
Chronic kidney disease (CKD) is a major public health problem worldwide and is associated with spatial learning deficits. The aim of the present study was to evaluate the protective effects of hydrogen sulfide (H2S) on CKD-mediated behavioral deficits with emphasis to the role of nitric oxide (NO) in these effects. Fifty rats were randomly allocated to five experimental groups including: sham, Five-sixth (5/6) nephrectomy (Nx), 5/6Nx + NaHS, 5/6Nx + NaHS+L-nitroarginine methyl ester (L-NAME), and 5/6Nx + NaHS+aminoguanidine (AMG). Twelve weeks after 5/6Nx, we evaluated proteinuria, creatinine clearance (CrCl), oxidative/antioxidant status, and hippocampus neuro-inflammation and NO synthase genes in all groups. Furthermore, training trials of all animals were conducted in the Morris water maze (MWM) task one day before animal euthanizing. As predicted, 5/6Nx induced several injuries, including enhancement of proteinuria and reduction of CCr, oxidant/antioxidant imbalance and up-regulation of TNF-α and IL-1ß gene expressions in the hippocampus tissues. As predicted, 5/6Nx resulted in learning and memory impairments, and increased escape latency during acquisition trials in the MWM task. Interestingly, NaHS (H2S donor) improved behavioral deficits, renal dysfunction, accelerated anti-oxidant/anti-inflammatory responses and increased eNOS and decreased iNOS. Moreover, these effects of NaHS were prevented by L-NAME but not AMG co-administration. In conclusion, H2S ameliorates CKD-mediated brain dysfunctions, through interaction with NO signaling in the hippocampus.