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1.
Bioorg Chem ; 147: 107402, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38688199

ABSTRACT

A series of novel l-ascorbic acid derivatives bearing aryl and alkyl sulfonate substituents were synthesized and characterized. In vitro anticancer evaluation against MCF-7 (breast) and A-549 (lung) cancer cell lines revealed potent activity for most of the compounds, with 2b being equipotent to the standard drug colchicine against MCF-7 (IC50 = 0.04 µM). Notably, compound 2b displayed 89-fold selectivity for MCF-7 breast cancer over MCF-10A normal breast cells. Derivatives with two sulfonate groups (2a-g, 3a-g) exhibited superior potency over those with one sulfonate (4a-c,5g, 6b). Compounds 2b and 2c potently inhibited tubulin polymerization in A-549 cancer cells (73.12 % and 62.09 % inhibition, respectively), substantiating their anticancer potential through microtubule disruption. Molecular docking studies showed higher binding scores and affinities for these compounds at the colchicine-binding site of α, ß-tubulin compared to colchicine itself. In-silico ADMET predictions indicated favourable drug-like properties, with 2b exhibiting the highest binding affinity. These sulfonate derivatives of l-ascorbic acid represents promising lead scaffolds for anticancer drug development.


Subject(s)
Antineoplastic Agents , Ascorbic Acid , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Molecular Docking Simulation , Tubulin Modulators , Tubulin , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Ascorbic Acid/chemistry , Ascorbic Acid/pharmacology , Tubulin/metabolism , Structure-Activity Relationship , Tubulin Modulators/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Molecular Structure , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Polymerization/drug effects , Sulfonic Acids/chemistry , Sulfonic Acids/antagonists & inhibitors , Sulfonic Acids/pharmacology , Cell Line, Tumor
2.
Drug Dev Ind Pharm ; 50(1): 68-77, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38148515

ABSTRACT

AIM: The primary objective of the research was to develop a cubosomal in situ gel encapsulated with Triamcinolone acetonide (TCA) in order to enhance its penetration through the blood-brain barrier (BBB) when administered via the intranasal route, thus enabling efficient and rapid action. METHOD: Cubosomes were formulated by top-down approach using glyceryl monooleate (GMO), using pluronics127 (PF127) and polyvinyl alcohol (PVA) in varying proportions based on the Box-Behnken design. High resolution transmission electron microscopy (HR-TEM) analysis confirmed the morphology of the cubosomes. The in situ gel was formulated and optimized. Experiments involving ex vivo permeation and histopathology analyses were undertaken to evaluate drug permeation and tissue effects. RESULTS: The cubosomes exhibited a particle size (PS) of 197.9 nm, zeta potential (ZP) of -31.11 mV, and entrapment efficacy (EE) of 84.31%, with low deviation. Batch F4 (19% PF127) showed favorable results. In vitro and ex vivo permeation studies revealed drug release of 78.59% and 76.65%, respectively, after 8 h. Drug release followed the Hixson Crowell model of release kinetics. The histopathological examination revealed no signs of toxicity or adverse effects on the nasal mucosa of the sheep. The formulation exhibited short-term stability, maintaining its integrity and properties when stored at room temperature. CONCLUSION: The utilization of an intranasal cubosomal in situ gel encapsulated with TCA was anticipated to lower intracranial pressure and improve patient adherence by offering effective relief for individuals suffering from Brain edema. This efficacy is attributed to its rapid onset of action and its safe and well-tolerated dosage form.


Subject(s)
Drug Carriers , Triamcinolone Acetonide , Humans , Animals , Sheep , Administration, Intranasal , Drug Carriers/pharmacology , Triamcinolone Acetonide/pharmacology , Brain , Nasal Mucosa , Particle Size , Gels/pharmacology
3.
J Org Chem ; 88(13): 8010-8023, 2023 Jul 07.
Article in English | MEDLINE | ID: mdl-37262098

ABSTRACT

Quinoxalinones are a privileged class of compounds, and their structural framework is found in many bioactive compounds, natural compounds, and pharmaceuticals. Quinoxalinone is a promising scaffold for different types of functionalization, and the slight modification of the quinoxalinone skeleton is known to offer a wide range of compounds for drug discovery. Owing to the importance of the quinoxalinone scaffold, we have developed a base-mediated protocol for the C3-alkylation of quinoxalinone followed by tandem cyclization to access novel types of strenuous and fused dihalo-aziridino-quinoxalinone heterocycles via the construction of C-C and C-N bonds. The protocol proved to be simple and practical to access desired fused quinoxalinone heterocycles in excellent yields (up to 98% yield). As an application, the highly functionalized fused dihalo-aziridino-quinoxalinone molecule has been further utilized for mono-dehalogenation under visible light irradiation and selective amide reduction. Moreover, the protocol has also been demonstrated on a gram scale.


Subject(s)
Drug Discovery , Cyclization , Alkylation
4.
Mol Biol Rep ; 50(2): 1203-1208, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36436077

ABSTRACT

BACKGROUND: During gamete development and spermatogenesis, certain genes on the Y chromosome (Yq) in the Male-Specific Region (MSR) are responsible for human gametes formation. The long arm Yq is composed of both euchromatin and the genetically inactive heterochromatin regions. This region contains the Azoospermia factors AZFa, AZFb and AZFc. In the case of male infertility, microdeletions on the Yq chromosome appear to be structural chromosomal anomalies linked to sperm abnormality. METHODS: The present study aimed to look at the incidence, of Asthenospermia (AS), Teratospermia (TS), Oligospermia (OS) and Oligoasthenoteratospermia (OAT) patterns of Y chromosomal microdeletions in Indian infertile men with an (AZF a, b, c). This study was conducted with 75 infertile men as cases and 75 fertile men as a control for AZF locus microdeletion utilizing sequence-tagged sites. RESULTS: The AZFc region of germ cell DNA (50.6%) was the most deleted section in infertile men when compared to blood DNA (21.3%), followed by deletions in the AZFb region (21.3%) in germ cell DNA whereas blood DNA had no microdeletion in the AZFa region in both germ cell DNA and blood DNA. Infertile men displayed significant Yq microdeletion in both AZFb and also AZFc. Around 33% (25) of 75 infertile men had AZF (a, b, c) region microdeletion in blood DNA, compared to it germ cell DNA had a larger percentage of 72% (54) of Y chromosome microdeletions in the study samples. CONCLUSION: A high-frequency rate of microdeletions seen in germ cell DNA. PCR-based Y chromosome microdeletion screening using germ cell DNA along with Genomic DNA might help in screening for genetic abnormality in infertile men who endure assisted reproductive technology treatments. This study might be attributable to the interplay of lifestyle and genetic factors, both contributing to the risk of developing these germ-line deletions.


Subject(s)
Azoospermia , Infertility, Male , Oligospermia , Male , Humans , Incidence , Semen , Infertility, Male/epidemiology , Infertility, Male/genetics , Infertility, Male/diagnosis , Oligospermia/epidemiology , Oligospermia/genetics , Oligospermia/diagnosis , Chromosome Deletion , Spermatozoa , Chromosomes, Human, Y/genetics , DNA , Azoospermia/genetics
5.
Soft Matter ; 18(32): 6043-6050, 2022 Aug 17.
Article in English | MEDLINE | ID: mdl-35924926

ABSTRACT

We study DC and AC electrophoresis of silica nano and microrods in a thin film of a nematic liquid crystal. These particles induce virtual topological defects and demonstrate nontrivial electrophoresis. We measure several electrophoretic mobility coefficients and compare with those calculated theoretically. We demonstrate a competing effect of elastic and electrostatic torques that arises due to tilting of the rods in the liquid crystal. A simple theory describing this effect allows us to measure the effective polarisability of the rods. Our approach is simple and applicable to a wide variety of asymmetric and polarisable particles.

6.
Org Biomol Chem ; 20(6): 1315-1319, 2022 02 09.
Article in English | MEDLINE | ID: mdl-35076051

ABSTRACT

A visible light-mediated, metal-free, regioselective dihydrothionation of terminal aromatic as well as heteroaromatic alkynes has been achieved using Eosin Y as a photoredox catalyst at room temperature. The protocol gives direct access to different 1,3-dithiolanes under neutral and mild reaction conditions without the use of any base or additives. The electron-donating, electron-withdrawing and electron-deactivating groups tolerated the photocatalytic reaction conditions. The control experiments, cyclic voltammetry, and Stern-Volmer experiment were carried out to gain an insight into the mechanistic pathway. The protocol proved to be scalable at the gram level and also for practicality the deprotection of 1,3-dithiolanes has been demonstrated. The method uses clean energy under sustainable conditions.

7.
J Trop Pediatr ; 68(4)2022 06 06.
Article in English | MEDLINE | ID: mdl-35737952

ABSTRACT

OBJECTIVE: The objective of the study was to assess the efficacy of immediate skin-to-skin care (SSC) versus swaddling in pain response to intramuscular injection of vitamin K at 30 min of birth in neonates. METHODS: Healthy full-term newborns were enrolled immediately after normal vaginal delivery and randomized in two groups, SSC and swaddling. Neonatal Infant Pain Scale (NIPS) was measured before, immediately after and at 2 min after the injection. RESULTS: Total 100 newborns were enrolled in the study (50 in each group). The mean (SD) birth weight of newborns in the SSC and swaddling group was 2668 (256) and 2730 (348) g, respectively. NIPS was comparable between the SSC and swaddling at before [1.78 (0.58) vs. 1.96 (0.83), p = 0.21], and immediately after the injection [4.82 (0.72) vs. 5.08 (0.75), p = 0.08]. NIPS at 2 min after the injection was significantly low in the SSC group compared to the swaddling group [1.38 (0.70) vs. 2.88 (1.00), p < 0.001]. At 2 min after injection, the NIPS score was significantly lower than baseline in the SSC group (p = 0.002), while it was significantly higher in the swaddling group (p < 0.001). A significantly higher proportion of newborns had a NIPS score of more than three at 2 min after injection in the swaddling group as compared to the SSC group (22% vs. 2%, p < 0.001). CONCLUSION: Immediate SSC was more efficacious as compared to swaddling as a pain control intervention while giving vitamin K injection. CLINICAL TRIAL REGISTRATION: The trial is registered with the Clinical Trial Registry of India with Registration number: CTRI/2020/01/022984.


Skin-to-skin care and swaddling are commonly used non-pharmacological measures to reduce pain perception in neonates for invasive procedures like heel prick, venipuncture and vaccination. We did this randomized control trial to compare the efficacy of immediate skin-to-skin care after birth vs. swaddling for reducing neonatal pain associated with intramuscular injection of vitamin K at 30 min after birth. We observed that the immediate skin-to-skin care, a standard of care, is more efficacious in controlling pain compared to swaddling for giving routine intramuscular vitamin K injection within one hour of birth.


Subject(s)
Pain Management , Vitamin K , Female , Humans , Infant, Newborn , Injections, Intramuscular , Pain/drug therapy , Pain/etiology , Pain/prevention & control , Skin Care
8.
J Contemp Dent Pract ; 22(11): 1308-1313, 2021 Nov 01.
Article in English | MEDLINE | ID: mdl-35343459

ABSTRACT

AIM: The aim of the present study was to assess the effectiveness of three various remineralizing agents on artificial enamel lesions in deciduous teeth. MATERIALS AND METHODS: Eighty primary teeth that were implicated for extraction were taken from patients of 4 to 14 years of age. Every specimen was subjected to air drying followed by the creation of 3 × 3 mm window positioned on the central surface of the coronal portion of the tooth to restrict the area of investigation. A digital pH meter was utilized to formulate a demineralizing solution by checking the pH before and following formulation of the solution. A total of 80 specimens (20 in every group) were allocated to three of the following experimental groups and one control group: group I: control, group II: tricalcium phosphate, group III: casein phosphopeptide-amorphous calcium phosphatefluoride (CPP-ACPF), and group IV: calcium sucrose phosphate (CaSP). Specimens in every group were subjected to treatment with the assigned remineralizing substance once in 24 hours for 14 days. Confocal laser scanning microscopic (CLSM) evaluation of the samples was performed to assess the baseline and posttreatment remineralization as well as demineralization. RESULTS: CPP-ACPF group (110.73 ± 0.11) displayed the greatest mean remineralization depth, in pursuit by the calcium orthophosphate complex (CaSP) group (122.19 ± 0.28), tricalcium phosphate group (126.87 ± 0.15) as well as the control group (158.46 ± 0.07). These differences amid the investigational groups for remineralization were significant. The greatest depth µ area of remineralization was seen in the CPP-ACPF group (50.29 ± 0.06) in pursuit by the CaSP group (36.70 ± 0.17) as well as the tricalcium phosphate group (33.29 ± 0.06). This difference amid the remineralizing agents was statistically significant. CONCLUSION: Amid the confines of the limitations of the current research, it may be concluded that the three remineralizing agents studied, exhibited a remineralization capability on the artificially induced lesions in enamel. CPP-ACPF exhibited the greatest remineralization capability in comparison with the CaSP and tricalcium phosphate groups. CLINICAL SIGNIFICANCE: Dental caries is an unalterable course that leads to everlasting loss of dental hard tissues with eventual formation of a cavity. Off late, numerous techniques have centered on applying remineralizing substances to early lesions due to dental caries, aiming at arresting demineralization while encouraging remineralization. Such remineralizing substances form an atmosphere that is superconcentrated with calcium and phosphate, thereby forcing these ions to diffuse into the unoccupied areas, thereby avoiding further loss of minerals.


Subject(s)
Dental Caries , Tooth Remineralization , Caseins/pharmacology , Caseins/therapeutic use , Dental Caries/drug therapy , Dental Enamel , Humans , Tooth Remineralization/methods , Tooth, Deciduous
9.
Proteins ; 88(11): 1513-1527, 2020 11.
Article in English | MEDLINE | ID: mdl-32543729

ABSTRACT

Protein domains exist by themselves or in combination with other domains to form complex multidomain proteins. Defining domain boundaries in proteins is essential for understanding their evolution and function but is not trivial. More specifically, partitioning domains that interact by forming a single ß-sheet is known to be particularly troublesome for automatic structure-based domain decomposition pipelines. Here, we study edge-to-edge ß-strand interactions between domains in a protein chain, to help define the boundaries for some more difficult cases where a single ß-sheet spanning over two domains gives an appearance of one. We give a number of examples where ß-strands belonging to a single ß-sheet do not belong to a single domain and highlight the difficulties of automatic domain parsers on these examples. This work can be used as a baseline for defining domain boundaries in homologous proteins or proteins with similar domain interactions in the future.


Subject(s)
Amino Acid Isomerases/chemistry , Penicillin-Binding Proteins/chemistry , Protein Interaction Domains and Motifs , Racemases and Epimerases/chemistry , Amino Acid Isomerases/metabolism , Amino Acid Sequence , Animals , Bacteria/chemistry , Binding Sites , Databases, Protein , Datasets as Topic , Humans , Models, Molecular , Penicillin-Binding Proteins/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Racemases and Epimerases/metabolism , Thermodynamics
10.
Physiol Mol Biol Plants ; 26(6): 1249-1261, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32549687

ABSTRACT

The present study investigates the genetic diversity and population structure among 42 diverse pomegranate genotypes using a set of twenty one class I hypervariable SSR markers (> 24 bp), which were reported earlier from the analysis of cv. Dabenzi genome. The study material comprised 16 indigenous and 13 exotic cultivars, and 13 wild accessions. A total of 66 alleles (Na) were detected with an average of 3.14 alleles per marker. The average values of polymorphic information content (PIC), observed heterozygosity (Ho) and Shannon's gene diversity index (I) were 0.44, 0.21 and 0.95, respectively suggesting moderate genetic diversity. The pairwise genetic distance ranged from 0.07 to 0.80 with a mean value of 0.53. Population structure analysis divided all the genotypes into four subpopulations (SP1, SP2, SP3 and SP4). Interestingly, the results of phylogenetic and principal component analyses coincided with the results of structure analysis and the grouping of genotypes followed the geographical origins. AMOVA revealed that 25% of the variation was attributed to differences among populations, whereas 75% within the subpopulations with significant F ST value 0.25 (p < 0.001), indicating a high level of genetic differentiations or low level of gene flow. Based on the F ST values, pomegranate genotypes belonging to SP4 (indigenous cultivars) followed by SP1 (exotic lines) exhibited higher gene diversity and genetic differentiations within and among populations. These genetic relationships based on SSR markers could be harnessed in future genetic improvement of pomegranate through informed hybridization programs.

11.
Cytokine ; 118: 144-159, 2019 06.
Article in English | MEDLINE | ID: mdl-29580751

ABSTRACT

We attempted a preclinical study using DMH-induced CRC rat model to evaluate the antitumor potential of our recently synthesized 1,3,4-thiadiazoles. The molecular insights were confirmed through ELISA, qRT-PCR and western blot analyses. The CRC condition was produced in response to COX-2 and IL-6 induced activation of JAK2/STAT3 which, in turn, was due to the enhanced phosphorylation of JAK2 and STAT3. The treatment with 1,3,4-thiadiazole derivatives (VR24 and VR27) caused the significant blockade of this signaling pathway. The behavior of STAT3 populations in response to IL-6 and COX-2 stimulations was further confirmed through data-based mathematical modeling using the quantitative western blot data. Finally, VR24 and VR27 restored the perturbed metabolites associated to DMH-induced CRC as evidenced through 1H NMR based serum metabolomics. The tumor protecting ability of VR24 and VR27 was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.


Subject(s)
Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Cyclooxygenase 2/metabolism , Interleukin-6/metabolism , Janus Kinase 2/metabolism , STAT3 Transcription Factor/metabolism , Thiadiazoles/pharmacology , Animals , Fluorouracil/pharmacology , Male , Metabolomics/methods , Models, Theoretical , Rats , Rats, Wistar , Signal Transduction/drug effects
12.
Mol Reprod Dev ; 86(11): 1485-1504, 2019 11.
Article in English | MEDLINE | ID: mdl-31518041

ABSTRACT

Declining fertility rates in both human and animals is a cause for concern. While many of the infertility cases are due to known causes, idiopathic infertility is reported in 30% of the infertile couples. In such cases, 18% of the infertile males carry antisperm antibodies (ASAs). Such data are lacking in livestock, wherein 20-30% of the animals are being culled due to low fertility. In males, the blood-testis barrier (BTB) and biomolecules in the semen provide an immuno-tolerant microenvironment for spermatozoa as they traverse the immunologic milieu of both the male and female reproductive tracts. For example, insults from environmental contaminants, infections and inflammatory conditions are likely to impact the immune privilege state of the testis and fertility. The female mucosal immune system can recognize allogenic spermatozoa-specific proteins affecting sperm kinematics and sperm-zona binding leading to immune infertility. Elucidating the functions and pathways of the immune regulatory molecules associated with fertilization are prerequisites for understanding their impact on fertility. An insight into biomolecules associated with spermatozoal immune tolerance may generate inputs to develop diagnostic tools and modulate fertility. High-throughput sequencing technologies coupled with bioinformatics analyses provides a path forward to define the array of molecules influencing pregnancy outcome. This review discusses the seminal immune regulatory molecules from their origin in the testis until they traverse the uterine environment enabling fertilization and embryonic development. Well-designed experiments and the identification of biomarkers may provide a pathway to understand the finer details of reproductive immunology that will afford personalized therapies.


Subject(s)
Blood-Testis Barrier/immunology , Fertility/immunology , Immune Tolerance , Semen/immunology , Spermatozoa/immunology , Animals , Female , Humans , Infertility, Male/immunology , Male , Testis/immunology , Uterus/immunology
13.
J Postgrad Med ; 65(3): 134-140, 2019.
Article in English | MEDLINE | ID: mdl-31169130

ABSTRACT

Introduction: Body adiposity measured by percentage of body fat (BF%) is found to be better predictor of cardiovascular morbidity and mortality than body mass index (BMI). Limited information exists showing relationship between BMI and BF% in North Indian population. Objectives: To study the relationship between BMI and BF% among North Indian adult females across various age strata and level of BMI. Materials and Methods: This was a cross-sectional study conducted at Ballabgarh Health and Demographic Surveillance Site (HDSS) among randomly selected females. BMI using standard techniques and BF% using bioelectrical impedance analysis was estimated. Linear regression was performed using general linear model with BF% as dependent variable and BMI as main independent variable. Results: Mean (±2 SD) age of participants was 41.3 ± 15.7 years. Mean BMI (±SD) was 23.3 (±4.6) kg/m2, whereas mean fat mass (±2 SD) and BF% (±95% CI) was 19.2 (±7.9) kg and 33.6 (±6.9) %. BMI and BF% were highly correlated among obese (r = 0.77), whereas least correlated (r = 0.32) in underweight females. Across age strata, correlation between BMI and BF% was maximum in 18-35 years age group (r = 0.95), whereas least in females ≥56 years (r = 0.67). Age and BMI together predicted 73% of variability in BF% in hierarchical linear regression model. Conclusions: In this population, we have found strong correlation between BMI and BF% particularly at higher level of BMI and in younger females. There is need to conduct more robust prospective longitudinal studies to assess BF%, which is a better predictor of cardiovascular morbidity and mortality.


Subject(s)
Adipose Tissue , Body Mass Index , Obesity/epidemiology , Population Surveillance , Thinness/epidemiology , Adiposity , Adolescent , Adult , Cross-Sectional Studies , Electric Impedance , Female , Humans , India/epidemiology , Linear Models , Middle Aged , Rural Population/statistics & numerical data , Young Adult
14.
J Trop Pediatr ; 65(2): 122-129, 2019 Apr 01.
Article in English | MEDLINE | ID: mdl-29800322

ABSTRACT

OBJECTIVE: The objective of this study was to determine the efficacy of polyethylene skin wrapping on thermoregulation in preterm neonates. METHODS: Total 151 neonates were enrolled in this randomized control trial. In the control group, neonates were transferred to the radiant warmer and covered with warm cloth after initial care. In the study group, neonates were transferred to the radiant warmer and placed in a food-grade polyethylene bag for 1 h. Axillary temperature of all neonates was recorded for first 24 h at frequent time intervals. RESULTS: Mean temperature reached to normal range earlier and remained significantly higher in the study group for most time intervals, and this difference persisted even at 24 h. Significantly less number of preterm newborns suffered from hypothermia in the study group as compared with the control group [50 (67.6%) vs. 67 (87%), p = 0.004]. CONCLUSIONS: Polyethylene wraps achieved rapid, sustained thermal control and were effective in preventing hypothermia in preterm newborns.


Subject(s)
Body Temperature Regulation , Hypothermia/prevention & control , Infant, Premature, Diseases/prevention & control , Polyethylene/therapeutic use , Rewarming/methods , Body Temperature , Female , Humans , Infant, Newborn , Infant, Premature , Intensive Care Units, Neonatal , Male , Treatment Outcome
15.
Indian J Public Health ; 63(3): 227-232, 2019.
Article in English | MEDLINE | ID: mdl-31552853

ABSTRACT

BACKGROUND: The study on self-perceived uselessness may help health-care workers to provide opportunities for intervention for increased quality of health and greater survival rate in elderly. OBJECTIVES: To find the prevalence of self-perceived uselessness and its determinants among the elderly residents of old age homes of North Bengaluru. METHODS: A cross-sectional descriptive study was undertaken on 129 elderly aged 60 years and above in the old age homes of North Bengaluru. Self-perceived uselessness, sociodemographic variables, morbidity status, functional status, financial status, and personal habits were assessed using a semi-structured questionnaire. Proportions, percentages, and Chi-square test were used for analysis. RESULTS: Nearly half (45%) of the elderly had agreed that they had perceived themselves as useless as they age. Majority of those who perceived uselessness had one or >1 chronic morbidities and were functionally dependent (81.2%). Significant association was seen between self-perceived uselessness and functional dependency, gender, education, and having some form of activities during their leisure time. CONCLUSIONS: It can be concluded that self-perceived uselessness is quite prevalent in nearly one-half of the elderly in the old age homes in North Bengaluru having significant association with variables such as gender, education, leisure activities, and functional status.


Subject(s)
Aging/psychology , Homes for the Aged/statistics & numerical data , Self Concept , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Health Status , Humans , India , Male , Middle Aged , Physical Functional Performance , Socioeconomic Factors
16.
Bioorg Med Chem ; 26(8): 1511-1522, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29429576

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.


Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Imidazoles/pharmacology , Neuroprotective Agents/pharmacology , Alzheimer Disease/metabolism , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Electrophorus , Female , Horses , Imidazoles/chemical synthesis , Imidazoles/chemistry , Male , Maze Learning/drug effects , Memory Disorders/drug therapy , Memory Disorders/metabolism , Mice , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Structure-Activity Relationship
17.
Biochem J ; 474(5): 731-749, 2017 02 20.
Article in English | MEDLINE | ID: mdl-28057718

ABSTRACT

The role of reactive oxygen species (ROS) in osmotic stress, dextran sulfate sodium (DSS) and cyclic stretch-induced tight junction (TJ) disruption was investigated in Caco-2 cell monolayers in vitro and restraint stress-induced barrier dysfunction in mouse colon in vivo Live cell imaging showed that osmotic stress, cyclic stretch and DSS triggered rapid production of ROS in Caco-2 cell monolayers, which was blocked by depletion of intracellular Ca2+ by 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Knockdown of CaV1.3 or TRPV6 channels blocked osmotic stress and DSS-induced ROS production and attenuated TJ disruption and barrier dysfunction. N-Acetyl l-cysteine (NAC) and l-NG-Nitroarginine methyl ester (l-NAME) blocked stress-induced TJ disruption and barrier dysfunction. NAC and l-NAME also blocked stress-induced activation of c-Jun N-terminal kinase (JNK) and c-Src. ROS was colocalized with the mitochondrial marker in stressed cells. Cyclosporin A blocked osmotic stress and DSS-induced ROS production, barrier dysfunction, TJ disruption and JNK activation. Mitochondria-targeted Mito-TEMPO blocked osmotic stress and DSS-induced barrier dysfunction and TJ disruption. Chronic restraint stress in mice resulted in the elevation of intracellular Ca2+, activation of JNK and c-Src, and disruption of TJ in the colonic epithelium. Furthermore, corticosterone administration induced JNK and c-Src activation, TJ disruption and protein thiol oxidation in colonic mucosa. The present study demonstrates that oxidative stress is a common signal in the mechanism of TJ disruption in the intestinal epithelium by different types of cellular stress in vitro and bio behavioral stress in vivo.


Subject(s)
Calcium/metabolism , Colon/metabolism , Reactive Oxygen Species/metabolism , Stress, Psychological/metabolism , Tight Junctions/metabolism , Animals , CSK Tyrosine-Protein Kinase , Caco-2 Cells , Calcium Channels/genetics , Calcium Channels/metabolism , Calcium Channels, L-Type/genetics , Calcium Channels, L-Type/metabolism , Chelating Agents/pharmacology , Colon/cytology , Colon/drug effects , Corticosterone/pharmacology , Cyclosporine/pharmacology , Dextran Sulfate/pharmacology , Egtazic Acid/analogs & derivatives , Egtazic Acid/pharmacology , Gene Expression Regulation , Humans , JNK Mitogen-Activated Protein Kinases/genetics , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Mechanotransduction, Cellular , Mice , Mice, Inbred C57BL , NG-Nitroarginine Methyl Ester/pharmacology , Osmotic Pressure/drug effects , Oxidative Stress/drug effects , Reactive Oxygen Species/agonists , Stress, Mechanical , Stress, Psychological/genetics , Stress, Psychological/physiopathology , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolism , Tight Junctions/drug effects , Tight Junctions/pathology , src-Family Kinases/genetics , src-Family Kinases/metabolism
18.
Pain Manag Nurs ; 18(1): 24-32, 2017 02.
Article in English | MEDLINE | ID: mdl-27964909

ABSTRACT

Accurate assessment of pain and its management is a challenging aspect of pediatric care. Nurses, usually the primary caregivers, showed inadequate knowledge and restrictive attitudes toward pain assessment. We evaluated an educational intervention to improve nurses' assessment of pain in a teaching hospital in India. A convenient sample of nurses working in the neonatal intensive care unit, pediatric ward, pediatric intensive care unit, and pediatric cardiac intensive care unit were included in the study. Workshops to improve understanding of pain, its assessment, and management strategies were conducted. A modified and consensually validated Knowledge and Attitudes Survey Regarding Pain questionnaire-2008 consisting of 25 true/false questions, eight multiple choice questions, and two case scenarios was administered before, immediately after, and 3 months after the workshops to evaluate impact of the intervention. Eighty-seven nurses participated. Mean (standard deviation) experience was 4.04 (5.9) years. Thirty-seven percent felt that they could assess pain without pain scales. About half (49.4%) of the nurses had not previously heard of pain scales, while 47.1% reported using a pain scale in their routine practice. Significant improvement was observed between pretest and post-test total scores (15.69 [2.94] vs. 17.51 [3.47], p < .001) as well as the pretest and retention score (15.69 [2.94] vs. 19.40 [4.6], p < .001). Albeit the study site and sampling frame may limit the reliability of the findings, the educational intervention was successful, and better retention test scores suggest a cascading effect. Pain assessment and management education of children should be incorporated in the nursing curriculum and should be reinforced in all pediatric units.


Subject(s)
Education, Nursing, Continuing/methods , Nurses/standards , Pain Measurement/standards , Pain/nursing , Adult , Education, Nursing, Continuing/statistics & numerical data , Female , Humans , India , Male , Middle Aged , Nurses/statistics & numerical data , Pain/physiopathology , Pain Management/nursing , Pain Management/statistics & numerical data , Pain Measurement/methods , Pain Measurement/nursing , Pediatric Nursing/education , Pediatric Nursing/methods , Pediatric Nursing/statistics & numerical data , Surveys and Questionnaires
19.
J Trop Pediatr ; 63(5): 374-379, 2017 10 01.
Article in English | MEDLINE | ID: mdl-28077611

ABSTRACT

Peripherally inserted central catheter (PICC) and umbilical venous catheter (UVC) in terms of success rate, complications, cost and time of insertion in neonatal intensive care were compared. Neonates requiring vascular access for minimum 7 days were included. Sample size of 72 per group was determined. Trial was registered at Clinical Trials Registry of India (CTRI/2015/02/005529). Success rates of the UVC and PICC were 68.1% and 65.3%, respectively (p = 0.724). Mean (SD) time needed for PICC and UVC insertion was 34.13 (34.69) and 28.31 (17.19) min, respectively (p = 0.205). Mean (SD) cost of PICC insertion vs. UVC insertion was 60.9 (8.6) vs. 11.9 (8.7) US dollars (p < 0.0001). Commonest cause for failure of UVC was displacement [6 (8.3%)] and that for PICC was blockage [9 (12.5%)]. CONCLUSIONS: UVC is a cheaper alternative to PICC, with similar success rate, short-term complications and time needed for insertion.


Subject(s)
Catheterization, Peripheral/adverse effects , Catheterization, Peripheral/instrumentation , Catheterization, Central Venous/adverse effects , Catheterization, Central Venous/economics , Catheterization, Peripheral/economics , Female , Health Care Costs , Humans , India , Infant, Newborn , Intensive Care Units, Neonatal , Male , Outcome and Process Assessment, Health Care , Risk , Time Factors , Umbilical Veins
20.
Gastrointest Endosc ; 81(5): 1215-24, 2015 May.
Article in English | MEDLINE | ID: mdl-25660979

ABSTRACT

BACKGROUND: Peritoneal carcinomatosis (PC) greatly affects cancer staging and resectability. OBJECTIVE: To compare the PC detection rate by using EUS and noninvasive imaging and to determine the impact on staging and resectability. DESIGN: Retrospective study. SETTING: Single tertiary-care referral center. PATIENTS: A prospectively maintained EUS database was reviewed to identify patients who underwent EUS-guided FNA (EUS-FNA) of a peritoneal anomaly. Findings were compared with a strict criterion standard that incorporated cytohistologic, radiologic, and clinical data. INTERVENTION: EUS-FNA of a peritoneal anomaly. MAIN OUTCOME MEASUREMENTS: Safety and diagnostic yield. RESULTS: Of 106 patients, a criterion standard was available in 98 (39 female patients; median age, 65 years). The sensitivity, specificity, and accuracy of EUS-FNA versus CT/magnetic resonance imaging (MRI) was 91% versus 28%, 100% versus 85%, and 94% versus 47%, respectively. In newly diagnosed cancer patients, peritoneal FNA upstaged 17 patients (23.6%). Of 32 patients deemed resectable by pre-EUS CT/MRI, 15 (46.9%) were deemed unresectable based solely on peritoneal FNA. The odds of FNA changing the resectability status remained highly significant after adjustment for cancer type, time between CT/MRI and EUS-FNA, and the quality of CT/MRI. The malignant appearance of the peritoneal anomaly but not the presence of ascites on EUS predicted a positive FNA finding (odds ratio 2.56; 95% confidence interval, 1.23-5.4 and odds ratio 0.83; 95% confidence interval, 0.4-1.8, respectively). There were 3 adverse events among 4 patients. Two of the patients developed abdominal pain and one each hypertensive urgency and pancreatitis. LIMITATIONS: Retrospective design, single-center, bias toward EUS as a diagnostic test. CONCLUSION: Peritoneal EUS-FNA appears to safely detect radiographically occult PC and improve cancer staging and patient care.


Subject(s)
Peritoneal Neoplasms/diagnosis , Aged , Aged, 80 and over , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasm Staging/methods , Peritoneal Neoplasms/diagnostic imaging , Peritoneal Neoplasms/pathology , Retrospective Studies , Tomography, X-Ray Computed
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