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Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild-type bone marrow-derived DCs to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single-cell RNA-sequencing (RNA-seq) identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease.
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Células Dendríticas , Encefalomielite Autoimune Experimental , Interleucina-23 , Fator de Transcrição STAT4 , Transdução de Sinais , Animais , Fator de Transcrição STAT4/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-23/metabolismo , Interleucina-23/imunologia , Camundongos , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Camundongos Knockout , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/imunologia , Inflamação/metabolismo , Inflamação/imunologia , Transferência Adotiva , Camundongos Endogâmicos C57BL , Humanos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
The pathobiology of rheumatoid inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis, involves the interplay between innate and adaptive immune components and resident synoviocytes. Single-cell analyses of patient samples and relevant mouse models have characterized many cellular subsets in RA. However, the impact of interactions between cell types is not fully understood. In this study, we temporally profiled murine arthritic synovial isolates at the single-cell level to identify perturbations similar to those found in human RA. Notably, murine macrophage subtypes like those found in RA patients were expanded in arthritis and linked to promoting the function of Th17 cells in the joint. In vitro experiments identified a capacity for murine macrophages to maintain the functionality and expansion of Th17 cells. Reciprocally, murine Th17 cell-derived TNF-α induced CD38+ macrophages that enhanced Th17 functionality. Murine synovial CD38+ macrophages were expanded during arthritis, and their depletion or blockade via TNF-α neutralization alleviated disease while reducing IL-17A-producing cells. These findings identify a cellular feedback loop that promotes Th17 cell pathogenicity through TNF-α to drive inflammatory arthritis.
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Artrite Reumatoide , Células Th17 , ADP-Ribosil Ciclase 1/imunologia , Animais , Citocinas/metabolismo , Retroalimentação , Humanos , Macrófagos/metabolismo , Glicoproteínas de Membrana/imunologia , Camundongos , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, we infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
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Proteína BRCA1/deficiência , Dineínas do Citoplasma/metabolismo , DNA/metabolismo , Genes BRCA1 , Proteína Homóloga a MRE11/metabolismo , Reparo de DNA por Recombinação , Proteína BRCA1/genética , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Aberrações Cromossômicas , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Edição de Genes , Instabilidade Genômica/efeitos dos fármacos , Recombinação Homóloga/efeitos dos fármacos , Humanos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Platina/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ligação Proteica , Reparo de DNA por Recombinação/efeitos dos fármacos , Fatores de Transcrição/metabolismoRESUMO
Thiazolidinedione has been used successfully by medicinal chemists all over the world in the development of potent antidiabetic derivatives. The few compounds with excellent antidiabetic potency that we have identified in this review could be used as a lead for further research into additional antidiabetic mechanisms. The information provided in this review regarding the design, biological activity, structure-activity relationships, and docking studies may be useful for scientists who wish to further explore this scaffold in order to fully utilize its biological potential and develop antidiabetic agents that would overcome the limitations of currently available medications for the treatment of diabetes. This review outlines the antidiabetic potential of Thiazolidinedione-based derivatives that have been published in the year 2021- till date.
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Xanthine oxidase (XO) inhibitors, both synthetic and semisynthetic, have been developed extensively over the past few decades. The increased level of XO is not only the major cause of gout but is also responsible for various conditions associated with hyperuricemia, such as cardiovascular disorders, chronic kidney disorders, diabetes, Alzheimer's disease and chronic wounds. Marketed available XO inhibitors (allopurinol, febuxostat, and topiroxostat) are used to treat hyperuricemia but they are associated with fatal side effects, which pose serious problems for the healthcare system, rising the need for new, more potent, safer compounds. This review summarizes recent findings on XO and describes their design, synthesis, biological significance in the development of anti-hyperuricemic drugs with ADME profile, structure activity relationship (SAR) and molecular docking studies. The results might help medicinal chemists to develop more efficacious XO inhibitors.
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Considerable ingenuity has been shown in the recent years in the discovery of novel xanthine oxidase (XO) inhibitors that fall outside the purine scaffold. The triazole nucleus has been the cornerstone for the development of many enzyme inhibitors for the clinical management of several diseases, where hyperuricemia is one of them. Here, we give a critical overview of significant research on triazole-based XO inhibitors, with respect to their design, synthesis, inhibition potential, toxicity, and docking studies, done till now. Based on these literature findings, we can expect a burst of modifications on triazole-based scaffolds in the near future by targeting XO, which will treat hyperuricemics, that is, painful conditions like gout that at present are hard to deal with.
Assuntos
Hiperuricemia , Xantina Oxidase , Humanos , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Hiperuricemia/tratamento farmacológico , Triazóis/farmacologia , Simulação de Acoplamento MolecularRESUMO
Serotonin transporter (SERT) deficiency has been implicated in metabolic syndrome, intestinal inflammation, and microbial dysbiosis. Interestingly, changes in microbiome metabolic capacity and several alterations in host gene expression, including lipid metabolism, were previously observed in SERT-/- mice ileal mucosa. However, the precise host or microbial metabolites altered by SERT deficiency that may contribute to the pleiotropic phenotype of SERT KO mice are not yet understood. This study investigated the hypothesis that SERT deficiency impacts lipid and microbial metabolite abundances in the ileal mucosa, where SERT is highly expressed. Ileal mucosal metabolomics was performed by Metabolon on wild-type (WT) and homozygous SERT knockout (KO) mice. Fluorescent-activated cell sorting (FACS) was utilized to measure immune cell populations in ileal lamina propria to assess immunomodulatory effects caused by SERT deficiency. SERT KO mice exhibited a unique ileal mucosal metabolomic signature, with the most differentially altered metabolites being lipids. Such changes included increased diacylglycerols and decreased monoacylglycerols in the ileal mucosa of SERT KO mice compared to WT mice. Further, the ileal mucosa of SERT KO mice exhibited several changes in microbial-related metabolites known to play roles in intestinal inflammation and insulin resistance. SERT KO mice also had a significant reduction in the abundance of ileal group 3 innate lymphoid cells (ILC3). In conclusion, SERT deficiency induces complex alterations in the ileal mucosal environment, indicating potential links between serotonergic signaling, gut microbiota, mucosal immunity, intestinal inflammation, and metabolic syndrome.
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Microbioma Gastrointestinal , Íleo , Mucosa Intestinal , Camundongos Knockout , Proteínas da Membrana Plasmática de Transporte de Serotonina , Animais , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Íleo/metabolismo , Íleo/patologia , Mucosa Intestinal/metabolismo , Camundongos , Metabolismo dos Lipídeos , Metabolômica/métodos , Masculino , Metaboloma , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: The traditional drug delivery system is not much effective when treating chronopathological diseases like arthritis. Consequently, there is a gap in the market for a delivery system that can provide an explicit treatment following the chronopharmacology of this disorder. The present study is based on the objective to develop Eudragit coated dual release bilayer tablet designed by the quality by design (QbD) and based on the chronotherapeutic approach. The dual release tablet contained an immediate release layer of etoricoxib and a sustained release layer of thiocolchicoside. MATERIAL AND METHOD: The quality target product profile (QTTP) of the formulation was established along with critical quality attributes (CQA). The optimization of the dual release layer was done using a three-level, three-factor Box-Behnken design. A total of thirteen formulations of etoricoxib (ET1-ET13) and thiocolchicoside (TH1-TH13) were developed based on the design composition of etoricoxib, sodium starch glycolate and sodium bicarbonate for the immediate release (IR) layer and thiocolchicoside, HPMC E5 LV and magnesium stearate for the sustained release (SR) layer respectively. The developed dual release layers were compressed to form a bilayer tablet. The bilayer tablets were further coated with pH-dependent polymer Eudragit S-100 to avoid drug release in upper GIT. The initial characterization and drug-excipient interaction studies were performed initially using infra-red (IR) spectroscopy and X-ray diffraction studies (XRD). Formulations showing good micrometric properties, disintegration and drug release were selected for final compression of bilayer tablets. RESULT: Formulation ET13 showed the fastest drug release (88%) at 15minutes and quick disintegration time (21s). The sustained release thiocolchicoside tablet layer (TH1-TH13) had a hardness that varied from 4.01 to 4.45kg/cm2. Formulation TH12 had the highest hardness, whereas TH6 showed the lowest hardness. The sustained release layer showing 97.63% of drug release after 8hours was selected for the compression to bilayer tablet. The developed dual layer tablets were investigated for quality parameters like hardness, percentage friability, weight variation, disintegration and dissolution. CONCLUSION: A high level of patient compliance is ensured through the current design as the patient does not need to get out of bed at night to take the medication.
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Human immunodeficiency virus-1 (HIV-1) clade C is the most prevalent form of HIV-1 comprising nearly 46% of global infections and is the dominant subtype in India. Despite its predominance, the impact of HIV-1 clade C infection on cognitive function has been understudied in comparison with other subtypes, notably clade B, which is primarily found in Europe and North America. Few studies have assessed cognitive impairment in antiretroviral therapy (ART) naïve men and women with HIV-1 clade C infection. In this study conducted in Northern India, differences in neuropsychological functioning were compared between 109 participants (70 men, 39 women) with untreated HIV-1 clade C infection and 110 demographically matched healthy controls (74 men, 36 women). A comprehensive neuropsychological battery was used to examine depression, self-assessment of functioning, and cognitive performance in six domains of functioning. Group differences were assessed by HIV-1 status and sex, controlling for age and education. Results indicated that cognitive deficits were substantially greater among male participants with HIV-1 clade C compared to male controls in all domains of cognitive functioning; in contrast, women with HIV-1 clade C had only minor deficits compared to healthy female participants. In addition, a larger proportion of men with HIV-1 clade C exhibited high levels of depression than women with HIV-1 clade C. These findings suggest that untreated HIV-1 clade C infection in men can have debilitating effects on neuropsychological function and depression, and stress the importance of facilitating rapid access to treatment to reduce the impact of HIV-1 infection.
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Infecções por HIV , HIV-1 , Humanos , Feminino , Masculino , HIV-1/genética , Caracteres Sexuais , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Cognição , Índia , Testes NeuropsicológicosRESUMO
Emergence of antimicrobial resistance has become a great threat to human species as there is shortage of development of new antimicrobial agents. So, its mandatary to combat AMR by initiating research and developing new novel antimicrobial agents. Among phytoconstituents, Quinoline (nitrogen containing heterocyclic) have played a wide role in providing new bioactive molecules. So, this review provides rational approaches, design strategies, structure activity relationship and mechanistic insights of newly developed quinoline derivatives as antimicrobial agents.
Assuntos
Anti-Infecciosos , Quinolinas , Humanos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Relação Estrutura-Atividade , Quinolinas/farmacologia , Quinolinas/químicaRESUMO
Interactions between bovine γ-globulin (BGG) and borohydride-capped silver nanoparticles (BAgNPs) were studied using dynamic light scattering (DLS) and spectroscopic techniques such as UV-vis spectroscopy, fluorescence, and circular dichroism. The results were compared with earlier reported interactions between γ-globulin and citrate-coated AgNPs (CAgNPs). BAgNPs were synthesized and characterized. Irrespective of the coating on AgNPs, nanoparticles had formed ground-state complexes with the protein. CAgNPs, as well as BAgNPs had caused static quenching of tryptophan (Trp) fluorescence of the protein. The change in the capping agent from citrate to borohydride weakened the binding of nanoparticles with the protein. But the same change in capping agent had increased the fluorescence quenching efficiency of AgNPs. Hydrogen bonding and van der Waals interactions were involved in BGG-BAgNPs complex similar to the CAgNPs complex with γ-globulin. Polarity of the Trp microenvironment in BGG was not altered using BAgNPs as opposed to CAgNPs, as supported using synchronous and three-dimensional fluorescence. Resonance light scattering experiments also suggested nano-bio conjugation. Far-UV and near-UV circular dichroism (CD) spectra respectively pointed towards changes in the secondary and tertiary structure of BGG by BAgNPs, which was not observed for CAgNPs.
Assuntos
Nanopartículas Metálicas , Prata , Animais , Boroidretos , Bovinos , Dicroísmo Circular , Citratos , Nanopartículas Metálicas/química , Prata/química , Espectrometria de Fluorescência/métodos , gama-GlobulinasRESUMO
A novel series of triazole-linked isatin-indole-3-carboxaldehyde hybrids based on the febuxostat skeleton and its binding site interactions were rationally designed and synthesized as potential xanthine oxidase inhibitors. Among the synthesized hybrids, A19 showed the most potent xanthine oxidase inhibition (IC50 = 0.37 µM) with the mixed-type inhibitory scenario. Structure-activity relationship studies revealed that methoxy (OCH3 ) substitution on position 5 of the isatin nucleus and a two-carbon distance between isatin and the triazole moiety is most tolerable for the inhibitory potential. Various binding interactions of A19 with the binding site of xanthine oxidase are also streamlined by molecular docking studies, which showcase the favorable binding pattern for xanthine oxidase inhibition by the hybrid. Furthermore, molecular dynamic studies were performed that suggest the stability of the enzyme-hybrid complex. Overall, the study suggests that hybrid A19 can act as an effective hit lead for further development of potent xanthine oxidase inhibitors.
Assuntos
Isatina , Xantina Oxidase , Inibidores Enzimáticos/química , Indóis , Isatina/química , Isatina/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer's disease, Huntington's chorea, migraine, Parkinson's disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure-activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.
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Desenho de Fármacos , Moduladores GABAérgicos/síntese química , Moduladores GABAérgicos/farmacologia , Animais , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Receptores de GABA/química , Receptores de GABA/metabolismoRESUMO
Although the catalog of cancer-associated mutations in protein-coding regions is nearly complete for all major cancer types, an assessment of regulatory changes in cancer genomes and their clinical significance remain largely preliminary. Adopting bottom-up approach, we quantify the effects of different sources of gene expression variation in a cohort of 3899 samples from 10 cancer types. We find that copy number alterations, epigenetic changes, transcription factors and microRNAs collectively explain, on average, only 31-38% and 18-26% expression variation for cancer-associated and other genes, respectively, and that among these factors copy number alteration has the highest effect. We show that the genes with systematic, large expression variation that could not be attributed to these factors are enriched for pathways related to cancer hallmarks. Integrating whole genome sequencing data and focusing on genes with systematic expression variation we identify novel, recurrent regulatory mutations affecting known cancer genes such as NKX2-1 and GRIN2D in multiple cancer types. Nonetheless, at a genome-wide scale proportions of gene expression variation attributed to recurrent point mutations appear to be modest so far, especially when compared to that attributed to copy number changes - a pattern different from that observed for other complex diseases and traits. We suspect that, owing to plasticity and redundancy in biological pathways, regulatory alterations show complex combinatorial patterns, modulating gene expression in cancer genomes at a finer scale.
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Expressão Gênica , Mutação , Neoplasias/genética , Variação Genética , Humanos , Regiões Promotoras GenéticasRESUMO
We report here the data of Y chromosome haplotypes of 259 unrelated males from the population of Himachal Pradesh, India, using the Yfiler® multiplex kit. A total of 188 haplotypes were detected, out of which 148 were unique. Three samples showed bi-allelic pattern on locus DYS448. The observed genetic diversity and discrimination capacity were 0.996 and 0.73, respectively. In order to compare the genetic distance of the studied population with the published populations, multidimensional scaling (MDS) plot was constructed. The reported data is expected to be valuable for both forensic and population genetics.
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Cromossomos Humanos Y/genética , Loci Gênicos , Genética Populacional , Haplótipos , Repetições de Microssatélites , Bases de Dados Genéticas , Variação Genética , Humanos , Índia/etnologia , Masculino , Reação em Cadeia da Polimerase Multiplex , Análise de Sequência de DNARESUMO
BACKGROUD: ß-hydroxyacyl-acyl carrier protein dehydratase (FabZ) is an essential component of type II fatty acid biosynthesis (FAS II) pathway in bacteria. It performs dehydration of ß-hydroxyacyl-ACP to trans-2-acyl-ACP in the elongation cycle of the FAS II pathway. FabZ is ubiquitously expressed and has uniform distribution, which makes FabZ an excellent target for developing novel drugs against pathogenic bacteria. METHODS: We focused on the biochemical and biophysical characterization of FabZ from drug-resistant pathogen Moraxella catarrhalis (McFabZ). More importantly, we have identified and characterized new inhibitors against McFabZ using biochemical, biophysical and in silico based studies. RESULTS: We have identified three isoflavones (daidzein, biochanin A and genistein) as novel inhibitors against McFabZ. Mode of inhibition of these compounds is competitive with IC50 values lie in the range of 6.85µΜ to 27.7µΜ. Conformational changes observed in secondary and tertiary structure marked by a decrease in the helical and the sheet content in McFabZ structure upon inhibitors binding. In addition, thermodynamic data suggest that biochanin A has a strong binding affinity for McFabZ as compare to daidzein and genistein. Molecular docking studies have revealed that these inhibitors are interacting with the active site of McFabZ and making contacts with catalytic and substrate binding tunnel residues. CONCLUSION AND GENERAL SIGNIFICANCE: Three new inhibitors against McFabZ have been identified and characterized. These biochemical and biophysical findings lead to the identification of chemical scaffolds, which can lead to broad-spectrum antimicrobial drugs targeted against FabZ, and modification to existing FabZ inhibitors to improve affinity and potency.
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Proteínas de Bactérias/antagonistas & inibidores , Flavonoides/farmacologia , Hidroliases/antagonistas & inibidores , Moraxella catarrhalis/enzimologia , Acil Coenzima A/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/química , Sítios de Ligação/efeitos dos fármacos , Domínio Catalítico/efeitos dos fármacos , Dicroísmo Circular , Sequência Conservada , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Genisteína/farmacologia , Hidroliases/química , Concentração de Íons de Hidrogênio , Isoflavonas/farmacologia , Cinética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Moraxella catarrhalis/efeitos dos fármacos , Filogenia , Conformação Proteica , Proteínas Recombinantes/química , Alinhamento de Sequência , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Temperatura , TermodinâmicaRESUMO
CONTEXT: Hypotension following spinal anaesthesia for caesarean delivery may decrease uteroplacental perfusion and produce foetal acidosis. The optimal anaesthetic technique for mothers with foetal growth restriction and impaired Doppler flow is unclear. OBJECTIVE: To compare the effects of low-dose spinal anaesthesia and general anaesthesia on neonatal outcome and maternal haemodynamics. DESIGN: Prospective, randomised clinical trial. SETTING: Tertiary care hospital. PATIENTS: Forty pregnant women with foetal growth restriction and impaired Doppler flow scheduled for elective caesarean delivery. INTERVENTIONS: The women were allocated randomly to receive a low-dose spinal anaesthetic (8-mg hyperbaric bupivacaine 0.5% with fentanyl 20 µg) or standard general anaesthesia for elective caesarean delivery. SBP was maintained between 80 and 100% of baseline using bolus doses of phenylephrine. The total duration of hypotension, dose of phenylephrine used and any incidence of hypotension, nausea or vomiting were recorded. MAIN OUTCOME MEASURES: The primary outcome variable was arterial and venous umbilical cord base deficit. Neonatal outcome and maternal haemodynamics were analysed as secondary endpoints. RESULTS: The mean umbilical artery pH was significantly lower in the low-dose spinal anaesthesia group than in the general anaesthesia group (7.23 ± 0.06 vs. 7.27 ± 0.04, P = 0.01). Cord base deficit was similar in the two groups. Higher partial pressures of oxygen occurred in the general anaesthesia group (20.9 ± 6.5 kPa) than in the low-dose spinal anaesthesia group (13.6 ± 6.1 kPa, P = 0.001). No difference was observed between groups in 1 and 5-min Apgar scores. There appeared to be a greater need for immediate resuscitation of neonates in the general anaesthesia group, but the difference was not statistically significant (Pâ=â0.51). Low-dose spinal anaesthesia was associated with hypotension of short duration (0.7â±â1.1âmin). CONCLUSION: In this study, there was no difference in umbilical cord base deficit between the groups. Larger studies would be required to assess whether the mode of anaesthesia influences the incidence of clinically important neonatal acidosis in neonates with foetal growth restriction.
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Cordão Umbilical/efeitos dos fármacos , Acidose/prevenção & controle , Adulto , Anestesia Geral/efeitos adversos , Anestesia Obstétrica/efeitos adversos , Raquianestesia/efeitos adversos , Anestésicos , Gasometria , Cesárea , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/terapia , Hemodinâmica , Humanos , Recém-Nascido , Gravidez , Estudos Prospectivos , Resultado do Tratamento , Ultrassonografia Doppler/métodosRESUMO
Improper disposal of waste poses a grave environmental threat, contributing to pollution of air, water, and soil. It is necessary to address this issue in order to mitigate the adverse effects of solid waste on both the environment and public health. In many developing nations, municipal authorities of bigger cities are enduring significant challenges in proper management of waste. The present study evaluates the impacts of various waste management alternative scenarios for environmental impacts for the selected study locations using Life Cycle Assessment (LCA) methodology. The methodology comprised of five different scenarios of waste management including an existing baseline scenario. In this context, the environmental impact categories analyzed were Global Warming potential (GWP), Acidification potential (AP), Eutrophication potential (EP) and Human Toxicity potential (HTP). The results indicated that amongst all the proposed scenarios, Scenario 1 and 4 exhibited the maximum and minimum environmental impacts respectively. The study revealed that least greenhouse gas emissions, acidification potential, eutrophication potential and human toxicity potential were comparatively lesser for scenario 4 varying from 5.65 to 11.36 kg CO2eq t-1; 1.24-3.345 kg SO2eq t-1, EP 0.19-0.68 kg PO4eq t-1, and 0.35-4.22 kg 1,4-DBeq t-1 respectively. Further, a sensitivity analysis was also performed to evaluate the influence of recycling rate of valuable resources in all the considered scenarios. The sensitivity analysis indicated an inversely proportional relation between change in recycling rate and total environmental burdens.
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BACKGROUND: Biodegradable polymeric nanoparticles have garnered pharmaceutical industry attention throughout the past decade. PLGA [Poly(lactic-co-glycolic acid)] is an excellent biodegradable polymer explored for the preparation of nanoparticles that are administered through various routes like intravenous and transdermal. PLGA's versatility makes it a good choice for the preparation of nanoparticles. OBJECTIVE: The main objective of this review paper was to summarize methods of preparation and characterization of PLGA nanoparticles along with their role in the transdermal delivery of various therapeutic agents. METHODS: A literature survey for the present review paper was done using various search engines like Pubmed, Google Scholar, and Science Direct. RESULTS: In comparison to traditional transdermal administration systems, PLGA nanoparticles have demonstrated several benefits in preclinical investigations, including fewer side effects, low dosage frequency, high skin permeability, and simplicity of application. CONCLUSION: PLGA nanoparticles can be considered efficient nanocarriers for the transdermal delivery of drugs. Nevertheless, the clinical investigation of PLGA nanoparticles for the transdermal administration of therapeutic agents remains a formidable obstacle.
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Sistemas de Liberação de Medicamentos , Nanopartículas , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Administração Cutânea , Sistemas de Liberação de Medicamentos/métodos , Ácido Poliglicólico , Glicóis , Ácido Láctico , Portadores de FármacosRESUMO
Induction of hypersensitivity reactions (may be fatal too) by specific XO inhibitors has led to development of new molecules that are efficacious and have safer ADME profile. Among natural compounds, biologically active Alkannin/Shikonin (A/S) derivatives have unexplored XO inhibition potential. Therefore, their iso-hexenylnaphthazarin nucleus was studied and found that the nucleus is similar to that of allopurinol, signifying the XO inhibitory potential of these derivatives. For confirmation of their potential, ß,ß-dimethylacrylshikonin and deoxyshikonin were successfully isolated and characterised from Arnebia euchroma (Royle.) Johnst. (Boraginaceae) and were evaluated for in vitro XO inhibitory potential. ß,ß-dimethylacrylshikonin and deoxyshikonin showed a good XO inhibition potential with IC50 values of 7.475 ± 1.46 µg/mL and 4.487 ± 0.88 µg/mL, respectively. Results also validated the pharmacophore hypothesis, and it was concluded that nucleus iso-hexenylnaphthazarin can be remodelled for optimising the efficacy.