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1.
J Assoc Physicians India ; 71(8): 11-12, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37651248

ABSTRACT

Gastroesophageal reflux disease (GERD) is among the most prevalent gastrointestinal (GI) disorders. It is known to often coexist with other chronic diseases such as asthma, chronic obstructive pulmonary disease (COPD), obesity, diabetes mellitus (DM), and hypertension. Upper endoscopy, esophageal manometry, and impedance-pH monitoring are a few invasive diagnostic options that are reserved for selected GERD patients. Symptom assessment by using questionnaires, such as the frequency scale for the symptoms of GERD (FSSG), is simple, convenient, noninvasive, and inexpensive. These questionnaires are widely used to facilitate diagnosis and appropriate treatment. Early diagnosis of GERD and timely management may improve clinical outcomes in patients. Proton pump inhibitors (PPIs) are the preferred therapy for GERD. However, evidence indicates that excessive and extended use of PPIs is linked to adverse events. An overview of the diagnosis and management of GERD, as well as an evidence-based overview of the relationship between GERD and asthma, COPD, obesity, DM, and hypertension, is presented in this review. Expert opinions and recommendations for diagnosing GERD using invasive tests and validated questionnaires have also been mentioned.


Subject(s)
Asthma , Gastroesophageal Reflux , Hypertension , Pulmonary Disease, Chronic Obstructive , Humans , Gastroesophageal Reflux/complications , Gastroesophageal Reflux/diagnosis , Gastroesophageal Reflux/epidemiology , Obesity/complications , Obesity/diagnosis , Obesity/epidemiology , Proton Pump Inhibitors/therapeutic use
2.
Protein Sci ; 32(10): e4736, 2023 10.
Article in English | MEDLINE | ID: mdl-37515406

ABSTRACT

Many proteins that self-assemble into amyloid and amyloid-like fibers can adopt diverse polymorphic forms. These forms have been observed both in vitro and in vivo and can arise through variations in the steric-zipper interactions between ß-sheets, variations in the arrangements between protofilaments, and differences in the number of protofilaments that make up a given fiber class. Different polymorphs arising from the same precursor molecule not only exhibit different levels of toxicity, but importantly can contribute to different disease conditions. However, the factors which contribute to formation of polymorphic forms of amyloid fibrils are not known. In this work, we show that in the presence of 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine, a highly abundant lipid in the plasma membrane of neurons, the aggregation of α-synuclein is markedly accelerated and yields a diversity of polymorphic forms under identical experimental conditions. This morphological diversity includes thin and curly fibrils, helical ribbons, twisted ribbons, nanotubes, and flat sheets. Furthermore, the amyloid fibrils formed incorporate lipids into their structures, which corroborates the previous report of the presence of α-synuclein fibrils with high lipid content in Lewy bodies. Thus, the present study demonstrates that an interface, such as that provided by a lipid membrane, can not only modulate the kinetics of α-synuclein amyloid aggregation but also plays an important role in the formation of morphological variants by incorporating lipid molecules in the process of amyloid fibril formation.


Subject(s)
Amyloid , alpha-Synuclein , alpha-Synuclein/chemistry , Amyloid/chemistry , Cell Membrane/metabolism , Lewy Bodies/metabolism , Lipids
3.
J Hum Hypertens ; 37(11): 1033-1039, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37208524

ABSTRACT

Low density of formal care providers in rural India results in restricted and delayed access to standardized management of hypertension. Task-sharing with pharmacies, typically the first point of contact for rural populations, can bridge the gap in access to formal care and improve health outcomes. In this study, we implemented a hypertension care program involving task-sharing with twenty private pharmacies between November 2020 and April 2021 in two blocks of Bihar, India. Pharmacists conducted free hypertension screening, and a trained physician offered free consultations at the pharmacy. We calculated the number of subjects screened, initiated on treatment (enrolled) and the change in blood pressure using the data collected through the program application. Of the 3403 subjects screened at pharmacies, 1415 either reported having a history of hypertension or had elevated blood pressure during screening. Of these, 371 (26.22%) were enrolled in the program. Of these, 129 (34.8%) made at least one follow-up visit. For these subjects, the adjusted average difference in systolic and diastolic blood pressure between the screening and follow-up visits was -11.53 (-16.95 to -6.11, 95% CI) and -4.68 (-8.53 to -0.82, 95% CI) mmHg, respectively. The adjusted odds of blood pressure being under control in this group during follow-up visits compared to screening visit was 7.07 (1.29 to 12.85, 95% CI). Task-sharing with private pharmacies can lead to early detection and improved control of blood pressure in a resource-constrained setting. Additional strategies to increase patient screening and retention rates are needed to ensure sustained health benefits.


Subject(s)
Hypertension , Pharmacies , Humans , Retrospective Studies , Rural Population , Hypertension/diagnosis , Hypertension/drug therapy , Hypertension/epidemiology , Blood Pressure/physiology
4.
Cureus ; 15(2): e34825, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36919064

ABSTRACT

Introduction Obstructive Airway Diseases (OADs) are the leading cause of death among chronic respiratory diseases worldwide, and novel therapies are direly needed. Fluticasone furoate/vilanterol (FF/Vi) (100/25 µg) is the first once-daily ICS/uLABA marketed in India for COPD since 2021. Considering its limited real-world experience in OAD patients in Indian clinical settings, a large drug utilization study (DUS) was planned. Methodology We conducted a cross-sectional, observational DUS at 1900 outpatient clinics in India from October 2021 to March 2022. Prescription data and medical history of patients who were prescribed the FF/Vi combination were collected. Results It was observed that FF/Vi was prescribed in an almost equal number of patients with COPD (44.2%) and asthma (42.9%). The majority of the patients (74%) were switched from previous ICS/LABA to this ICS/uLABA, while 26% of patients were treatment naïve. The average CAT score was 19.5±7.8 (43.2% GOLD Group C and 32.2% GOLD Group B) in COPD patients, while the average ACQ-5 score was 2.6±1.3 (33.1% GINA Step 3, 29.5% GINA Step 2) in asthmatic patients. Most of the patients (63.9%) had raised biomarkers (Blood eosinophil count >300 cells/µl). Prior history of exacerbation was present in 65% of patients with annual exacerbation rates of 1.2 in COPD, 1.1 in asthma, and 1.2 in asthma-COPD overlap syndrome (ACOS). Leukotriene inhibitors (42%) and LAMAs (30.8%) were common add-on medications. Conclusion We observed a trend towards a shift to once-daily ICS/uLABA (FF/Vi) by physicians, especially in symptomatic and exacerbating OAD patients with underlying comorbidities.

6.
Nat Neurosci ; 25(9): 1134-1148, 2022 09.
Article in English | MEDLINE | ID: mdl-36042314

ABSTRACT

Aggregation of alpha-synuclein (α-Syn) drives Parkinson's disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)-derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.


Subject(s)
Parkinson Disease , alpha-Synuclein , Cardiolipins/metabolism , Humans , Mitochondria/metabolism , Mitochondrial Membranes/metabolism , Neurons/metabolism , Neurons/pathology , Parkinson Disease/genetics , Parkinson Disease/metabolism , alpha-Synuclein/metabolism
7.
Pediatr Pulmonol ; 57(7): 1684-1692, 2022 07.
Article in English | MEDLINE | ID: mdl-35506424

ABSTRACT

OBJECTIVES: The objective of study was to find an association between the timing of tracheostomy with duration of mechanical ventilation (MV) and length of stay (LOS) in pediatric intensive care unit (PICU) and hospital. METHODS: The data were collected prospectively from 2000 to 2018 and were analyzed retrospectively. Data included clinical diagnosis, indication, and duration (days) of MV, LOS in PICU and hospital before and after tracheostomy. Patients who did not receive MV or underwent MV for <24 h were excluded. According to the indication of tracheostomy enrolled patients were divided into four groups-airways anomalies (AA), central neurological impairment (CNI), cardiopulmonary insufficiency (CPI), and neuromuscular disorders (NMD). Patients in each group were divided into early (ET) and late tracheostomy (LT) category based on the median (interquartile range interquartile range [IQR]) days of pretracheostomy MV. RESULTS: Two hundred and fifty six patients were analyzed. The frequency and median [IQR] days of pretracheostomy MV were -AA 54 [7(3,16)], CNI 120 [12(9,16)], CPI 51 [25(16.5,30.5)], and NMD 31[12(8,16.5)]. In AA patients, median (IQR) durations of posttracheostomy MV [2(1,5.2) versus 3.5(2,12); p = 0.032], PICU [7(5,8.2) versus11(7,18); p = 0.004] and hospital [12(9.7,21) versus 21.5(12,28); p = 0.027] stays were lower in ET as compared with LT group. Posttracheostomy MV duration was significantly short in ET patients with CNI and NMD (p < 0.005). The total days of MV, PICU and hospital stay were significantly lower in ET as compared with LT patients in all four groups (p < 0.01). CONCLUSION: As compared with LT, ET patient had shorter durations of total MV and PICU and hospital stay.


Subject(s)
Intensive Care Units, Pediatric , Tracheostomy , Child , Humans , Intensive Care Units , Length of Stay , Respiration, Artificial , Retrospective Studies
8.
Int J Toxicol ; 41(2): 143-162, 2022.
Article in English | MEDLINE | ID: mdl-35230174

ABSTRACT

Determining the adverse nature of findings from nonclinical safety studies often poses a challenge for the key stakeholders responsible for interpreting the results of definitive toxicity studies in support of pharmaceutical product development. Although there are instances in which responses to treatment clearly indicate intolerability or tissue injury associated with dysfunction; in practice, more often there is uncertainty in characterizing an effect of drug treatment as adverse or not. This is due to the inherent variability in responses of biological test systems to toxicological insults, leaving the ultimate analyses of adversity to individual interpretation and subjectivity. This article is a follow-up to the workshop entitled, "Adverse or Not Adverse?: Thinking process behind adversity determination during nonclinical drug development," conducted at the 58th Annual Meeting of the Society of Toxicology, March 2019 in Baltimore, MD. In this paper, we further discuss and incorporate the perspectives of authors representing different roles, such as Study Director, Study Pathologist, Pharmacology/Toxicology Reviewer (U.S. Food and Drug Administration), and Sponsor in the determination and use of adversity. We also present a practical stepwise approach as an aid in this assessment, and further apply these principles to discuss 10 case studies with different therapeutic modalities and unique challenges.


Subject(s)
Drug Development , Drug Evaluation, Preclinical/methods , No-Observed-Adverse-Effect Level , Pharmaceutical Preparations , Risk Assessment/methods , United States , United States Food and Drug Administration
9.
Indian J Crit Care Med ; 25(7): 803-811, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34316177

ABSTRACT

AIM AND OBJECTIVE: To study the profile, indications, related complications, and predictors of decannulation and mortality in patients who underwent tracheostomy in the pediatric intensive care unit (PICU). MATERIALS AND METHODS: Retrospective analysis of prospectively collected data of tracheostomies was done on patients admitted at PICU. Demographics, primary diagnosis, indication of tracheostomy, and durations of endotracheal intubation, mechanical ventilation, and tracheostomy cannulation were recorded. The indication was recorded in one of the four categories-upper airway obstruction (UAO), central neurological impairment (CNI), prolonged mechanical ventilation, and peripheral neuromuscular disorders). RESULTS: Two hundred ninety cases were analyzed. UAO (42%) and CNI (48.2%) were main indications in the halves of the study period, respectively. Decannulation was successful in 188 (64.8%) patients. Seventy-seven percentage UAO patients were decannulated successfully [OR (odds ratio); 95% CI (confidence interval), 2.647; 1.182-5.924, p = 0.018]. Age <1 year (0.378; 0.187-0.764; p = 0.007), nontraumatic, noninfectious central neurological diseases (0.398; 0.186-0.855; p = 0.018), and malignancy (0.078; 0.021-0.298; p <0.001), durations of posttracheostomy ventilation (0.937; 0.893-0.983; p = 0.008), and stay in the PICU (0.989; 0.979-0.999; p = 0.029) were predictors of unsuccessful decannulation. There were 91 (31.4%) deaths. Age <1 year (2.39 (1.13-5.05; p = 0.02), malignancy (17.55; 4.10-75.11; p <0.001), durations of posttracheostomy ventilation (1.06; 1.006-1.10; p = 0.028), and hospital stay (1.007; 1.0-1.013; p = 0.043) were independent predictors of mortality. Indication of UAO favored survivor (0.24; 0.09-0.57; p <0.001). CONCLUSION: The indications for tracheostomy in children had changed over the years. Infancy, primary diagnosis, length of posttracheostomy ventilation, and stay in the PICU and hospital were independent predictors of decannulation and mortality. WHAT THIS ADDS: Similar to developed countries, the age at the time of tracheostomy and indication are changing. Inability to decannulate and mortality were associated with the age of a child at the time of tracheostomy, indication, medical diagnosis, and duration of postprocedure mechanical ventilation and stay in the hospital. HOW TO CITE THIS ARTICLE: Sachdev A, Chaudhari ND, Singh BP, Sharma N, Gupta D, Gupta N, et al. Tracheostomy in Pediatric Intensive Care Unit-A Two Decades of Experience. Indian J Crit Care Med 2021;25(7):803-811.

10.
Toxicol Pathol ; 49(1): 5-109, 2021 01.
Article in English | MEDLINE | ID: mdl-33393871

ABSTRACT

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.


Subject(s)
Animals, Laboratory , Animals , Databases, Factual , Dogs , Europe , Japan
11.
RSC Adv ; 10(15): 9140-9145, 2020 Feb 27.
Article in English | MEDLINE | ID: mdl-35496569

ABSTRACT

We report the fabrication of single-phase polycrystalline Pb0.85Bi0.10(Zr0.52Ti0.48)O3 (PBiZT) ceramic which shows large polarization, i.e., ∼40 µC cm-2 and piezoelectric coefficients ∼130 pC N-1 and giant linear change in capacitive reactance and dielectric properties with increasing and decreasing pressure in the range of 1 kHz to 5 MHz. Nearly 70% change in dielectric constant and 56% change in capacitive reactance were obtained in the pressure range of 20-200 MPa, which makes it suitable for applications as a capacitive pressure sensor/gauge. The sensitivity of the device is calculated as 0.66 MPa-1 and 18.2 MPa-1 at 1 MHz and 5 MHz, respectively, which is the highest ever reported value so far for any bulk polycrystalline ceramic. The compressive stress of the device was tested according to the standard test method as a function of linear and volumetric strain, which yields the Young's modulus, Bulk modulus, and Poisson's ratio of the device. These values were further utilized to calculate actual stress in the sample and energy density using ANSYS software, which indicates at least four orders smaller pressure in the sample compared to the applied pressure.

12.
FEBS Lett ; 594(3): 509-518, 2020 02.
Article in English | MEDLINE | ID: mdl-31552690

ABSTRACT

The fibronectin type II (FnII) domain, present in diverse vertebrate proteins, plays crucial roles in several fundamental biological processes. PDC-109, the major bovine seminal plasma protein, contains two FnII domains that bind to choline phospholipids on sperm plasma membrane and induce lipid efflux crucial for successful fertilization. PDC-109 also exhibits chaperone-like activity and protects other proteins against various types of stress. Here, we show that a core tryptophan residue is highly conserved across species in the FnII domains. Mutation of conserved tryptophan residues W47, W93, and W106 in the FnII domains of PDC-109 to alanine leads to drastic decrease or complete abolition of membrane-binding and chaperone-like activities. These observations suggest that conserved tryptophans are important for the function of FnII proteins.


Subject(s)
Cell Membrane/metabolism , Conserved Sequence , Seminal Vesicle Secretory Proteins/chemistry , Seminal Vesicle Secretory Proteins/metabolism , Tryptophan , Amino Acid Sequence , Animals , Cattle , Ligands , Models, Molecular , Mutation , Protein Domains , Protein Multimerization , Protein Structure, Quaternary , Seminal Vesicle Secretory Proteins/genetics
13.
J Nanosci Nanotechnol ; 18(3): 1763-1771, 2018 Mar 01.
Article in English | MEDLINE | ID: mdl-29448656

ABSTRACT

The tuneability of oxygen containing groups in graphene oxide (GO) that controls physicochemical properties is highly desirable for device applications. In this context, the thermally reduced graphene oxide (r-GO) powders and spin coated thin films with varying sp2/sp3 carbon network have been prepared using highly exfoliated GO (synthesized using modified Hummer's method with an innovative conjunction of lyophilisation). The additional step of lyophilisation results in the formation of highly exfoliated and monodispersed GO nanosheets as evidenced from FESEM, TEM, XRD, and Raman, FT-IR and UV-Vis spectroscopy. Spectroscopic analysis revealed the systematic evolution of r-GO with tuneable structural, optical and electrical properties as results of varying annealing temperatures (100-400 °C), due to restoration of sp2 conducting carbon network i.e., the formation of new -C═C- network and Stones-Wales defect. The tuneability of physical properties is further corroborated by change in the resistance values, as evidenced through the current-voltage characteristics in GO thin film based lateral device structures with Ag and Al top contacts. Controlling physicochemical properties at relatively low processing temperature warrants the utilization of GO and r-GO in various electronic and optoelectronic devices.

14.
Braz. arch. biol. technol ; 60: e17160366, 2017. tab, graf
Article in English | LILACS | ID: biblio-951448

ABSTRACT

ABSTRACT Tacrolimus is a polyketide macrolide produced by Streptomyces species which is widely used as anti-fibrotic agent and potent immunosuppressant. In this article dual mutagenesis approach using mutagens (NTG+EMS+UV) was used to develop a mutant strain of Streptomyces tacrolimicus (ATCC 55098) for higher tacrolimus production and this strain showed higher tacrolimus production at 82.5 mg/l. Interestingly; addition of L-Lysine (0.2 g/l) into the production medium further enhanced the tacrolimus production to ~102 mg/l at 7-L fed-batch bioreactor. To the best of our knowledge this is the first report mentioning efficient strain development for higher production of tacrolimus using dual mutagenesis. The obtained data presents an impressive model for higher production of tacrolimus and enhanced our understanding regarding improvement in production capacity of tacrolimus in Streptomyces tacrolimicus.

15.
Microbiol Res ; 192: 300-312, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27664749

ABSTRACT

Sheath blight of rice (Oryza sativa L.) caused by Rhizoctonia solani is a major disease and attempts are being made to develop microbe based technologies for biocontrol of this pathogen. However, the mechanisms of biocontrol are not fully understood and still require indepth study in the backdrop of emerging concepts in biological systems. The present investigation was aimed at deciphering the mechanisms of biocontrol of sheath blight of rice employing Pseudomonas fluorescens and Trichoderma harzianum as model agents for biocontrol. Initially 25, 5 and 5 strains of P. fluorescens, T. viride and T. harzianum, respectively, were screened for their biocontrol potential. Out of which, six strains with higher value of percent inhibition of fungal mycelium in dual plate assay were selected. The role of P. fluorescens, T. viride and T. harzianum were investigated in induction and bioaccumulation of natural antioxidants, defence-related biomolecules and other changes in plant which lead not only to growth promotion but also protection from pathogenic stress conditions in rice. The two most promising strains, P. fluorescens PF-08 and T. harzianum UBSTH-501 selected on the basis of in planta evaluation, when applied individually or in combination, significantly enhanced the accumulation of defence-related biomolecules, enzymes and exhibited biocontrol potential against R. solani. A modified/newly developed delivery system was applied for the first time in the experiments involving inoculation of plants with both bioagents, viz. P. fluorescens PF-08 and T. harzianum UBSTH-501. Results suggested that application of P. fluorescens PF-08 and T. harzianum UBSTH-501 alone or in combination, not only helps in control of the disease but also increases plant growth along with reduction in application of toxic chemical pesticides.


Subject(s)
Antibiosis , Biological Control Agents , Microbiota , Oryza/microbiology , Plant Diseases/microbiology , Plant Roots/microbiology , Rhizosphere , Bacteria/classification , Bacteria/genetics , Fungi/classification , Fungi/genetics , Germination , Host-Pathogen Interactions , Seedlings
16.
Toxicol Pathol ; 43(1): 10-40, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25385331

ABSTRACT

The 2014 annual National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri" was held in Washington, D.C., in advance of the Society of Toxicologic Pathology's 33rd annual meeting. The goal of this annual NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for audience voting and discussion. Some lesions and topics covered during the symposium included a pulmonary mucinous adenocarcinoma in a male B6C3F1 mouse; plexiform vasculopathy in Wistar Han (Crl:WI[Han]) rats; staging of the estrous cycle in rats and mice; peri-islet fibrosis, hemorrhage, lobular atrophy and inflammation in male Sprague-Dawley (SD) rats; retinal dysplasia in Crl:WI[Han] rats and B6C3F1 mice; multicentric lymphoma with intravascular microemboli and tumor lysis syndrome, and 2 cases of myopathy and vascular anomaly in Tg.rasH2 mice; benign thymomas in Crl:WI[Han] rats; angiomatous lesions in the mesenteric lymph nodes of Crl:WI[Han] rats; an unusual foveal lesion in a cynomolgous monkey; and finally a series of nomenclatures challenges from the endocrine International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) Organ Working Group (OWG).

17.
Methods Appl Fluoresc ; 3(2): 025002, 2015 Feb 26.
Article in English | MEDLINE | ID: mdl-29148483

ABSTRACT

The interaction of Citrate-capped gold nanoparticles (AuNPs) with Bovine gamma globulin (BGG) was studied using Fourier transform infrared (FTIR), UV-Visible and Fluorescence spectroscopy. FTIR has confirmed the conjugation of AuNPs and BGG. Fluorescence quenching of tryptophan has confirmed the strong interaction between BGG and AuNPs. UV-Visible and Fluorescence spectroscopy have investigated the extent of interaction by determining the binding constants. Binding constants evaluated from UV-Visible and Fluorescence data are in good agreement with each other. An independent class of binding site on BGG for AuNPs has been predicted, where AuNPs interact with a highly solvent accessible tryptophan residue.

18.
Toxicol Pathol ; 40(3): 513-21, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22215515

ABSTRACT

The risk of hepatocellular carcinoma increases with the persistence of non-alcoholic fatty liver disease. Triacylglycerol synthesis is initiated by glycerol-3-phosphate acyltransferase (GPAT). Of four isoforms, GPAT1 contributes 30-50% of total liver GPAT activity, and we hypothesized that it might influence liver susceptibility to tumorigenesis. C57Bl/6 mice deficient in GPAT1 were backcrossed 6 times to C3H mice. After exposure to the carcinogen diethylnitrosamine (DEN) and the tumor promoter phenobarbital, male Gpat1⁻/⁻ mice, compared with controls (Gpat1⁺/⁺), had 93% fewer macroscopically visible nodules per liver at 21 weeks of age and 39% fewer at 34 weeks of age. Microscopically, control mice had increased numbers of foci of altered hepatocytes, particularly the basophilic subtype, as well as more, and malignant, liver neoplasms than did the Gpat1⁻/⁻ mice. At 21 weeks of age, 50% (4/8) of control mice (50%) had hepatocellular adenomas with an average multiplicity (tumors per tumor-bearing-animal) of 4.3, while none occurred in 8 Gpat1⁻/⁻ mice. At 34 weeks of age, all 15 control mice (100%) had hepatocellular adenomas with an average multiplicity of 5.2 compared to an incidence of 93% in Gpat1⁻/⁻ mice and multiplicity of 3.1. HCCs were observed in 13% of control mice and in only 6% of Gpat1⁻/⁻ mice. These data show that alterations in the formation of complex lipids catalyzed by Gpat1 reduce susceptibility to DEN-induced liver tumorigenesis.


Subject(s)
Glycerol-3-Phosphate O-Acyltransferase/deficiency , Liver Neoplasms, Experimental/enzymology , Animals , Cell Proliferation , Diethylnitrosamine/toxicity , Genetic Predisposition to Disease , Glycerol-3-Phosphate O-Acyltransferase/genetics , Glycerol-3-Phosphate O-Acyltransferase/metabolism , Hepatocytes/cytology , Hepatocytes/metabolism , Hepatocytes/pathology , Histocytochemistry , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Neoplasms, Experimental/chemically induced , Liver Neoplasms, Experimental/genetics , Liver Neoplasms, Experimental/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms, Experimental , Organ Size , PPAR alpha/metabolism , Phenobarbital/toxicity , RNA, Messenger , Statistics, Nonparametric
19.
Regul Toxicol Pharmacol ; 61(2): 141-53, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21840362

ABSTRACT

Toxicogenomics is the application of toxicology, genetics, molecular biology and environmental health to describe the response of organisms to environmental stimuli. The field of toxicogenomics has developed over the past 15 years mainly due to advances in toxicology, molecular genetics and cell biology. Its prospective use to resolve crucial data gaps and data inconsistencies could improve risk assessment by providing additional data to increase the understanding of mechanisms and modes of action (MOA) and enhance the reliability of dose-response extrapolation. Thus, toxicogenomics holds promise for advancing the scientific basis of risk assessments. However, one of the current issues is how genomic/transcriptional data is being used to further describe a MOA for oncogenicity and, in turn, its potential uses in cancer risk assessment. This commentary identifies how toxicogenomics could be used on a case by case basis to add information to a MOA addressing both the opportunities and challenges this technology holds. In addition, some pitfalls to avoid in the generation and interpretation of toxicogenomic data and validation issues that need to be addressed before toxicogenomics can be used in the risk assessment process and regulatory decisions are discussed.


Subject(s)
Genomics/methods , Toxicogenetics/methods , Toxicology/methods , Animals , Cell Transformation, Neoplastic/genetics , Dose-Response Relationship, Drug , Genomics/trends , Humans , Reproducibility of Results , Risk Assessment/methods , Risk Assessment/trends , Toxicogenetics/trends , Toxicology/trends
20.
Immunobiology ; 215(7): 527-34, 2010 Jul.
Article in English | MEDLINE | ID: mdl-19897276

ABSTRACT

Asthma is a chronic immune inflammatory disease characterized by variable airflow obstruction and increased bronchial hyperreactivity (BHR). Therapeutic interventions reduce airway inflammation and relieve symptoms but associated with potential side effects that limit their usefulness. The present study was undertaken to assess the effect of choline on immune inflammation and BHR in asthma subjects. The patients of asthma (n=76) were recruited and treated with choline supplement (1500 mg twice) or standard pharmacotherapy for 6 months in two groups. The patients were evaluated by clinical, immunologic and biochemical parameters. The treatment with choline showed significant reduction in symptom/drug score and improvement in PC(20) FEV1 compared to baseline or standard pharmacotherapy (p<0.01). Choline therapy significantly reduced IL-4, IL-5 and TNF-alpha level as compared to baseline or standard pharmacotherapy after 6 months (p<0.01). Blood eosinophil count and total IgE levels were reduced in both the treatment groups. Cysteinyl leukotriene and leukotriene B4 were suppressed significantly by choline treatment (p<0.01). This was accompanied by decreased 8-isoprostanes, a biomarker for oxidative stress after choline treatment (p<0.01). Choline therapy modulates immune inflammation and suppresses oxidative stress in asthma patients. It can be used as an adjunct therapy for asthma patients.


Subject(s)
Asthma/immunology , Choline/pharmacology , Eosinophils/drug effects , Adolescent , Adult , Asthma/diagnosis , Asthma/physiopathology , Bronchial Hyperreactivity , Cells, Cultured , Cytokines/metabolism , Eosinophils/pathology , Female , Follow-Up Studies , Forced Expiratory Volume , Humans , Immunosuppression Therapy , Inflammation , Leukotrienes/metabolism , Male , Middle Aged , Oxidative Stress/drug effects , Oxidative Stress/immunology , Skin Tests , Th2 Cells/drug effects , Th2 Cells/immunology
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