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Idiopathic pulmonary fibrosis (IPF) is a continuous, progressive, and lethal age-related respiratory disease. It is characterized by condensed and rigid lung tissue, which leads to a decline in the normal functioning of the lungs. The pathophysiology of IPF has still not been completely elucidated, so current strategies are lagging behind with respect to improving the condition of patients with IPF and increasing their survival rate. The desire for a better understanding of the pathobiology of IPF and its early detection has led to the identification of various biomarkers associated with IPF. The use of drugs such as pirfenidone and nintedanib as a safe and effective treatment alternative have marked a new chapter in the treatment of IPF. However, nonpharmacological therapies, involving long-term oxygen therapy, transplantation of the lungs, pulmonary rehabilitation, ventilation, and palliative care for cough and dyspnea, are still considered to be beneficial as supplementary methods for IPF therapy. A major risk factor for IPF is aging, with associated hallmarks such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis, and mitochondrial dysfunction. These are promising earmarks for the development of potential therapy for the disease. In this review, we have discussed current and emerging novel therapeutic strategies for IPF, especially for targets associated with age-related mechanisms.
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Fibrose Pulmonar Idiopática , Humanos , Fibrose Pulmonar Idiopática/terapia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/fisiopatologia , Indóis/uso terapêutico , Animais , Piridonas/uso terapêutico , Envelhecimento/fisiologiaRESUMO
Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.
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Leucemia Mieloide Aguda , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia , Imunoterapia Adotiva , Leucemia Mieloide Aguda/terapia , Receptores de Antígenos Quiméricos/genética , Linfócitos TRESUMO
Recently, mesenchymal stem/stromal cells (MSCs) due to their pro-angiogenic, anti-apoptotic, and immunoregulatory competencies along with fewer ethical issues are presented as a rational strategy for regenerative medicine. Current reports have signified that the pleiotropic effects of MSCs are not related to their differentiation potentials, but rather are exerted through the release of soluble paracrine molecules. Being nano-sized, non-toxic, biocompatible, barely immunogenic, and owning targeting capability and organotropism, exosomes are considered nanocarriers for their possible use in diagnosis and therapy. Exosomes convey functional molecules such as long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs), proteins (e.g., chemokine and cytokine), and lipids from MSCs to the target cells. They participate in intercellular interaction procedures and enable the repair of damaged or diseased tissues and organs. Findings have evidenced that exosomes alone are liable for the beneficial influences of MSCs in a myriad of experimental models, suggesting that MSC- exosomes can be utilized to establish a novel cell-free therapeutic strategy for the treatment of varied human disorders, encompassing myocardial infarction (MI), CNS-related disorders, musculoskeletal disorders (e.g. arthritis), kidney diseases, liver diseases, lung diseases, as well as cutaneous wounds. Importantly, compared with MSCs, MSC- exosomes serve more steady entities and reduced safety risks concerning the injection of live cells, such as microvasculature occlusion risk. In the current review, we will discuss the therapeutic potential of MSC- exosomes as an innovative approach in the context of regenerative medicine and highlight the recent knowledge on MSC- exosomes in translational medicine, focusing on in vivo researches.
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Exossomos , Células-Tronco Mesenquimais , MicroRNAs , Diferenciação Celular , Humanos , Medicina RegenerativaRESUMO
Mesenchymal stem/stromal cell (MSC)-based therapy has become an attractive and advanced scientific research area in the context of cancer therapy. This interest is closely linked to the MSC-marked tropism for tumors, suggesting them as a rational and effective vehicle for drug delivery for both hematological and solid malignancies. Nonetheless, the therapeutic application of the MSCs in human tumors is still controversial because of the induction of several signaling pathways largely contributing to tumor progression and metastasis. In spite of some evidence supporting that MSCs may sustain cancer pathogenesis, increasing proofs have indicated the suppressive influences of MSCs on tumor cells. During the last years, a myriad of preclinical and some clinical studies have been carried out or are ongoing to address the safety and efficacy of the MSC-based delivery of therapeutic agents in diverse types of malignancies. A large number of studies have focused on the MSC application as delivery vehicles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), chemotherapeutic drug such as gemcitabine (GCB), paclitaxel (PTX), and doxorubicin (DOX), prodrugs such as 5-fluorocytosine (5-FC) and ganciclovir (GCV), and immune cell-activating cytokines along with oncolytic virus. In the current review, we evaluate the latest findings rendering the potential of MSCs to be employed as potent gene/drug delivery vehicle for inducing tumor regression with a special focus on the in vivo reports performed during the last two decades.
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Non-Hodgkin's lymphoma (NHL) is a cancer that starts in the lymphatic system. In NHL, the important part of the immune system, a type of white blood cells called lymphocytes become cancerous. NHL subtypes include marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma (FL), and lymphoplasmacytic lymphoma. The disease can emerge in either aggressive or indolent form. 5-year survival duration after diagnosis is poor among patients with aggressive/relapsing form of NHL. Therefore, it is necessary to understand the molecular mechanisms of pathogenesis involved in NHL establishment and progression. In the next step, we can develop innovative therapies for NHL based on our knowledge in signaling pathways, surface antigens, and tumor milieu of NHL. In the recent few decades, several treatment solutions of NHL mainly based on targeted/directed therapies have been evaluated. These approaches include B-cell receptor (BCR) signaling inhibitors, immunomodulatory agents, monoclonal antibodies (mAbs), epigenetic modulators, Bcl-2 inhibitors, checkpoint inhibitors, and T-cell therapy. In recent years, methods based on T cell immunotherapy have been considered as a novel promising anti-cancer strategy in the treatment of various types of cancers, and particularly in blood cancers. These methods could significantly increase the capacity of the immune system to induce durable anti-cancer responses in patients with chemotherapy-resistant lymphoma. One of the promising therapy methods involved in the triumph of immunotherapy is the chimeric antigen receptor (CAR) T cells with dramatically improved killing activity against tumor cells. The CAR-T cell-based anti-cancer therapy targeting a pan-B-cell marker, CD19 is recently approved by the US Food and Drug Administration (FDA) for the treatment of chemotherapy-resistant B-cell NHL. In this review, we will discuss the structure, molecular mechanisms, results of clinical trials, and the toxicity of CAR-T cell-based therapies. Also, we will criticize the clinical aspects, the treatment considerations, and the challenges and possible drawbacks of the application of CAR-T cells in the treatment of NHL.
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Imunoterapia Adotiva/métodos , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Engenharia Genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/tendências , Resultado do TratamentoRESUMO
Adoptive cell therapy has received a great deal of interest in the treatment of advanced cancers that are resistant to traditional therapy. The tremendous success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells in the treatment of cancer, especially hematological cancers, has exposed CAR's potential. However, the toxicity and significant limitations of CAR-T cell immunotherapy prompted research into other immune cells as potential candidates for CAR engineering. NK cells are a major component of the innate immune system, especially for tumor immunosurveillance. They have a higher propensity for immunotherapy in hematologic malignancies because they can detect and eliminate cancerous cells more effectively. In comparison to CAR-T cells, CAR-NK cells can be prepared from allogeneic donors and are safer with a lower chance of cytokine release syndrome and graft-versus-host disease, as well as being a more efficient antitumor activity with high efficiency for off-the-shelf production. Moreover, CAR-NK cells may be modified to target various antigens while also increasing their expansion and survival in vivo. Extensive preclinical research has shown that NK cells can be effectively engineered to express CARs with substantial cytotoxic activity against both hematological and solid tumors, establishing evidence for potential clinical trials of CAR-NK cells. In this review, we discuss recent advances in CAR-NK cell engineering in a variety of hematological malignancies, as well as the main challenges that influence the outcomes of CAR-NK cell-based tumor immunotherapies.
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Neoplasias Hematológicas , Receptores de Antígenos Quiméricos , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia Adotiva , Células Matadoras Naturais , Receptores de Antígenos Quiméricos/genética , Linfócitos TRESUMO
Despite many recent advances on cancer novel therapies, researchers have yet a long way to cure cancer. They have to deal with tough challenges before they can reach success. Nonetheless, it seems that recently developed immunotherapy-based therapy approaches such as adoptive cell transfer (ACT) have emerged as a promising therapeutic strategy against various kinds of tumors even the cancers in the blood (liquid cancers). The hematological (liquid) cancers are hard to be targeted by usual cancer therapies, for they do not form localized solid tumors. Until recently, two types of ACTs have been developed and introduced; tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR)-T cells which the latter is the subject of our discussion. It is interesting about engineered CAR-T cells that they are genetically endowed with unique cancer-specific characteristics, so they can use the potency of the host immune system to fight against either solid or liquid cancers. Multiple myeloma (MM) or simply referred to as myeloma is a type of hematological malignancy that affects the plasma cells. The cancerous plasma cells produce immunoglobulins (antibodies) uncontrollably which consequently damage the tissues and organs and break the immune system function. Although the last few years have seen significant progressions in the treatment of MM, still a complete remission remains unconvincing. MM is a medically challenging and stubborn disease with a disappointingly low rate of survival rate. When comparing the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma), myeloma has the lowest 5-year survival rate (around 40%). A low survival rate indicates a high mortality rate with difficulty in treatment. Therefore, novel CAR-T cell-based therapies or combination therapies along with CAT-T cells may bring new hope for multiple myeloma patients. CAR-T cell therapy has a high potential to improve the remission success rate in patients with MM. To date, many preclinical and clinical trial studies have been conducted to investigate the ability and capacity of CAR T cells in targeting the antigens on myeloma cells. Despite the problems and obstacles, CAR-T cell experiments in MM patients revealed a robust therapeutic potential. However, several factors might be considered during CAR-T cell therapy for better response and reduced side effects. Also, incorporating the CAT-T cell method into a combinational treatment schedule may be a promising approach. In this paper, with a greater emphasis on CAR-T cell application in the treatment of MM, we will discuss and introduce CAR-T cell's history and functions, their limitations, and the solutions to defeat the limitations and different types of modifications on CAR-T cells.
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Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia , Imunoterapia Adotiva , Mieloma Múltiplo/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Linfócitos TRESUMO
Over recent years, mesenchymal stem/stromal cells (MSCs) and their potential biomedical applications have received much attention from the global scientific community in an increasing manner. Firstly, MSCs were successfully isolated from human bone marrow (BM), but in the next steps, they were also extracted from other sources, mostly from the umbilical cord (UC) and adipose tissue (AT). The International Society for Cellular Therapy (ISCT) has suggested minimum criteria to identify and characterize MSCs as follows: plastic adherence, surface expression of CD73, D90, CD105 in the lack of expression of CD14, CD34, CD45, and human leucocyte antigen-DR (HLA-DR), and also the capability to differentiate to multiple cell types including adipocyte, chondrocyte, or osteoblast in vitro depends on culture conditions. However, these distinct properties, including self-renewability, multipotency, and easy accessibility are just one side of the coin; another side is their huge secretome which is comprised of hundreds of mediators, cytokines, and signaling molecules and can effectively modulate the inflammatory responses and control the infiltration process that finally leads to a regulated tissue repair/healing or regeneration process. MSC-mediated immunomodulation is a direct result of a harmonic synergy of MSC-released signaling molecules (i.e., mediators, cytokines, and chemokines), the reaction of immune cells and other target cells to those molecules, and also feedback in the MSC-molecule-target cell axis. These features make MSCs a respectable and eligible therapeutic candidate to be evaluated in immune-mediated disorders, such as graft versus host diseases (GVHD), multiple sclerosis (MS), Crohn's disease (CD), and osteoarthritis (OA), and even in immune-dysregulating infectious diseases such as the novel coronavirus disease 2019 (COVID-19). This paper discussed the therapeutic applications of MSC secretome and its biomedical aspects related to immune-mediated conditions. Sources for MSC extraction, their migration and homing properties, therapeutic molecules released by MSCs, and the pathways and molecular mechanisms possibly involved in the exceptional immunoregulatory competence of MSCs were discussed. Besides, the novel discoveries and recent findings on immunomodulatory plasticity of MSCs, clinical applications, and the methods required for their use as an effective therapeutic option in patients with immune-mediated/immune-dysregulating diseases were highlighted.
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COVID-19 , Imunomodulação , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/terapia , HumanosRESUMO
Tuberculosis (TB) is a highly infectious disease, and it has the highest global burden on India with 21% prevalence rate and 27% of patients who do not receive pertinent medical treatment. Although India spends 23 billion dollars annually towards medical expenses for TB, India still ranks among the top 2 countries with the highest incidence and prevalence rates with more than 300,000 deaths excluding the patients with HIV and TB calling for prompt consideration. India faces a great challenge socially and economically. They lack a uniform health care system, making it burdensome to use effective surveillance techniques for prevention of TB. Currently, India is working on resolving the issue meticulously through the web-based application program 'Nikshay' with other strategies like Revised National Tuberculosis Control Program (RNTCP) and World Health Organization's The End TB Strategy. India's cardinal goal is to make advanced diagnostic tools made available and public-private healthcare sector collaboration. India needs to focus more on primary prevention by effective policy formation and campaign which promote proper sanitation and vaccine administration while educating the layman.
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Avaliação de Processos e Resultados em Cuidados de Saúde , Tuberculose Resistente a Múltiplos Medicamentos/prevenção & controle , Tuberculose Pulmonar/prevenção & controle , Humanos , Índia , Programas Nacionais de SaúdeRESUMO
BACKGROUND: CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. MAIN BODY: Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as "living drugs" presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. CONCLUSION: Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.
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Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos/genética , Linfócitos T , Microambiente TumoralRESUMO
Angiogenesis is a crucial area in scientific research because it involves many important physiological and pathological processes. Indeed, angiogenesis is critical for normal physiological processes, including wound healing and embryonic development, as well as being a component of many disorders, such as rheumatoid arthritis, obesity, and diabetic retinopathies. Investigations of angiogenic mechanisms require assays that can activate the critical steps of angiogenesis as well as provide a tool for assessing the efficacy of therapeutic agents. Thus, angiogenesis assays are key tools for studying the mechanisms of angiogenesis and identifying the potential therapeutic strategies to modulate neovascularization. However, the regulation of angiogenesis is highly complex and not fully understood. Difficulties in assessing the regulators of angiogenic response have necessitated the development of an alternative approach. In this paper, we review the standard models for the study of tumor angiogenesis on the macroscopic scale that include in vitro, in vivo, and computational models. We also highlight the differences in several modeling approaches and describe key advances in understanding the computational models that contributed to the knowledge base of the field.
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Inibidores da Angiogênese/uso terapêutico , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica/patologia , Animais , Proliferação de Células , Embrião de Galinha , Membrana Corioalantoide , Técnicas de Cocultura , Colágeno , Simulação por Computador , Combinação de Medicamentos , Células Endoteliais/metabolismo , Endotélio/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Técnicas In Vitro , Laminina , Camundongos , Modelos Teóricos , Proteoglicanas , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , CicatrizaçãoRESUMO
Ovarian cancer is the second most common gynaecological malignancy. It usually occurs in women older than 50 years, and because 75% of cases are diagnosed at stage III or IV it is associated with poor diagnosis. Despite the chemosensitivity of intraperitoneal chemotherapy, the majority of patients is relapsed and eventually dies. In addition to the challenge of early detection, its treatment presents several challenges like the route of administration, resistance to therapy with recurrence and specific targeting of cancer to reduce cytotoxicity and side effects. In ovarian cancer therapy, nanocarriers help overcome problems of poor aqueous solubility of chemotherapeutic drugs and enhance their delivery to the tumour sites either by passive or active targeting, and thus reducing adverse side effects to the healthy tissues. Moreover, the bioavailability to the tumour site is increased by the enhanced permeability and retention (EPR) mechanism. The present review aims to describe the current conventional treatment with special reference to passively and actively targeted drug delivery systems (DDSs) towards specific receptors designed against ovarian cancer to overcome the drawbacks of conventional delivery. Conclusively, targeted nanocarriers would optimise the intra-tumour distribution, followed by drug delivery into the intracellular compartment. These features may contribute to greater therapeutic effect.
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Sistemas de Liberação de Medicamentos/métodos , Terapia de Alvo Molecular/métodos , Nanomedicina/métodos , Neoplasias Ovarianas/terapia , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologiaRESUMO
Anti-vascular endothelial growth factor agents have been widely used to treat several eye diseases including age-related macular degeneration (AMD). An approach to maximize the local concentration of drug at the target site and minimize systemic exposure is to be sought. Sunitinib malate, a multiple receptor tyrosine kinase inhibitor was encapsulated in poly(lactic-co-glycolic acid) nanoparticles to impart sustained release. The residence time in vitreal fluid was further increased by incorporating nanoparticles in thermo-reversible gel. Nanoparticles were characterized using TEM, DSC, FTIR, and in vitro drug release profile. The cytotoxicity of the formulation was assessed on ARPE-19 cells using the MTT assay. The cellular uptake, wound scratch assay, and VEGF expression levels were determined in in vitro settings. The optimized formulation had a particle size of 164.5 nm and zeta potential of - 18.27 mV. The entrapment efficiency of 72.0% ± 3.5% and percent drug loading of 9.1 ± 0.7% were achieved. The viability of ARPE-19 cells was greater than 90% for gel loaded, as such and blank nanoparticles at 10 µM and 20 µM concentration tested, whereas for drug solution viability was found to be 83% and 71% respectively at above concentration. The cell viability results suggest the compatibility of the developed formulation. Evaluation of cellular uptake, wound scratch assay, and VEGF expression levels for the developed formulations indicated that the formulation had higher uptake, superior anti-angiogenic potential, and prolonged inhibition of VEGF activity compared with drug solution. The results showed successful development of sunitinib-loaded nanoparticle-based thermo-reversible gel which may be used for the treatment of neovascular AMD.
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Inibidores da Angiogênese/uso terapêutico , Nanopartículas/uso terapêutico , Sunitinibe/uso terapêutico , Degeneração Macular Exsudativa/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Humanos , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Sunitinibe/administração & dosagem , Acuidade VisualRESUMO
BACKGROUND: Toluene was an organic compound used in chemical and drug industries, the main source of toluene emissions from fires. To reduce and even eliminate toluene toxins in chemical component could be using detoxification by foods. AIM: This research aimed to calculate the intake of foods rich in CYP2E1 enzyme and glycine to improve toluene detoxification. METHODS: The type of research was a descriptive study. The subject of the study was 51 workers in Romokalisari Surabaya who had worked for more than or equal to 10 years. Variables were body weight, duration of working (years), working time per week (days), and working time per day (hours). The breathing rate, intake of non-carcinogen per respondent, can be calculated by variables before. Then, the effective dose of food rich in CYP2E1 enzyme and glycine will be obtained. RESULTS: Majority respondents had toluene concentrations below the threshold limit value (TLV). The highest effective dose of foods rich in CYP2E1 enzymes such as beef liver, beef brain, and salmon was 239.61 g, 745.45 g, and 203.3 g. Also, foods rich in glycines such as seaweed, tuna, and spinach were 432.98 mg, 934.41 mg, and 2070.71 mg. CONCLUSION: The level of adequacy of the CYP2E1 enzyme and glycine of each person was different and varied. The effective dose required by each respondent depending on weight, length of work, and concentration of benzene in the workplace. The greater the toluene concentration, the greater the needs for foods rich in CYP2E1 enzymes and glycine. Body weight can also be another factor in differences in individual intake. Weight, length of working, and toluene concentration can affect the intake of non-carcinogen in each which can affect the effective dose of foods.
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BACKGROUND: Benzene is a hazardous ingredient for health. Benzene is used as a latex glue solvent in the shoe industry. AIM: The purpose of the study was to analyse the relationship between benzene exposure with trans, trans-muconic acid (t, t-MA) and the blood profile of shoe workers in Romokalisari Surabaya. METHODS: The study was a cross-sectional design conducted in the shoe industry in Romokalisari Surabaya with some subjects of 20 shoe workers. Data collection was carried out by measuring benzene levels conducted at 8 measurement points in Surabaya Romokalisari, taking workers' blood, measuring body weight and conducting interviews with respondents. Data were analysed using correlation tests. RESULTS: The results showed that there was no relationship between benzene levels with t, t-MA (p-value = 0.205), there was no relationship between benzene Risk Quotient (RQ) and t, t-MA (p-value = 0.271) and there was no relationship between the Excess Cancer Risk (ECR) and blood profile of workers in Romokalisari. However, there were some abnormal blood profile parameters due to exposure to benzene although it was small. CONCLUSIONS: It seems another factors such as length of work, nutritional status, duration of exposure, weight, and frequency of exposure have a considerable contribution in the determination of intake of xenobiotic ingredients in the body to cause health effects especially blood profiles.
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BACKGROUND: The current treatment of ocular neovascularization requires frequent intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents that cause severe side effects. OBJECTIVE: The purpose of this study is to prepare and characterize a novel nanoscale delivery system of apatinib for ocular neovascularization. METHODS: The optimized formulation showed a particle size of 135.04 nm, polydispersity index (PDI) of 0.28 ± 0.07, encapsulation efficiency (EE) of 65.92%, zeta potential (ZP) of -23.70 ± 8.69 mV, and pH of 6.49 ± 0.20. In vitro release was carried out to demonstrate a 3.13-fold increase in the sustainability of apatinib-loaded nanoparticles versus free apatinib solution. RESULT: Cell viability and VEGFA and VEGFR2 expression were analyzed in animal retinal pigment epithelial (ARPE-19) cells. CONCLUSION: The results confirmed the hypothesis that apatinib nanoparticles decreased toxicity (1.36 ± 0.74 fold) and efficient VEGF inhibition (3.51 ± 0.02 fold) via VEGFR2 mediation.
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Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Antineoplásicos/química , Linhagem Celular , Portadores de Fármacos/química , Oftalmopatias/tratamento farmacológico , Humanos , Nanopartículas/química , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Piridinas/química , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Humanin is a novel neuronal peptide that has displayed potential in the treatment of Alzheimer's Disease through the suppression of inflammatory IL-6 cytokine receptors. Such receptors are found throughout the body, including the eye, suggesting its other potential applications. Age-related Macular Degeneration (AMD) is the leading cause of blindness in the developing world. There is no cure for this disease, and current treatments have several negative side effects associated with them, making finding other treatment options desirable. OBJECTIVE: In this study, the potential applications in treating AMD for a more potent humanin derivative, AGA-HNG, were studied. METHODS: AGA-HNG was synthesized and encapsulated in chitosan Nanoparticles (NPs), which were then characterized for their size, Encapsulation Efficiency (EE), and drug release. Their ability to suppress VEGF secretion and protect against oxidative apoptosis was studied in vitro using ARPE-19 cells. The chitosan NPs exhibited similar anti-VEGF properties and oxidative protection as the free protein while exhibiting superior pharmaceutical characteristics including biocompatibility and drug release. RESULTS: Drug-loaded NPs exhibited a radius of 346nm with desirable pharmacokinetic properties including a stable surface charge (19.5 ± 3.7 mV) and steady drug release capacity. AGA-HNG showed great promise in mediating apoptosis in hypoxic cells. They were also able to significantly reduce VEGF expression in vitro with reduced cellular toxicity compared to the free drug. CONCLUSION: The ability of this drug delivery system to reduce retinal apoptosis with desirable pharmacokinetic and biocompatible properties makes this a promising therapeutic option for AMD.
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Quitosana/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , Nanopartículas/administração & dosagem , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Degeneração Macular , Nanopartículas/química , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Idiopathic pulmonary fibrosis (IPF) is an age-related multifactorial disease featuring non-uniform lung fibrosis. The decisive cellular events at early stages of IPF are poorly understood. While the involvement of club cells in IPF pathogenesis is unclear, their migration has been associated with lung fibrosis. In this study, we labeled club cells immunohistochemically in IPF lungs using a club cell marker Claudin-10 (Cldn10), a unique protein based on the recent report which demonstrated that the appearance of Cldn10 in developing and repairing lungs precedes other club cell markers including club cell secretory protein (CCSP). Cldn10-positive cells in IPF lungs displayed marked pleomorphism and were found in varied arrangements, suggesting their phenoconversion. These results were corroborated by immunogold labeling for Cldn10. Further, immunohistochemical double-labeling for Cldn10 and α-smooth muscle actin (α-SMA) demonstrated that aberrant α-SMA signals are frequently encountered near disorganized Cldn10-positive cells in hyperplastic bronchiolar epithelium and thickened interstitium of IPF lungs. Collectively, these data indicate that club cells actively participate in the initiation and progression of IPF through phenoconversion involving the acquisition of proliferative and migratory abilities. Thus, our new findings open the possibility for club cell-targeted therapy to become a strategic option for the treatment of IPF.
Assuntos
Actinas/metabolismo , Células Epiteliais Alveolares/metabolismo , Movimento Celular , Claudinas/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Células Epiteliais Alveolares/citologia , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/metabolismo , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologiaRESUMO
Age-related macular degeneration (AMD) is one of the leading causes of blindness in the US affecting millions yearly. It is characterized by intraocular neovascularization, inflammation and retinal damage which can be ameliorated through intraocular injections of glucocorticoids. However, the complications that arise from repetitive injections as well as the difficulty posed by targeting the posterior segment of the eye make this interesting territory for the development of novel drug delivery systems (DDS). In the present study, we described the development of a DDS composed of triamcinolone acetonide-encapsulated PEGylated PLGA nanoparticles (NP) incorporated into PLGA-PEG-PLGA thermoreversible gel and its use against VEGF expression characteristic of AMD. We found that the NP with mean size of 208 ± 1.0 nm showed uniform size distribution and exhibited sustained release of the drug. We also demonstrated that the polymer can be injected as a solution and transition to a gel phase based on the biological temperature of the eye. Additionally, the proposed DDS was non-cytotoxic to ARPE-19 cells and significantly reduced VEGF expression by 43.5 ± 3.9% as compared to a 1.53 ± 11.1% reduction with triamcinolone. These results suggest the proposed DDS will contribute to the development of novel therapeutic strategies for AMD.