RESUMO
Photoperiod manipulation is emerging as an effective approach for regulating physiological functions in fish. This study aimed to assess the impact of photoperiod on the growth performance, haematological responses, and economic returns of the endangered and highly valued Indian butter catfish, Ompok bimaculatus. Fish with an average body weight of 28.60 ± 4.78 g were randomly placed in six FRP tanks, each measuring 120 × 45 × 60 cm3. Each tank contained 20 fish exposed to a light intensity of 1500 lx under different photoperiods [24:0 light: dark (L: D), 15 L: 9D, 12 L: 12D, 9 L: 15D, 0 L: 24D and a natural photoperiod (control)], and fed at a daily rate of 2% of their body weight twice daily for 60 days. The fish in the 15 L: 9D photoperiod exhibited the highest final weight (g), percentage weight gain, specific growth rate (SGR) and survival rate, while the lowest was displayed in 24 L: 0D photoperiod group. The feed conversion ratio (FCR) was at its lowest in the catfish subjected to the 15 L: 9D photoperiod. Regarding haematological parameters, the 15 L: 9D photoperiod group showed higher total erythrocyte count, total leukocyte count, haemoglobin levels, and haematocrit values compared to the other groups. Conversely, the 0 L: 24D group, which experienced prolonged darkness, exhibited the lowest values in these parameters. Moreover, the 24 L: 0D, 9 L: 15D, and 0 L: 24D groups displayed a lower mean corpuscular volume (MCV) but higher mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC) when compared to the control group. The economic analysis revealed that O. bimaculatus reared in a moderate photoperiod (15 L: 9D) displayed better growth, feed utilization, and overall health. This finding suggests that adopting a 15 L: 9D photoperiod can lead to enhanced production and improved economic returns for farmers culturing this high-value catfish in the future.
Assuntos
Peixes-Gato , Animais , Fotoperíodo , Peso Corporal , Índices de Eritrócitos/veterinária , Hematócrito/veterináriaRESUMO
Spinal cord injury (SCI) causes significant mortality and morbidity. Currently, no FDA-approved pharmacotherapy is available for treating SCI. Previously, low doses of estrogen (17ß-estradiol, E2) were shown to improve the post-injury outcome in a rat SCI model. However, the range of associated side effects makes advocating its therapeutic use difficult. Therefore, this study aimed at investigating the therapeutic efficacy of Premarin (PRM) in SCI. PRM is an FDA-approved E2 (10%) formulation, which is used for hormone replacement therapy with minimal risk of serious side effects. The effects of PRM on SCI were examined by magnetic resonance imaging, immunofluorescent staining, and western blot analysis in a rat model. SCI animals treated with vehicle alone, PRM, E2 receptor antagonist (ICI), or PRM + ICI were graded in a blinded way for locomotor function by using the Basso-Beattie-Bresnahan (BBB) locomotor scale. PRM treatment for 7 days decreased post-SCI lesion volume and attenuated neuronal cell death, inflammation, and axonal damage. PRM also altered the balance of pro- and anti-apoptotic proteins in favor of cell survival and improved angiogenesis and microvascular growth. Increased expression of estrogen receptors (ERs) ERα and ERß following PRM treatment and their inhibition by ER inhibitor indicated that the neuroprotection associated with PRM treatment might be E2-receptor mediated. The attenuation of glial activation with decreased inflammation and cell death, and increased angiogenesis by PRM led to improved functional outcome as determined by the BBB locomotor scale. These results suggest that PRM treatment has significant therapeutic implications for the improvement of post-SCI outcome.
Assuntos
Estrogênios Conjugados (USP)/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Modelos Animais de Doenças , Estradiol/metabolismo , Estrogênios/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Doenças Neurodegenerativas/metabolismo , Neuroproteção/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismoRESUMO
Background: Meningiomas represent â¼30% of primary central nervous system (CNS) tumors. Although advances in surgery and radiotherapy have significantly improved survival, there remains an important subset of patients whose tumors have more aggressive behavior and are refractory to conventional therapy. Recent advances in molecular genetics and epigenetics suggest that this aggressive behavior may be due to the deletion of the DNA repair and tumor suppressor gene, CHEK2, neurofibromatosis Type 2 (NF2) mutation on chromosome 22q12, and genetic abnormalities in multiple RTKs including FGFRs. Management of higher-grade meningiomas, such as anaplastic meningiomas (AM: WHO grade III), is truly challenging and there isn't an established chemotherapy option. We investigate the effect of active multi tyrosine receptor kinase inhibitor Dovitinib at stopping AM cell growth in in vitro with either frequent codeletion or mutated CHEK2 and NF2 gene.Methods: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot analysis, caspases assay, and DNA fragmentation assay.Results: Treatment of CH157MN and IOMM-Lee cells with Dovitinib suppressed multiple angiokinases-mainly FGFRs, leading to suppression of downstream signaling by RAS-RAF-MAPK molecules and PI3K-AKT molecules which are involved in cell proliferation, cell survival, and tumor invasion. Furthermore, Dovitinib induced apoptosis via downregulation of survival proteins (Bcl-XL), and over-expression of apoptotic factors (Bax and caspase-3) regardless of CHEK2 and NF2 mutation status.Conclusions: This study establishes the groundwork for the development of Dovitinib as a therapeutic agent for high-grade AM with either frequent codeletion or mutated CHEK2 and NF2, an avenue with high translational potential.
Assuntos
Benzimidazóis/farmacologia , Quinase do Ponto de Checagem 2/genética , Meningioma/tratamento farmacológico , Neurofibromina 2/genética , Quinolonas/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Meningioma/genética , Meningioma/patologia , Mutação/genética , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína bcl-X/genéticaRESUMO
Skin lesion is one of the important health hazards caused by high intake of arsenic through drinking water and diet, and the other hazards include several types of cancers (viz. skin, lung and urinary bladder), ischemic heart disease, hypertension, etc. Two most important biomarkers to measure arsenic intake in a human body are arsenic concentration in urine and hair. The primary interest of this paper is the association between skin lesion and arsenic concentration in hair for participants with chronic arsenic exposure from West Bengal, India, using bivariate regression model based on copula function. The result showed participants with high arsenic concentration in hair had higher incidence of developing skin lesion. Arsenic concentration in hair was significantly higher for the participants with an arsenic concentration in water > 10 mg/L.
Assuntos
Arsênio/toxicidade , Exposição Ambiental/análise , Poluentes Ambientais/toxicidade , Cabelo/química , Dermatopatias/epidemiologia , Dermatopatias/patologia , Adulto , Dieta , Feminino , Humanos , Incidência , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Análise de RegressãoRESUMO
BACKGROUND: Immunotherapy can be an effective treatment for pediatric medulloblastoma (MB) patients. However, major subpopulations do not respond to immunotherapy, due to the lack of antigenic mutations or the immune-evasive properties of MB cells. Clinical observations suggest that radiation therapy (RT) may expand the therapeutic reach of immunotherapy. The aim of the present investigation is to study the effect of low-dose X-ray radiation (LDXR, 1 Gy) on the functional immunological responses of MB cells (DAOY, D283, and D341). METHODS: Induction of MB cell death was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Production of reactive oxygen species (ROS) was measured by fluorescent probes. Changes in the expression of human leukocyte antigen (HLA) molecules and caspase-3 activities during treatment were analyzed using Western blotting and caspase-3 assay. RESULTS: Western blot analysis demonstrated that LDXR upregulated the expression of HLA class I and HLA II molecules by more than 20% compared with control and high-dose (12 Gy) groups in vitro. Several of these HLA subtypes, such as MAGE C1, CD137, and ICAM-1, have demonstrated upregulation. In addition, LDXR increases ROS production in association with phosphorylation of NF-κB and cell surface expression of mAb target molecules (HER2 and VEGF). These data suggest that a combined LDXR and mAb therapy can create a synergistic effect in vitro. CONCLUSION: These results suggest that LDXR modulates HLA molecules, leading to alterations in T-cell/tumor-cell interaction and enhancement of T-cell-mediated MB cell death. Also, low-dose radiotherapy combined with monoclonal antibody therapy may one day augment the standard treatment for MB, but more investigation is needed to prove its utility as a new therapeutic combination for MB patients.
Assuntos
Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Antígenos HLA/metabolismo , Meduloblastoma/metabolismo , Radiação , Ligante 4-1BB/metabolismo , Análise de Variância , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta à Radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígenos HLA/imunologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Meduloblastoma/patologia , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor ErbB-2/imunologia , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/imunologiaRESUMO
Spinal cord injury (SCI) causes loss of neurological function and, depending upon the severity of injury, may lead to paralysis. Currently, no FDA-approved pharmacotherapy is available for SCI. High-dose methylprednisolone is widely used, but this treatment is controversial. We have previously shown that low doses of estrogen reduces inflammation, attenuates cell death, and protects axon and myelin in SCI rats, but its effectiveness in recovery of function is not known. Therefore, the goal of this study was to investigate whether low doses of estrogen in post-SCI would reduce inflammation, protect cells and axons, and improve locomotor function during the chronic phase of injury. Injury (40 g.cm force) was induced at thoracic 10 in young adult male rats. Rats were treated with 10 or 100 µg 17ß-estradiol (estrogen) for 7 days following SCI and compared with vehicle-treated injury and laminectomy (sham) controls. Histology (H&E staining), immunohistofluorescence, Doppler laser technique, and Western blotting were used to monitor tissue integrity, gliosis, blood flow, angiogenesis, the expression of angiogenic factors, axonal degeneration, and locomotor function (Basso, Beattie, and Bresnahan rating) following injury. To assess the progression of recovery, rats were sacrificed at 7, 14, or 42 days post injury. A reduction in glial reactivity, attenuation of axonal and myelin damage, protection of cells, increased expression of angiogenic factors and microvessel growth, and improved locomotor function were found following estrogen treatment compared with vehicle-treated SCI rats. These results suggest that treatment with a very low dose of estrogen has significant therapeutic implications for the improvement of locomotor function in chronic SCI. Experimental studies with low dose estrogen therapy in chronic spinal cord injury (SCI) demonstrated the potential for multi-active beneficial outcomes that could ameliorate the degenerative pathways in chronic SCI as shown in (a). Furthermore, the alterations in local spinal blood flow could be significantly alleviated with low dose estrogen therapy. This therapy led to the preservation of the structural integrity of the spinal cord (b), which in turn led to the improved functional recovery as shown (c).
Assuntos
Indutores da Angiogênese/administração & dosagem , Estradiol/administração & dosagem , Locomoção/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Doença Crônica , Estrogênios/administração & dosagem , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Locomoção/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologiaRESUMO
Spinal cord injury (SCI) is a debilitating condition with neurological deficits and loss of motor function that, depending on the severity, may lead to paralysis. The only treatment currently available is methylprednisolone, which is widely used and renders limited efficacy in SCI. Therefore, other therapeutic agents must be developed. The neuroprotective efficacy of estrogen in SCI was studied with a pre-clinical and pro-translational perspective. Acute SCI was induced in rats that were treated with low doses of estrogen (1, 5, 10, or 100 µg/kg) and compared with vehicle-treated injured rats or laminectomy control (sham) rats at 48 h post-SCI. Changes in gliosis and other pro-inflammatory responses, expression and activity of proteolytic enzymes (e.g., calpain, caspase-3), apoptosis of neurons in SCI, and cell death were monitored via Western blotting and immunohistochemistry. Negligible pro-inflammatory responses or proteolytic events and very low levels of neuronal death were found in sham rats. In contrast, vehicle-treated SCI rats showed profound pro-inflammatory responses with reactive gliosis, elevated expression and activity of calpain and caspase-3, elevated Bax:Bcl-2 ratio, and high levels of neuronal death in lesion and caudal regions of the injured spinal cord. Estrogen treatment at each dose reduced pro-inflammatory and proteolytic activities and protected neurons in the caudal penumbra in acute SCI. Estrogen treatment at 10 µg was found to be as effective as 100 µg in ameliorating the above parameters in injured animals. Results from this investigation indicated that estrogen at a low dose could be a promising therapeutic agent for treating acute SCI. Experimental studies with low dose estrogen therapy in acute spinal cord injury (SCI) demonstrated the potential for multi-active beneficial outcomes. Estrogen has been found to ameliorate several degenerative pathways following SCI. Thus, such early protective effects may even lead to functional recovery in long term injury. Studies are underway in chronic SCI in a follow up manuscript.
Assuntos
Estrogênios/administração & dosagem , Estrogênios/farmacologia , Gliose/tratamento farmacológico , Neurônios/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Gliose/patologia , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Medula Espinal/fisiopatologia , Medula Espinal/cirurgia , Traumatismos da Medula Espinal/patologiaRESUMO
Activated microglia release pro-inflammatory factors and calpain into the extracellular milieu, damaging surrounding neurons. However, mechanistic links to progressive neurodegeneration in disease such as multiple sclerosis (MS) remain obscure. We hypothesize that persistent damaged/dying neurons may also release cytotoxic factors and calpain into the media, which then activate microglia again. Thus, inflammation, neuronal damage, and microglia activation, i.e., bi-directional interaction between neurons and microglia, may be involved in the progressive neurodegeneration. We tested this hypothesis using two in vitro models: (i) the effects of soluble factors from damaged primary cortical neurons upon primary rat neurons and microglia and (ii) soluble factors released from CD3/CD28 activated peripheral blood mononuclear cells of MS patients on primary human neurons and microglia. The first model indicated that neurons due to injury with pro-inflammatory agents (IFN-γ) release soluble neurotoxic factors, including COX-2, reactive oxygen species, and calpain, thus activating microglia, which in turn released neurotoxic factors as well. This repeated microglial activation leads to persistent inflammation and neurodegeneration. The released calpain from neurons and microglia was confirmed by the use of calpain inhibitor calpeptin or SNJ-1945 as well as µ- and m-calpain knock down using the small interfering RNA (siRNA) technology. Our second model using activated peripheral blood mononuclear cells, a source of pro-inflammatory Th1/Th17 cytokines and calpain released from auto-reactive T cells, corroborated similar results in human primary cell cultures and confirmed calpain to be involved in progressive MS. These insights into reciprocal paracrine regulation of cell injury and calpain activation in the progressive phase of MS, Parkinson's disease, and other neurodegenerative diseases suggest potentially beneficial preventive and therapeutic strategies, including calpain inhibition.
Assuntos
Calpaína/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Calpaína/antagonistas & inibidores , Calpaína/genética , Carbamatos/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/farmacologia , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Células Th1/metabolismo , Células Th17/metabolismoRESUMO
Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK'872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma.
Assuntos
Raios gama/efeitos adversos , Glioblastoma/radioterapia , Necrose/metabolismo , Necrose/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Western Blotting , Caspases , Proliferação de Células , Glioblastoma/metabolismo , Glioblastoma/patologia , Técnicas Imunoenzimáticas , Masculino , Necrose/etiologia , Lesões por Radiação/etiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recurrent meningiomas constitute an uncommon but significant problem after standard (surgery and radiation) therapy failure. Current chemotherapies (hydroxyurea, RU-486, and interferon-α) are only of marginal benefit. There is an urgent need for more effective treatments for meningioma patients who have failed surgery and radiation therapy. Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM are some of the plant derivatives that have anti-tumorgenic properties and cause cell death in meningioma cells in vitro. Due to its ease of administration, long-term tolerability, and low incidence of long-term side effects, we explored its potential as a therapeutic agent against meningiomas by examining their efficacy in vitro against meningioma cells. Treatment effects were assessed using MTT assay, Western blot analysis, caspases assay, and DNA fragmentation assay. Results indicated that treatments of IOMM-Lee and CH157MN meningioma cells with Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM induced apoptosis with enhanced phosphorylation of glycogen synthase kinase 3 ß (GSK3ß) via inhibition of the Wnt5/ß-catenin pathway. These drugs did not induce apoptosis in normal human neurons. Other events in apoptosis included downregulation of tetraspanin protein (TSPAN12), survival proteins (Bcl-XL and Mcl-1), and overexpression apoptotic factors (Bax and caspase-3). These results provide preliminary strong evidence that medicinal plants containing Limonin, Tangeritin, 6-Gingerol, Zerumbone, Ganoderic Acid A, and Ganoderic Acid DM can be applied to high-grade meningiomas as a therapeutic agent, and suggests that further in vivo studies are necessary to explore its potential as a therapeutic agent against malignant meningiomas.
Assuntos
Catecóis/administração & dosagem , Álcoois Graxos/administração & dosagem , Flavonas/administração & dosagem , Ácidos Heptanoicos/administração & dosagem , Lanosterol/análogos & derivados , Limoninas/administração & dosagem , Meningioma/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Triterpenos/administração & dosagem , Apoptose/efeitos dos fármacos , Catecóis/química , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Álcoois Graxos/química , Flavonas/química , Quinase 3 da Glicogênio Sintase/biossíntese , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Ácidos Heptanoicos/química , Humanos , Lanosterol/administração & dosagem , Lanosterol/química , Limoninas/química , Meningioma/genética , Meningioma/patologia , Sesquiterpenos/química , Triterpenos/química , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
The authors investigated association of arsenic intake through water and diet and arsenic level in urine in people living in arsenic endemic region in West Bengal supplied with arsenic-safe water (<50 µg L(-1)). Out of 94 (Group-1A) study participants using water with arsenic level <50 µg L(-1), 72 participants (Group-1B) were taking water with arsenic level <10 µg L(-1). Multiple regressions analysis conducted on the Group-1A participants showed that daily arsenic dose from water and diet were found to be significantly positively associated with urinary arsenic level. However, daily arsenic dose from diet was found to be significantly positively associated with urinary arsenic level in Group-1B participants only, but no significant association was found with arsenic dose from water in this group. In a separate analysis, out of 68 participants with arsenic exposure through diet only, urinary arsenic concentration was found to correlate positively (r = 0.573) with dietary arsenic in 45 participants with skin lesion while this correlation was insignificant (r = 0.007) in 23 participants without skin lesion. Our study suggested that dietary arsenic intake was a potential pathway of arsenic exposure even where arsenic intake through water was reduced significantly in arsenic endemic region in West Bengal. Observation of variation in urinary arsenic excretion in arsenic-exposed subjects with and without skin lesion needed further study.
Assuntos
Arsênio/urina , Biomarcadores/urina , Água Potável/análise , Poluentes Químicos da Água/urina , Adolescente , Adulto , Idoso , Arsênio/análise , Dieta , Feminino , Contaminação de Alimentos/análise , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Poluentes Químicos da Água/análise , Adulto JovemRESUMO
Lung affection in chronic arsenicosis developing from chronic ingestion of arsenic contaminated groundwater has been known but little is known on its effect on pulmonary arterial system. A cross sectional study was carried out at two geographically similar areas and demographically similar populations with or without evidence of chronic arsenic exposure in West Bengal, India. The willing participants in both the groups with chronic respiratory symptoms were evaluated with High Resolution Computerized Tomography (HRCT) of Chest. Evaluation of High Resolution Computerized Tomography of chest followed clinical assessment of lung disease in194 and 196 subjects from the arsenic exposed and unexposed people; the former had a higher prevalence of cough OR(Odds Ratio) 3.23 (95% CI(Confidence Interval): 1.72-6.07) and shortness of breath OR1.76 (95% CI: 0.84-3.71), respectively. The arsenic exposed individuals showed higher score for bronchiectasis [mean ± SD(Standard Deviation)] as 2.41 ± 2.32 vs. 1.22 ± 1.48 (P <0.001), pulmonary artery branch dilatation (PAD) as 2.48 ± 2.33 vs. 0.78 ± 1.56, (P <0.001) and pulmonary trunk dilatation as 0.26 ± 0.45 vs. nil. Age-adjusted prevalence odds ratio (POR) for Pulmonary Artery Dilatation Found in HRCT comparing those exposed to arsenic (Group 1) to unexposed participants (Group 2) was found to be 6.98 (CI: 2.26-16.48). There was a strong dose-response relationship between the PAD (Pulmonary Artery Dilatation) and cumulative arsenic exposure. Pulmonary trunk and branch dilatation in chronic arsenicosis is a frequent abnormality seen in HRCT Chest of arsenicosis patients. The significance of such finding needs further investigation.
Assuntos
Intoxicação por Arsênico/epidemiologia , Pneumopatias/epidemiologia , Artéria Pulmonar/fisiopatologia , Adolescente , Adulto , Intoxicação por Arsênico/diagnóstico por imagem , Intoxicação por Arsênico/fisiopatologia , Doença Crônica , Estudos Transversais , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Índia/epidemiologia , Pneumopatias/diagnóstico por imagem , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Artéria Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Vasodilatação , Poluentes Químicos da Água/toxicidade , Adulto JovemRESUMO
Multiple sclerosis (MS) is an autoimmune disease characterized by immune-mediated attacks on the central nervous system (CNS), resulting in demyelination and recurring T-cell responses. Unfortunately, there is no cure for it. Current therapies that target immunomodulation and/or immunosuppression show only modest beneficial effects, have many side effects, and do not block neurodegeneration or progression of the disease. Since neurodegeneration and in particular axonal degeneration is implicated in disability in progressive MS, development of novel therapeutic strategies to attenuate the neurodegenerative processes is imperative. This study aims to develop new safe and efficacious treatments that address both the inflammatory and neurodegenerative aspects of MS using its animal model, experimental allergic encephalomyelitis (EAE). In EAE, the cysteine protease calpain is upregulated in CNS tissue, and its activity correlates with neurodegeneration. Our immunologic studies on MS have indicated that increased calpain activity promotes pro-inflammatory T helper (Th)1 cells and the severity of the disease in EAE, suggesting that calpain inhibition could be a novel target to combat neurodegeneration in MS/EAE. While calpain inhibition by SNJ1945 reduced disease severity, treatment of EAE animals with a novel protease-resistant altered small peptide ligand (3aza-APL) that mimic myelin basic protein (MBP), also decreased the incidence of EAE, disease severity, infiltration of inflammatory cells, and protected myelin. A reduction in inflammatory T-cells with an increase in Tregs and myeloid suppressor cells is also found in EAE mice treated with SNJ1945 and 3aza-APL. Thus, a novel combination strategy was tested in chronic EAE mouse model in B10 mice which showed multiple pathological mechanisms could be addressed by simultaneous treatment with calpain inhibitor SNJ1945 and protease-resistant 3aza-APL to achieve a stronger therapeutic effect.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Calpaína/metabolismo , Calpaína/uso terapêutico , Inflamação/tratamento farmacológico , Sistema Nervoso Central/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Optic neuritis (ON), which is an acute inflammatory autoimmune demyelinating disease of the central nervous system (CNS), often occurs in multiple sclerosis (MS). ON is an early diagnostic sign in most MS patients caused by damage to the optic nerve leading to visual dysfunction. Various features of both MS and ON can be studied following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in Lewis rats. Inflammation and cell death in the optic nerve, with subsequent damage to the retinal ganglion cells in the retina, are thought to correlate with visual dysfunction. Thus, characterizing the pathophysiological changes that lead to visual dysfunction in EAE animals may help develop novel targets for therapeutic intervention. We treated EAE animals with and without the calpain inhibitor calpeptin (CP). Our studies demonstrated that the Ca(2+)-activated neutral protease calpain was upregulated in the optic nerve following induction of EAE at the onset of clinical signs (OCS) of the disease, and these changes were attenuated following treatment with CP. These reductions correlated with decreases in inflammation (cytokines, iNOS, COX-2, and NF-κB), and microgliosis (i.e. activated microglia). We observed that calpain inhibition reduced astrogliosis (reactive astroglia) and expression of aquaporin 4 (AQP4). The balance of Th1/Th2 cytokine production and also expression of the Th1-related CCR5 and CXCR3 chemokine receptors influence many pathological processes and play both causative and protective roles in neuron damage. Our data indicated that CP suppressed cytokine imbalances. Also, Bax:Bcl-2 ratio, production of tBid, PARP-1, expression and activities of calpain and caspases, and internucleosomal DNA fragmentation were attenuated after treatment with CP. Our results demonstrated that CP decreased demyelination [loss of myelin basic protein (MBP)] and axonal damage [increase in dephosphorylated neurofilament protein (de-NFP)], and also promoted intracellular neuroprotective pathways in optic nerve in EAE rats. Thus, these data suggest that calpain is involved in inflammatory as well as in neurodegenerative aspects of the disease and may be a promising target for treating ON in EAE and MS.
Assuntos
Dipeptídeos/uso terapêutico , Glicoproteínas/uso terapêutico , Nervo Óptico/patologia , Neurite Óptica/tratamento farmacológico , Neurite Óptica/patologia , Animais , Apoptose/efeitos dos fármacos , Aquaporina 4/genética , Aquaporina 4/metabolismo , Cálcio/metabolismo , Calpaína/genética , Calpaína/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/complicações , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/tratamento farmacológico , Gliose/etiologia , Masculino , Peso Molecular , Proteína Básica da Mielina/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/metabolismo , Neurite Óptica/complicações , Ratos , Ratos Endogâmicos Lew , Transdução de Sinais/efeitos dos fármacosRESUMO
The incidence of acute and chronic spinal cord injury (SCI) in the United States is more than 10,000 per year, resulting in 720 cases per million persons enduring permanent disability each year. The economic impact of SCI is estimated to be more than 4 billion dollars annually. Preclinical studies, case reports, and small clinical trials suggest that early treatment may improve neurological recovery. To date, no proven therapeutic modality exists that has demonstrated a positive effect on neurological outcome. Emerging data from recent preclinical and clinical studies offer hope for this devastating condition. This review gives an overview of current basic research and clinical studies for the treatment of SCI.
Assuntos
Traumatismos da Medula Espinal , Ensaios Clínicos como Assunto , Humanos , Traumatismos da Medula Espinal/epidemiologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Estados Unidos/epidemiologiaRESUMO
Glioblastoma, the most lethal brain tumor, remains incurable despite aggressive chemotherapy and surgical interventions. New chemotherapeutics for glioblastoma have been explored in preclinical models and some agents have reached the clinical setting. However, success rates are not significant. Previous investigations involving diallyl trisulfide (DATS), a garlic compound, indicated significant anti-cancer effects in glioblastoma in vitro. DATS has also been shown to inhibit histone deacetylase activity and impede glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG tumor by multiple pro-apoptotic pathways via inhibiting histone deacetylase (HDAC). To prove this, we developed ectopic U87MG tumors in SCID mice and treated them daily with intraperitoneal injections of DATS for 7 days. Results indicated that DATS (10 µg/kg-10 mg/kg) dose-dependently reduced tumor mass and number of mitotic cells within tumors. Histological and biochemical assays demonstrated that DATS reduced mitosis in tumors, decreased HDAC activity, increased acetylation of H3 and H4, inhibited cell cycle progression, decreased pro-tumor markers (e.g., survivin, Bcl-2, c-Myc, mTOR, EGFR, VEGF), promoted apoptotic factors (e.g., bax, mcalpian, active caspase-3), and induced DNA fragmentation. Our data also demonstrated an increase in p21Waf1 expression, which correlated with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. Collectively, our results clearly demonstrated that DATS could be an effective therapeutic agent in preventing tumor progression and inducing apoptosis in human glioblastoma in vivo, without impairing hepatic function.
Assuntos
Compostos Alílicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Histona Desacetilases/metabolismo , Sulfetos/uso terapêutico , Análise de Variância , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Marcação In Situ das Extremidades Cortadas , Fígado/patologia , Camundongos , Camundongos SCID , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Melatonin has shown particular promise as a neuroprotective agent to prevent motoneuron death in animal models of both amyotrophic lateral sclerosis (ALS) and spinal cord injuries (SCI). However, an understanding of the roles of endogenous melatonin receptors including MT1, MT2, and orphan G-protein receptor 50 (GPR50) in neuroprotection is lacking. To address this deficiency, we utilized plasmids for transfection and overexpression of individual melatonin receptors in the ventral spinal cord 4.1 (VSC4.1) motoneuron cell line. Receptor-mediated cytoprotection following exposure to glutamate at a toxic level (25 µm) was determined by assessing cell viability, apoptosis, and intracellular free Ca(2+) levels. Our findings indicate a novel role for MT1 and MT2 for increasing expression of the calcium-binding proteins calbindin D28K and parvalbumin. Increased levels of calbindin D28K and parvalbumin in VSC4.1 cells overexpressing MT1 and MT2 were associated with cytoprotective effects including inhibition of proapoptotic signaling, downregulation of inflammatory factors, and expression of prosurvival markers. Interestingly, the neuroprotective effects conferred by overexpression of MT1 and/or MT2 were also associated with increases in the estrogen receptor ß (ERß): estrogen receptor α (ERα) ratio and upregulation of angiogenic factors. GPR50 did not exhibit cytoprotective effects. To further confirm the involvement of the melatonin receptors, we silenced both MT1 and MT2 in VSC4.1 cells using RNA interference technology. Knockdown of MT1 and MT2 led to an increase in glutamate toxicity, which was only partially reversed by melatonin treatment. Taken together, our findings suggest that the neuroprotection against glutamate toxicity exhibited by melatonin may depend on MT1 and MT2 but not GPR50.
Assuntos
Ácido Glutâmico/toxicidade , Neurônios Motores/efeitos dos fármacos , Receptores de Melatonina/biossíntese , Animais , Apoptose/efeitos dos fármacos , Calbindinas/biossíntese , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Camundongos , Neurônios Motores/metabolismo , Proteínas do Tecido Nervoso/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Parvalbuminas/biossíntese , RNA Interferente Pequeno/farmacologia , Receptor MT1 de Melatonina/genética , Receptor MT2 de Melatonina/genética , Receptores Acoplados a Proteínas G/efeitos dos fármacosRESUMO
OBJECTIVE: To assess whether nutritional deficiency increases susceptibility to arsenic-related health effects. DESIGN: Assessment of nutrition was based on a 24 h recall method of all dietary constituents. SETTING: Epidemiological cross-sectional study was conducted in an arsenic endemic area of West Bengal with groundwater arsenic contamination. SUBJECTS: The study was composed of two groups Group 1 (cases, n 108) exhibiting skin lesions and Group 2 (exposed controls, n 100) not exhibiting skin lesions age- and sex-matched and having similar arsenic exposure through drinking water and arsenic levels in urine and hair. RESULTS: Both groups belonged to low socio-economic strata (Group 1 significantly poorer, P<0·01) and had low BMI (prevalence of BMI<18·5 kg/m2: in 38% in Group 1 and 27% in Group 2). Energy intake was below the Recommended Daily Allowance (set by the Indian Council of Medical Research) in males and females in both groups. Increased risk of arsenical skin lesions was found for those in the lowest quintile of protein intake (v. highest quintile: OR=4·60, 95% CI 1·36, 15·50 in males; OR=5·62, 95% CI 1·19, 34·57 in females). Significantly lower intakes of energy, protein, thiamin, niacin, Mg, Zn and choline were observed in both males and females of Group 1 compared with Group 2. Significantly lower intakes of carbohydrate, riboflavin, niacin and Cu were also observed in female cases with skin lesions compared with non-cases. CONCLUSIONS: Deficiencies of Zn, Mg and Cu, in addition to protein, B vitamins and choline, are found to be associated with arsenical skin lesions in West Bengal.
Assuntos
Arsênio/efeitos adversos , Deficiências Nutricionais/epidemiologia , Dieta , Água Potável/química , Exposição Ambiental/efeitos adversos , Desnutrição Proteico-Calórica/epidemiologia , Dermatopatias/induzido quimicamente , Adolescente , Adulto , Arsênio/metabolismo , Arsênio/urina , Índice de Massa Corporal , Estudos Transversais , Deficiências Nutricionais/complicações , Proteínas Alimentares/administração & dosagem , Doenças Endêmicas , Ingestão de Energia , Feminino , Humanos , Índia/epidemiologia , Masculino , Micronutrientes/administração & dosagem , Pessoa de Meia-Idade , Avaliação Nutricional , Desnutrição Proteico-Calórica/complicações , Fatores de Risco , Dermatopatias/epidemiologia , Dermatopatias/metabolismo , Dermatopatias/patologia , Classe Social , Magreza/epidemiologia , Poluentes Químicos da Água/efeitos adversos , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/urina , Adulto JovemRESUMO
Glioblastoma is the most common aggressive, highly glycolytic, and lethal brain tumor. In fact, it is among the most commonly diagnosed lethal malignancies, with thousands of new cases reported in the United States each year. Glioblastoma's lethality is derived from a number of factors including highly active pro-mitotic and pro-metastatic pathways. Two factors increasingly associated with the intracellular signaling and transcriptional machinery required for such changes are anaplastic lymphoma kinase (ALK) and the hepatocyte growth factor receptor (HGFR or, more commonly MET). Both receptors are members of the receptor tyrosine kinase (RTK) family, which has itself gained much attention for its role in modulating mitosis, migration, and survival in cancer cells. ALK was first described as a vital oncogene in lymphoma studies, but it has since been connected to many carcinomas, including non-small cell lung cancer and glioblastoma. As the receptor for HGF, MET has also been highly characterized and regulates numerous developmental and wound healing events which, when upregulated in cancer, can promote tumor progression. The wealth of information gathered over the last 30 years regarding these RTKs suggests three downstream cascades that depend upon activation of STAT3, Ras, and AKT. This review outlines the significance of ALK and MET as they relate to glioblastoma, explores the significance of STAT3, Ras, and AKT downstream of ALK/MET, and touches on the potential for new chemotherapeutics targeting ALK and MET to improve glioblastoma patient prognosis.