RESUMEN

Endothelial dysfunction and inflammation are clinically significant risk factors for cardiovascular diseases in hypertension. Although immune cells play a role in hypertension, the impact of plasmacytoid dendritic cells in established renovascular hypertension-induced cardiovascular complications is not fully understood. We investigated plasmacytoid dendritic cells' contribution to arterial endothelial dysfunction and inflammation in renovascular hypertension. A two-kidney one-clip (2K1C) model for four weeks in both male and female mice was used to induce renovascular hypertension. We treated mice with or without anti-PDCA-1 antibodies for one week to deplete the plasmacytoid dendritic cells. Renovascular hypertension causes cardiac hypertrophy, lung edema, and microvascular endothelial dysfunction associated with inflammation induction in mice. Moreover, renovascular hypertension affects the profile of immune cells, including dendritic cells and macrophages, with variations between male and female mice. Interestingly, the depletion of plasmacytoid dendritic cells significantly reduces blood pressure, cardiac hypertrophy, lung edema, inflammation, and oxidative stress and improves microvascular endothelial function via the endoplasmic reticulum (ER) stress, autophagy, and mTOR-dependent mechanisms. Plasmacytoid dendritic cells significantly contribute to the development of cardiovascular complications in renovascular hypertension by modulating immune cells, inflammation, oxidative stress, and ER stress.

RESUMEN

Background Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin-1ß in HFpEF pathogenesis are poorly understood. Methods and Results C57/Bl6J and interleukin-1ß-/- male mice were randomly divided into 4 groups. Groups 1 and 2: C57/Bl6J and interleukin-1ß-/- mice were fed a regular diet for 4 months and considered controls. Groups 3 and 4: C57/Bl6 and interleukin-1ß-/- mice were fed a high-fat diet with N[w]-nitro-l-arginine methyl ester (endothelial nitric oxide synthase inhibitor, 0.5 g/L) in the drinking water for 4 months. We measured body weight, blood pressure, diabetes status, cardiac function/hypertrophy/inflammation, fibrosis, vascular endothelial function, and signaling. C57/Bl6 fed a high-fat diet and N[w]-nitro-l-arginine methyl ester in the drinking water for 4 months developed HFpEF pathogenesis characterized by obesity, diabetes, hypertension, cardiac hypertrophy, lung edema, low running performance, macrovascular and microvascular endothelial dysfunction, and diastolic cardiac dysfunction but no change in cardiac ejection fraction compared with control mice. Interestingly, the genetic disruption of interleukin-1ß protected mice from HFpEF pathogenesis through the modulation of the inflammation and endoplasmic reticulum stress mechanisms. Conclusions Our data suggest that interleukin-1ß is a critical driver in the development of HFpEF pathogenesis, likely through regulating inflammation and endoplasmic reticulum stress pathways. Our findings provide a potential therapeutic target for HFpEF treatment.

Asunto(s)

Cardiomiopatías , Agua Potable , Insuficiencia Cardíaca , Ratones , Masculino , Animales , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/prevención & control , Volumen Sistólico/fisiología , Interleucina-1beta , Cardiomiopatías/complicaciones , Inflamación/patología

RESUMEN

BACKGROUND AND AIMS: The association of mitochondrial NADH dehydrogenase gene mutations with type 2 diabetes in the Karaikudi population was previously reported. This is a case report that demonstrated rare mutations are responsible for maternally inherited peripheral neuropathy of diabetes. METHODS: We describe a 70-year-old male and his family (n = 25) with type 2 diabetic peripheral neuropathy having four rare mutations, 8597T > C, 8699T > C, 8966T > C, 10188A > G, and 9 bp deletion in various regions of the mitochondrial genes. Mutations were identified through direct sequencing of DNA isolated from the blood of the selected individuals. Blood samples were also analyzed for glucose, hemoglobin A1c, triglyceride, total cholesterol, oxidative stress markers, antioxidant status, cytochrome-C-oxidase and mitochondrial DNA content using appropriate methods. RESULTS: Oxidative stress markers were found elevated while the antioxidant status, mitochondrial DNA content and the activity of cytochrome C-oxidase was reduced significantly. Analysis of mtDNA showed the presence of several mutations in various regions of mitochondrial genome. However, 8597T > C, 8699T > C, 8966T > C, 10188A > G, and 9 bp deletion were observed in the patient's family including his siblings. CONCLUSION: This study shows that the mutations observed in the patient and his family is maternally inherited and suspected to be pathogenic in developing T2D associated peripheral neuropathy.

Asunto(s)

Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Anciano , Antioxidantes , ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Neuropatías Diabéticas/genética , Humanos , Masculino , Mutación , Oxidorreductasas/genética

RESUMEN

In the present study aimed to purify the lectin from the sap of Musa acuminata pseudostem and elucidate the apoptotic and angiogenic molecular mechanism in both in-vitro and in-vivo model. Mannose specific lectin was purified by using mannose affinity column chromatography and analyzed by RP-HPLC, SDS-PAGE, and PAS staining method. Furthermore, the protein was identified by MALDI-MS/MS. MAL effectively agglutinates trypsinized RBCs and showed effective cytotoxicity against various human cancer cell lines. MAL mitigates the cell proliferation, colony formation, cell migration, arrest the cell cycle in the G2/M phase, and induce apoptosis by altering the expression of apoptotic proteins/mRNA level (Bax and Bcl-2) via caspase 8/9, 3 dependent pathway in both in-vitro and in-vivo. Supporting this, in-vivo EAC tumor mice models prove the efficacy of MAL by inducing cell death and inhibiting the neovessel formation by targeting the MVD, inhibition of VEGF secretion, suppressing the expression of MMPs, HIF-1α, Flt-1, Akt, Jnk, and Erk1/2. More importantly, the MAL treatment leads to effective inhibition of tumor growth and an increase in the survivability of EAC mice. Our study summarizes that the MAL having a significant anticancer potential expressively degenerates the tumor development by inducing apoptosis and suppressing neoangiogenesis.

Asunto(s)

Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma de Ehrlich/patología , Caspasas/metabolismo , Lectinas/uso terapéutico , Sistema de Señalización de MAP Quinasas , Musa/química , Neovascularización Patológica/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Aglutinación/efectos de los fármacos , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Pollos , Membrana Corioalantoides/efectos de los fármacos , Membrana Corioalantoides/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Femenino , Células HeLa , Humanos , Lectinas/aislamiento & purificación , Lectinas/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos BALB C , Proteínas de Neoplasias/metabolismo , Fosforilación/efectos de los fármacos , Pruebas de Toxicidad Aguda

RESUMEN

Biosynthesis of silver nanoparticles (CTNP's) by Clitoria ternatea flower in the aqueous extract was investigated. Synthesized nanoparticles were characterized by using UV-Visible spectroscopy, followed by DLS, Zeta potential, XRD, FTIR, SEM, and AFM. The biocompatibility nature of CTNP's was determined using erythrocytes model system. Cytotoxicity of CTNP's against MCF-7 and EAC cells were determined by using MTT and Trypan blue exclusion method and their IC50 was found to be 19.37 µg/mL and 24 µg/mL. Cytotoxic potential of CTNP's was further confirmed by clonogenic assay. Further in vivo studies using EAC mice model supports the anti-cancer potential of silver nanoparticles. Results found that the CTNP's effectively control the proliferation rate by inhibiting the ascites secretion and cellular density. Further quantification of VEGF, microvessel density counts and CAM assays show the anti-angiogenic potential of the CTNP's. The apoptotic inducing activity of CTNP's was confirmed by DNA fragmentation, fluorescent staining studies. More interestingly, EAC treated mice exhibit significant increase in lifespan (~ 2.25 fold) compared to control EAC mice. Interestingly CTNP's did not exhibit any secondary complications against normal mice. The present findings give an experimental proof that the CTNP's could serve as a promising candidate to overcome limitations of existing conventional cancer therapeutics.

Asunto(s)

Inductores de la Angiogénesis/metabolismo , Inductores de la Angiogénesis/farmacología , Clitoria/química , Flores/química , Nanopartículas del Metal , Plata/metabolismo , Plata/farmacología , Inductores de la Angiogénesis/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Células MCF-7 , Extractos Vegetales/metabolismo , Plata/química

RESUMEN

Lifestyle and nutritional changes have contributed much to the somatic genetic changes which have concurrently led to an increase cancer in humans. Hence the plant-based and nutritional involvements block oncogenic transformation are in good demand. We evaluate Phloem exudates of the dietary plant, Musa acuminate pseudostem, the initial domesticated plant species with the effective lectin activity for its functional role against the tumor development and its mechanism of action. Our experimental data exhibit that Musa acuminata Lectin Protein (MALP) shows a promising cytotoxic effect against the various human cancer cell lines. Supporting this, we evaluate the in vivo anti-tumor and anti-angiogenic activity of MALP in Ehrlich Ascites Carcinoma mice model (EAC). MALP treatment resulted in tumor growth inhibition and increased the lifespan of the EAC-bearing mice without showing any side effects on normal mice, as revealed by histological parameters. Further, a significant decrease in the ascites vascular endothelial growth factor (VEGF) secretion and microvessel density supports the anti-angiogenic property of the MALP. Apoptosis-inducing activity of MALP was revealed by DNA fragmentation assay, Caspase-3 inhibitor assay and cellular morphology were studied by fluorescence staining methods. Our study delivers the real evidence that MALP with a promising an anticancer potential expressively degenerates the tumor development by affecting angiogenesis and apoptosis.

Asunto(s)

Inhibidores de la Angiogénesis/farmacología , Carcinoma de Ehrlich/irrigación sanguínea , Carcinoma de Ehrlich/tratamiento farmacológico , Lectinas/farmacología , Musa/química , Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aglutininas/farmacología , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Ehrlich/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Extractos Vegetales/farmacología , Factores de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

Praecitrullus fistulosus, belonging to the family of Cucurbitaceae is a tropical vegetable and medicinal plant, grown and consumed extensively in subtropical countries, including the subcontinent India. However, there are limited reports on the medicinal properties of the plant and need to be explored. The lectin identified from the fruit sap of Praecitrullus fistulosus, named as PfLP, possesses potent agglutinating activity against trypsinized rabbit erythrocytes and exhibited its functional role against tumor progression, on in vitro &in vivo models. Experimental results revealed that PfLP shows a promising cytotoxic effect against multiple cancer cell lines. Further, we examined the in vivo anticancer and anti-angiogenic properties of PfLP against EAC bearing mice. PfLP treatment resulted in tumor growth inhibition and increased the life-span of the EAC bearing mice, without showing any detectable side effects, as revealed by histological parameters. Further, a significant decrease in the ascites VEGF secretion level was parallel with a drastic reduction in tumoral neovasculature as evidence for angiogenic parameters. Gelatin zymogram study reveals that PfLP inhibits metalloproteinases (MMP-2 & MMP-9) activity in order to execute its anti-angiogenic effect. PfLP has also inducing apoptosis, in cancer cells was revealed by DNA fragmentation assay followed by Giemsa and AO/EBr staining method, showed the apoptotic bodies and condensed nuclei compared to control cells. More interestingly, PfLP did not exhibit any adverse side effects or secondary complications in normal mice. These results clearly exhibit the potential role of PfLP in regressing the tumor progression by targeting angiogenesis and inducing cell death in mouse transplantable tumor.

Asunto(s)

Inhibidores de la Angiogénesis/farmacología , Antineoplásicos Fitogénicos/farmacología , Cucurbitaceae/química , Frutas/química , Lectinas/farmacología , Neoplasias/tratamiento farmacológico , Plantas Medicinales/química , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HT29 , Células HeLa , Humanos , Células K562 , Células MCF-7 , Metaloproteasas/metabolismo , Ratones , Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Extractos Vegetales/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

BACKGROUND: Glasgow Coma Scale has been a long sought model to classify patients with head injury. However, the major limitation of the score is its assessment in the patients who are either sedated or under the influence of drugs or intubated for airway protection. The rational approach for prognostication of such patients is the utility of scoring system based on the morphological criteria based on radiological imaging. Among the current armamentarium, a scoring system based on computed tomography (CT) imaging holds the greatest promise in conquering our conquest for the same. METHODS: We included a total of 634 consecutive neurosurgical trauma patients in this series, who presented with mild-to-severe traumatic brain injury (TBI) from January 2013 to April 2014 at a tertiary care center in rural Nepal. All pertinent medical records (including all available imaging studies) were reviewed by the neurosurgical consultant and the radiologist on call. Patients' worst CT image scores and their outcome at 30 days were assessed and recorded. We then assessed their independent performance in predicting the mortality and also tried to seek the individual variables that had significant interplay for determining the same. RESULTS: Both imaging score (Marshall) and clinical score (Rotterdam) can be used to reliably predict mortality in patients with acute TBI with high prognostic accuracy. Other specific CT characteristics that can be used to predict early mortality are traumatic subarachnoid hemorrhage, midline shift, and status of the peri-mesencephalic cisterns. CONCLUSION: We demonstrated in this cohort that though the Marshall score has the high predictive power to determine the mortality, better discrimination could be sought through the application of the Rotterdam score that encompasses various individual CT parameters. We thereby recommend the use of such comprehensive prognostic model so as to augment our predictive power for properly dichotomizing the prognosis of the patients with TBI. In the future, it will therefore be important to develop prognostic models that are applicable for the majority of patients in the world they live in, and not just a privileged few who can use resources not necessarily representative of their societal environment.

RESUMEN

Here we present a very rare case of a woman with a bone fragment in the third ventricle of the brain following compound-depressed skull fractures due to a road traffic accident. There are only few case reports of bullets and textiloma being removed from the third ventricle. Following operative removal of the fragment, the patient was started on cortisol, mineralocorticoid and thyroid hormone replacement. However, the patient eventually died of the severe traumatic hypothalamic insult.

RESUMEN

Primary dural lymphoma is a subentity of primary leptomeningeal lymphoma which represents 0.1% of all non-Hodgkin's lymphomas. Only five cases have been reported so far. We report a very rare case of primary dural-based lymphoma in a 14 year-old boy presenting with mass effect. The patient was managed with excision of the lesion and removal of the involved bone. Post-operatively, the patient showed good recovery. He was then referred to the oncology unit for further chemo- and radiation therapy. A high index of suspicion should therefore be kept in order to diagnose the condition in a timely fashion and then plan for appropriate management since diffuse large cell lymphoma has a relatively benign clinical prognosis.

RESUMEN

Spinal extradural cysts do not normally present as a visible paraspinal mass or cause compression of the abdominal organs. The authors describe the case of a 9-month-old boy with multiple spinal extradural cysts. The largest of these cysts was along the right L-2 nerve root with significant extraspinal extension resulting in a visible slow-growing swelling in the right paraspinal region and radiological evidence of compression of the right kidney with hydronephrosis. Another large cyst along the left T-12 root caused radiologically evident compression of the left kidney but to a lesser degree. The patient also had monoparesis of the left lower limb and phenotypic features of Noonan syndrome. The authors performed marsupialization of the cysts, as well as repair of the fistula between the subarachnoid space and the cyst on the right side along the L-2 root and on the left side along the T-12 root. At 1-year follow-up, there was no paraspinal mass and the lower limbs exhibited normal power. Magnetic resonance imaging confirmed marked reduction in the size of the cysts and relief of the renal compression. To the authors' knowledge, their patient is the youngest reported in literature to have a spinal extradural cyst and also the first with the cyst presenting as a paraspinal mass.

Asunto(s)

Quistes Aracnoideos/diagnóstico , Hidronefrosis/diagnóstico , Vértebras Lumbares , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Raíces Nerviosas Espinales , Quistes Aracnoideos/cirugía , Descompresión Quirúrgica , Espacio Epidural , Estudios de Seguimiento , Humanos , Hidronefrosis/cirugía , Procesamiento de Imagen Asistido por Computador , Lactante , Vértebras Lumbares/patología , Vértebras Lumbares/cirugía , Imagen por Resonancia Magnética , Masculino , Debilidad Muscular/etiología , Debilidad Muscular/cirugía , Examen Neurológico , Síndrome de Noonan/diagnóstico , Enfermedades del Sistema Nervioso Periférico/cirugía , Complicaciones Posoperatorias/diagnóstico , Raíces Nerviosas Espinales/patología , Raíces Nerviosas Espinales/cirugía , Tomografía Computarizada por Rayos X

RESUMEN

Recent upsurge in the interest of breast cancer metastasis is partly attributed to the discovery of novel, yet unclear, mechanisms of breast cancer interaction with sites of distant metastasis such as the bone marrow microenvironment. In this review, we discuss the significance of the interactions between breast cancer cells and cells of the bone marrow. This is a subject of intense research studies aim to provide new methods of treatments and perhaps the identification of new drug targets. This review also discusses the role of inflammation and the bimodal function of the transforming growth factor-beta signaling pathway in the process of tumorigenesis. We bring attention to future prospects in breast cancer research, including the role of microRNAs in cancer quiescence in the bone marrow and the application of microRNAs to basic science discoveries in oncology. Finally, we discuss the cancer stem cell hypothesis, which is not a new idea, but has resurged with investigative questions.