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Innate immune cells play a pivotal role in controlling tissue repair and rejection after biomaterial implantation. Calcium supplementation regulates cellular responses and alter the pathophysiology of various diseases. A series of macrophage activations through differential plasticity has been observed after cell-to-material interactions. We investigated the role of calcium supplementation in controlling macrophage phenotypes in pro-inflammatory and pre-reparative states. Oxidative defence and mitochondria involvement in cellular plasticity and the sequential M0 to M1 and M1 to M2 transitions were observed after calcium supplementation. This study describes the molecular mechanism of reactive oxygen species and drives the interconnected cellular plasticity of macrophages in the presence of calcium. Gene expression, and immunostaining, revealed a relationship between MHC class II maturation and cellular plasticity. This study elucidated the role of controlled calcium supplementation under various conditions. These findings underscore the molecular mechanism of calcium-mediated immune induction and its favourable use in different calcium-containing biomaterials., essential for tissue regeneration.
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Calcio , Monocitos , Humanos , Monocitos/metabolismo , Calcio/metabolismo , Macrófagos/metabolismo , Fenotipo , Materiales Biocompatibles/farmacologíaRESUMEN
OBJECTIVE: This study aimed to analyze and summarize the evidence on the accuracy of different ultrasound methods in the diagnosis of retained products of conception. DATA SOURCES: We searched Ovid SP, the Cumulative Register to Nursing & Allied Health Literature, EBSCO, and grey literature including Core, Trip, Networked Digital Library of Theses and Dissertations Global ETD search, BMJ Best Practice, PubMed, GreyLit report website (http://www.greylit.org/), Cochrane Central Register of Controlled Trials, and Google scholar (https://scholar.google.com/). STUDY ELIGIBILITY CRITERIA: We included prospective and retrospective cross-sectional or Cohort studies that evaluated both ultrasound findings (before management of retained products of conception) and histopathologic results of retained products of conception at all gestational ages. METHODS: We used Covidence for data extraction from the studies and quality assessment. The meta-analysis was performed using RevMan 5.4 (forest plot), MetaDTA version 2.01, and Meta-DiSc 2.0 online software. RESULTS: In total, 11 studies were eligible for data extraction and meta-analysis. The total number of study participants from these 11 studies were 1567. Of these, 9 studies were included to test the accuracy of an echogenic mass, 4 studies analyzed the accuracy of endometrial thickness, and 5 studies analyzed the accuracy of color Doppler flow to predict retained products of conception. We found that echogenic mass had the highest sensitivity, specificity, and diagnostic odds ratio for predicting retained products of conception. The sensitivity, specificity, and diagnostic odds ratio were 0.915 (95% confidence interval, 0.844-0.955), 0.843 (95% confidence interval, 0.615-0.947), and 57.787 (95% confidence interval, 15.171-220.112), respectively. The diagnostic threshold for endometrial thickness was set at 10 mm with a sensitivity, specificity, and diagnostic odds ratio of 0.667 (95% confidence interval, 0.072-0.981), 0.866 (95% confidence interval, 0.375-0.986), and 12.927 (95% confidence interval, 0.23-726.582). The sensitivity, specificity, and diagnostic odds ratio of color Doppler flow were 0.850 (95% confidence interval, 0.756-0.913), 0.406 (95% confidence interval, 0.198-0.655), and 3.893 (95% confidence interval, 1.005-15.081). CONCLUSION: Our review concluded that an echogenic mass is the most sensitive and specific predictor of retained products of conception after any pregnancy event. The most important limitation of our review is that the design of the studies included led to significant statistical heterogeneity.
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We study here the dynamics of opinion formation in a society where we take into account the internally held beliefs and externally expressed opinions of the individuals, which are not necessarily the same at all times. While these two components can influence one another, their difference, both in dynamics and in the steady state, poses interesting scenarios in terms of the transition to consensus in the society and characterizations of such consensus. Here we study this public and private opinion dynamics and the critical behaviour of the consensus forming transitions, using a kinetic exchange model. This article is part of the theme issue 'Kinetic exchange models of societies and economies'.
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Actitud , Consenso , HumanosRESUMEN
Gamma linolenic acid is a polyunsaturated fatty acid having selective anti-tumour properties with negligible systemic toxicity. In the present study, the anti-cancer potential of gamma linolenic acid and its effects on mitochondrial as well as hypoxia-associated marker was evaluated. The effect of gamma linolenic acid was scrutinised against ER + MCF-7 cells by using fluorescence microscopy, JC-1 staining, dot plot assay and cell cycle analysis. The in vitro results were also confirmed using carcinogen (n-methyl-n-nitrosourea) induced in vivo model. The early and late apoptotic signals in the conjugation with mitochondrial depolarisation were found once scrutinised through mitochondrial membrane potential and life death staining after gamma linolenic acid treatment. Gamma linolenic acid arrested the cell cycle in G0/G1 phase with the majority of cell populations in the early apoptotic stage. The translocation of phosphatidylserine was studied through annexin-V FITC dot plot assay. The markers of cellular proliferation (decreased alveolar bud count, histopathological architecture restoration and loss of tumour micro-vessels) were diminished after gamma linolenic acid treatment. Gamma linolenic acid ameliorates the biological effects of n-methyl-n-nitrosourea persuading the mitochondrial mediated death pathway and impeding the hypoxic microenvironment to make a halt in palmitic acid synthesis. SIGNIFICANCE: The present study elaborates the effect of gamma linolenic acid on mammary gland cancer by following mitochondrial-mediated death apoptosis pathway. Gamma linolenic acid also inhibits cell-wall synthesis by the curtailment of HIF-1α and FASN level in mammary gland cancer.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Ácido Graso Sintasas/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Mitocondrias/efectos de los fármacos , Ácido gammalinolénico/farmacología , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácido Graso Sintasas/metabolismo , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Células MCF-7 , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Metilnitrosourea , Microscopía Fluorescente , Mitocondrias/metabolismo , Células Tumorales CultivadasRESUMEN
CRISPR systems have emerged as transformative tools for altering genomes in living cells with unprecedented ease, inspiring keen interest in increasing their specificity for perfectly matched targets. We have developed a novel approach for improving specificity by incorporating chemical modifications in guide RNAs (gRNAs) at specific sites in their DNA recognition sequence ('guide sequence') and systematically evaluating their on-target and off-target activities in biochemical DNA cleavage assays and cell-based assays. Our results show that a chemical modification (2'-O-methyl-3'-phosphonoacetate, or 'MP') incorporated at select sites in the ribose-phosphate backbone of gRNAs can dramatically reduce off-target cleavage activities while maintaining high on-target performance, as demonstrated in clinically relevant genes. These findings reveal a unique method for enhancing specificity by chemically modifying the guide sequence in gRNAs. Our approach introduces a versatile tool for augmenting the performance of CRISPR systems for research, industrial and therapeutic applications.
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Sistemas CRISPR-Cas , División del ADN , Edición Génica/métodos , ARN Guía de Kinetoplastida/genética , Secuencia de Bases , Sitios de Unión/genética , Humanos , Células K562 , Ácido Fosfonoacético/química , ARN Guía de Kinetoplastida/química , ARN Guía de Kinetoplastida/metabolismoRESUMEN
The current study investigates the therapeutic efficacy of an α-linolenic acid (ALA, 18:3n-3)-based intramammary nanosuspension (ALA-NS) for treatment of subclinical mastitis. After confirmation of mastitis with the help of field-based testing, a total of 9 mixed-breed cows (23 udder quarter samples) were divided into 3 groups and treated with ALA-NS and cefoperazone intramammary suspension for 10 d. Subclinical mastitis on d 1 was confirmed through field-based tests such as pH, California Mastitis Test (CMT), Whiteside test (WST), and bromothymol blue test (BBT) scores. Treatment with ALA-NS (F1 and F2) exhibited significant effects on field-based parameters, along with curtailment of total microbial count [28 ± 3.16 (mean ± standard deviation) and 25 ± 4.24 cfu/50 µL] and somatic cell count (SCC; 3.9 and 2.8 log SCC cells/mL), respectively for ALA-NS F1 and F2, after 10-d treatment. The efficacy of ALA-NS was further affirmed using more stringent markers for inflammation (nuclear factor kappa-light-chain-enhancer of activated B cells, NFκB-p65), milk quality (sterol response element-binding protein-1c, SREBP-1c), and bacterial resistance (ubiquitin carboxyl-terminal hydrolase-1, UCHL-1) in milk samples. Treatment with ALA-NS (at 2 concentrations of ALA, F1 and F2) significantly decreased expression of NFκB-p65, SREBP-1c, and UCHL-1 after d 10 of treatment. Apparently, anti-inflammatory, antibacterial, peripheral analgesic properties of ALA could account for the therapeutic efficacy of the proposed regimen.
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Analgésicos/administración & dosificación , Antibacterianos/administración & dosificación , Antiinflamatorios/administración & dosificación , Inflamación/tratamiento farmacológico , Mastitis Bovina/tratamiento farmacológico , Leche/normas , Ácido alfa-Linolénico/administración & dosificación , Animales , Bovinos , Cefoperazona/administración & dosificación , Recuento de Células/veterinaria , Femenino , Glándulas Mamarias Animales/microbiología , Mastitis Bovina/microbiología , NanotecnologíaRESUMEN
The study elucidates the effect of É-linolenic acid (ALA) on mitochondrial stress, hypoxic cancer microenvironment, and intervention of cholinergic anti-inflammatory pathway using N-methyl-N-nitrosourea (MNU) induced estrogen receptor (ER+) mammary gland carcinoma and Caenorhabditis elegans model, respectively. The efficacy of ALA was scrutinized in vivo and in vitro using various experiments like hemodynamic studies, morphological analysis, antioxidants parameters, immunoblotting, and quantitative reverse transcription polymerase chain reaction. The effect of ALA was also validated using C. elegans worms. ALA administration had a positive effect on tissue architecture of the malignancy when scrutinized through the whole mount carmine staining, hematoxylin and eosin staining, and scanning electron microscopy. The proteomic and genomic checkpoint revealed the participation of mitochondrial dysfunction, alteration of hypoxic microenvironment, and involvement of cholinergic anti-inflammatory response after treatment with ALA. ALA treatment has also increased the level of synaptic acetylcholine and acetylcholine esterase with a significant decrease in lipid content. It was concluded that ALA persuaded the mitochondrial stress, activation of downstream cholinergic anti-inflammatory markers, and favorable regulation of hypoxia microenvironment through inhibition of fatty acid synthase and sterol regulatory element-binding protein.
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Anticarcinógenos/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Glándulas Mamarias Animales/efectos de los fármacos , Neoplasias Mamarias Experimentales/prevención & control , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ácido alfa-Linolénico/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Acetilcolina/metabolismo , Acetilcolinesterasa/genética , Acetilcolinesterasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Metabolismo de los Lípidos/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Metilnitrosourea , Mitocondrias/metabolismo , Mitocondrias/patología , Ratas Wistar , Transducción de Señal , Receptor Nicotínico de Acetilcolina alfa 7/genéticaRESUMEN
BACKGROUND: This study evaluates the anti-cancer effects of Tadalafil (potent PDE-5 inhibitor) in female albino wistar rats against n-methyl n-nitrosourea induced mammary gland carcinogenesis. METHODS: The animals were selected and randomly divided among four groups and each group contains six animals per group. The animal tissue and serum samples were evaluated for the presence of antioxidant parameters and the cellular morphology was studied using carminic staining, haematoxylin staining and scanning electron microscopy followed by immunoblotting analysis. RESULTS: On the grounds of hemodynamic recordings and morphology, n-methyl n-nitrosourea treated group showed distorted changes along with distorted morphological parameters. For morphological analysis, the mammary gland tissues were evaluated using scanning electron microscopy, whole mount carmine staining, haematoxylin and eosin staining. The serum samples were evaluated for the evaluation of oxidative stress markers and inflammatory markers. The level of caspase 3 and 8 were also evaluated for the estimation of apoptosis. The fatty acid profiling of mammary gland tissue was evaluated using fatty acid methyl esters formation. The mitochondrial mediated apoptosis and inflammatory markers were evaluated using immunoblotting assay. CONCLUSION: The results confirm that Tadalafil treatment restored all the biological markers to the normal and its involvement in mitochondrial mediated death apoptosis pathway along with inhibition of inflammatory markers.
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Lipooxigenasa/metabolismo , Neoplasias Mamarias Experimentales/prevención & control , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Prostaglandina-Endoperóxido Sintasas/metabolismo , Transducción de Señal/efectos de los fármacos , Tadalafilo/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Carcinogénesis/metabolismo , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Mediadores de Inflamación/sangre , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Metilnitrosourea/efectos adversos , Metilnitrosourea/farmacología , Mitocondrias/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The present study was undertaken to inquest the chemical activation of prolyl hydroxylase-2 for the curtailment of hypoxia-inducible factor-1α and fatty acid synthase. It was well documented that hypoxia-inducible factor-1α and fatty acid synthase were overexpressed in mammary gland carcinomas. After screening a battery of compounds, BBAP-2 was retrieved as a potential prolyl hydroxylase-2 activator and validates its activity using ER + MCF-7 cell line and n-methyl-n-nitrosourea-induced rat in vivo model, respectively. BBAP-2 was palpable for the morphological characteristics of apoptosis along with changes in the mitochondrial intergrity as visualized by acridine orange/ethidium bromide and JC-1 staining against ER + MCF-7 cells. BBAP-2 also arrest the cell cycle of ER + MCF-7 cells at G2/M phase. Afterward, BBAP-2 has scrutinized against n-methyl-n-nitrosourea-induced mammary gland carcinoma in albino Wistar rats. BBAP-2 restored the morphological architecture when screened through carmine staining, haematoxylin and eosin staining, and scanning electron microscopy. BBAP-2 also delineated the markers of oxidative stress favourably. The immunoblotting and mRNA expression analysis validated that BBAP-2 has a potentialty activate the prolyl hydroxylase-2 with sequential downregulating effect on hypoxia-inducible factor-1α and its downstream checkpoint. BBAP-2 also fostered apoptosis through mitochondrial-mediated death pathway. The present study elaborates the chemical activation of prolyl hydroxylase-2 by which the increased expression of HIF-1α and FASN can be reduced in mammary gland carcinoma.
Asunto(s)
Neoplasias de la Mama/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Acido Graso Sintasa Tipo I/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mitocondrias/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzopiranos/química , Benzopiranos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Mitocondrias/metabolismo , Mitocondrias/patología , Ratas , Ratas WistarRESUMEN
Polyunsaturated fatty acids (PUFA's) are majorly classified as ω-3 and ω-6 fatty acids. The eicosapentaenoic acid (EPA, ω-3:20-5), docosahexaenoic acid (DHA, ω-3:22-6) and alpha-linolenic acid (ALA, ω-3:18-3) are known ω-3 fatty acids, extracted from animal (e.g fish oil) and plant sources (e.g flaxseed oil). Furthermore, linoleic acid (LA, ω-6:18-2) is recognized as ω-6 fatty acid and the most prominent biological fatty acid with a pro-inflammatory response. Flaxseed oil has variety of biological roles, due to the significant amount of ω-3/ω-6 fatty acids. Numerous studies have reported that ALA (ω-3:18-3) and LA (ω-6:18-2) has diverse pharmacological activities. The ALA (ω-3:18-3) and LA (ω-6:18-2) are recognised to be the pharmacological antagonist. For example, ALA (ω-3:18-3) is recognised as anti-inflammatory, whereas LA (ω-6:18-2) is considered to be pro-inflammatory. PUFA's get oxidized in three ways; firstly, free radical-mediated pathway, secondly non-free radical non-enzymatic metabolism, and lastly enzymatic degradation. The present report is an attempt to summarize various modes of PUFA's metabolism and elaborate biological effects of the associated metabolites concerning flaxseed oil.
Asunto(s)
Aceite de Linaza/farmacología , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-6/farmacología , HumanosRESUMEN
BACKGROUND: Obstetric units across the UK face resource pressures alongside a rising rate of Caesarean section (CS). It is assumed that this places a further burden in the form of postnatal bed demands. The number of inpatient beds has fallen nationally, and this may be used to justify attempts to restrict the CS rate. We set out to replace such assumptions with evidence. We did not find any similar contemporary analysis in a literature search. METHODS: The postnatal length of stay (LOS) of women delivering at Watford General Hospital, a large unit hosting around 5500 deliveries per annum, was stratified by mode of delivery. Differences within and across time periods were analysed. RESULTS: The CS rate rose from 14.5% in 1995 to 30.9% in 2015. The mean LOS post-CS declined from 4.2 to 2.4 days. These data were statistically significant to p < 0.001. Over this period the standardised total postnatal bed use for all delivery modes fell from 11083 days to 7894 days. A 113% rise in the CS rate was accommodated by only a 19.8% rise in postnatal bed use attributable to CS patients. CONCLUSIONS: Whatever pressures may be exacerbated by the rising CS rate, bed occupancy is not one of them. In discussion we widen our argument to suggest that resource pressures should not be used to justify limitations in the CS rate.
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Ocupación de Camas/estadística & datos numéricos , Cesárea/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Atención Posnatal/estadística & datos numéricos , Adulto , Cesárea/rehabilitación , Práctica Clínica Basada en la Evidencia , Femenino , Humanos , Embarazo , Estudios RetrospectivosRESUMEN
The present research was ventured to examine the effect of l-cysteine on neuro-inflammation persuaded by peripheral lipopolysaccharides (LPS, 125⯵g/kg, i.p.) administration. No behavioral, biochemical, and inflammatory abnormality was perceived in the brain tissues of experimental animals after LPS administration. l-cysteine precipitated marginal symptoms of toxicity in the brain tissue. Similar pattern of wholesome effect of LPS were perceived when evaluated through the brain tissue fatty acid profile, histopathologically and NF-ĸBP65 protein expression. LPS was unsuccessful to alter the levels of hydrogen sulphide (H2S), cyclooxygenase (COX) and lipoxygenase (LOX) enzyme in brain tissue. LPS afforded significant peripheral toxicity, when figured out through inflammatory markers (COX, LOX), gaseous signaling molecules nitric oxide (NO), H2S, liver toxicity (SGOT, SGPT), and inflammatory transcription factor (NF-ĸBP65) and l-cysteine also provided a momentous protection against the same as well. The study inculcated two major finding, firstly LPS (i.p.) cannot impart inflammatory changes to brain and secondly, l-cysteine can afford peripheral protection against deleterious effect of LPS (i.p.).
RESUMEN
The synthesis of previously unknown derivatives of boranephosphonate that contain amine substitutions at boron and the incorporation of these derivatives into the backbone of DNA oligonucleotides is described. These derivatives result from iodine-mediated replacement of one BH3 hydride of a boranephosphonate linkage by pyridine, various substituted pyridines, other aromatic amines, and certain unsaturated amines. Oligonucleotides containing these backbone modifications show enhanced uptake, relative to unmodified DNA, in mammalian cells. The redox behavior of the boranephosphonate and pyridinium boranephosphonate conjugated linkages has also been studied.
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Boranos/química , ADN de Neoplasias/química , Oligonucleótidos/química , Fosfatos/química , Compuestos de Piridinio/química , Boranos/síntesis química , Boranos/farmacocinética , Células HeLa , Humanos , Fosfatos/síntesis química , Fosfatos/farmacocinética , Compuestos de Piridinio/síntesis química , Compuestos de Piridinio/farmacocinéticaRESUMEN
BACKGROUND: The present study was in quested to study the effects of ß-sitosterol on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. METHODS: Animals were randomized and divided into four groups of eight animals each. Group I (sham control 1 % CMC in normal saline p.o.); Group II (toxic control, MNU 47 mg/kg, i.v); Group III (MNU 47 mg/kg, i.v + ß-sitosterol, 10 mg/kg, p.o); Group IV (MNU 47 mg/kg, i.v + ß-sitosterol, 20 mg/kg, p.o). Toxicity was induced by single i.v. injection of MNU followed by ß-sitosterol supplementation therapy for 115 days at the dose mentioned above. RESULTS: Treatment with ß-sitosterol evidenced decrease in the alveolar bud and lobule score in the whole mount of the mammary gland. ß-sitosterol exhibited diminishing effect on oxidative stress through synchronizing lipid and enzymatic antioxidant defense. A significant decrease in the saturated and unsaturated fatty acid was evident with the MNU treatment and ß-sitosterol demonstrated a marked effect on it. Pgp 9.5 expression was dose dependently upregulated by ß-sitosterol treatment in comparison to MNU treatment. On the contrary, downregulated NF-kB expression was perceived, when ß-sitosterol was concomitantly administered with MNU. CONCLUSION: ß-sitosterol afforded significant protection against the deleterious effects of MNU.
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Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Metilnitrosourea/efectos adversos , Sustancias Protectoras/uso terapéutico , Animales , Femenino , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/patología , Sustancias Protectoras/química , Ratas , Ratas WistarRESUMEN
This study was undertaken to investigate the effect of α-chymotrypsin on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized into four groups (six animals in each). Group I (sham control 0.9 % normal saline p.o.); Group II (toxic control, MNU 47 mg/kg, i.v.); Group III (α-chymotrypsin, 5 mg/kg, p.o.); Group IV (α-chymotrypsin, 10 mg/kg p.o.). Toxicity was induced by single i.v. injection of MNU followed by α-chymotrypsin supplementation therapy for 100 days. MNU treatment was evident with increased alveolar bud count, differentiation score, upregulated inflammatory enzymes markers (COX, LOX and NO) antioxidative stress markers (TBARs, SOD, catalase and GSH).MNU associated toxicity was also ascertained by PGP 9.5 and NF-κB expression in the mammary gland tissue followed by FAME analysis for fatty acid profiling. α-chymotrypsin afforded significant protection against the deleterious effects of MNU.
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Quimotripsina/uso terapéutico , Ácidos Grasos no Esterificados/metabolismo , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Metilnitrosourea/toxicidad , Ubiquitina Tiolesterasa/metabolismo , Animales , Bovinos , Femenino , Neoplasias Mamarias Experimentales/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas WistarRESUMEN
OBJECTIVE: The present study was aimed to enumerate the role of metformin-associated H2S release against lipopolysaccharide (LPS) induced neuroinflammation. MATERIALS AND METHODS: Five groups of animals were subjected to treatment as control (normal saline), toxic control (LPS, 125 µg/kg, i.p.), and three separate groups treated with 6.25, 12.5, and 25 mg/kg of metformin along with LPS for a period of 28 days. LPS was administered on 1st, 2nd, 3rd, 4th, 23rd, 24th, 25th and 26th day. The animals were evaluated for behavioral (elevated plus maze, rotarod and actophotometer); biochemical (plasma and tissue H2S, COX, LOX and NO), antioxidant (TBARS, SOD, catalase, protein carbonyl and GSH) and liver toxicity (SGOT and SGPT) markers. The brain tissues were further evaluated histopathologically, free fatty acid profile and NF-κB expression. RESULT: The LPS could not hasten any significant behavioral, biochemical, antioxidant and histopathological changes in the brain tissue. LPS also failed to modify the free fatty acid profile and NF-κB expression in the brain tissue. The LPS demarcated a well-defined peripheral inflammation as perceived through the plasma H2S, NO, SGOT and SGPT. Metformin administration demonstrated a marked effect on the peripheral inflammation induced by LPS. CONCLUSION: The LPS (i.p.) administration is devoid of any neuroinflammatory effects; however, precipitates peripheral inflammatory reactions and the same can could be attributed to the fact that LPS is devoid of/confined by very minimal permeability across the blood brain barrier. Metformin demonstrated a significant effect on peripheral inflammatory reactions precipitated through LPS.
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Sulfuro de Hidrógeno/metabolismo , Hipoglucemiantes/uso terapéutico , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Metformina/uso terapéutico , Animales , Hipoglucemiantes/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Metformina/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
The introduction of modifications into oligonucleotides is important for a large number of applications in the nucleic acids field. However, the method of solid-phase DNA synthesis presents significant challenges for incorporating many useful modifications that are unstable to the conditions for preparing synthetic DNA. Here we report that boranephosphonate diesters undergo facile nucleophilic substitution in a stereospecific manner upon activation by iodine. We have subsequently used this reactivity to post-synthetically introduce modifications including azides and fluorophores into DNA by first synthesizing boranephosphonate-linked 2'-deoxyoligonucleotides and then treating these oligomers with iodine and various nucleophiles. In addition, we show that this reaction is an attractive method for preparing stereodefined phosphorus-modified oligonucleotides. We have also examined the mechanism of this reaction and show that it proceeds via an iodophosphate intermediate. Beyond nucleic acids synthesis, due to the ubiquity of phosphate derivatives in natural compounds and therapeutics, this stereospecific reaction has many potential applications in organophosphorus chemistry.
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Compuestos de Boro/química , ADN/química , Oligonucleótidos/síntesis química , Organofosfonatos/química , Amidas/química , Azidas/química , Técnicas de Química Sintética , ADN/síntesis química , Dimerización , Ésteres/química , Etilaminas/química , Yodo/química , Espectroscopía de Resonancia Magnética , Oligonucleótidos/química , Oxidación-Reducción , Ácidos Fosfóricos/química , EstereoisomerismoRESUMEN
We investigate the efficiency of incorporation of boranephosphonate-modified nucleotides by phi29 DNA polymerase and present a simple method for forming large defined silver nanostructures by rolling circle amplification (RCA) using boranephosphonate internucleotide linkages. RCA is a linear DNA amplification technique that can use specifically circularized DNA probes for detection of target nucleic acids and proteins. The resulting product is a collapsed single-stranded DNA molecule with tandem repeats of the DNA probe. By substituting each of the natural nucleotides with the corresponding 5'-(α-P-borano)deoxynucleosidetriphosphate, only a small reduction in amplification rate is observed. Also, by substituting all four natural nucleotides, it is possible to enzymatically synthesize a micrometer-sized, single-stranded DNA molecule with only boranephosphonate internucleotide linkages. Well-defined silver particles are then readily formed along the rolling circle product.