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1.
J Environ Manage ; 360: 121189, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38759553

RESUMO

Pyrolysis, a thermochemical conversion approach of transforming plastic waste to energy has tremendous potential to manage the exponentially increasing plastic waste. However, understanding the process kinetics is fundamental to engineering a sustainable process. Conventional analysis techniques do not provide insights into the influence of characteristics of feedstock on the process kinetics. Present study exemplifies the efficacy of using machine learning for predictive modeling of pyrolysis of waste plastics to understand the complexities of the interrelations of predictor variables and their influence on activation energy. The activation energy for pyrolysis of waste plastics was evaluated using machine learning models namely Random Forest, XGBoost, CatBoost, and AdaBoost regression models. Feature selection based on the multicollinearity of data and hyperparameter tuning of the models utilizing RandomizedSearchCV was conducted. Random forest model outperformed the other models with coefficient of determination (R2) value of 0.941, root mean square error (RMSE) value of 14.69 and mean absolute error (MAE) value of 8.66 for the testing dataset. The explainable artificial intelligence-based feature importance plot and the summary plot of the shapely additive explanations projected fixed carbon content, ash content, conversion value, and carbon content as significant parameters of the model in the order; fixed carbon > carbon > ash content > degree of conversion. Present study highlighted the potential of machine learning as a powerful tool to understand the influence of the characteristics of plastic waste and the degree of conversion on the activation energy of a process that is essential for designing the large-scale operations and future scale-up of the process.

2.
Mol Neurodegener ; 19(1): 18, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38365827

RESUMO

It has recently become well-established that there is a connection between Alzheimer's disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aß deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aß amyloidosis in the 5XFAD mouse model that were treated at a point when Aß burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aß amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other's experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aß burden was detectable upto 12 weeks of age when Aß burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aß burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-ß deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer's disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aß deposition or when given after Aß deposition is already at higher levels.


Assuntos
Doença de Alzheimer , Amiloidose , Microbioma Gastrointestinal , Humanos , Camundongos , Masculino , Feminino , Animais , Doença de Alzheimer/metabolismo , Microglia/metabolismo , Camundongos Transgênicos , Amiloidose/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/patologia , Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Modelos Animais de Doenças
3.
PLOS Glob Public Health ; 4(2): e0002766, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38381748

RESUMO

Luminescence is ubiquitous in biology research and medicine. Conceptually simple, the detection of luminescence nonetheless faces technical challenges because relevant signals can exhibit exceptionally low radiant power densities. Although low light detection is well-established in centralized laboratory settings, the cost, size, and environmental requirements of high-performance benchtop luminometers are not compatible with geographically-distributed global health studies or resource-constrained settings. Here we present the design and application of a ~$700 US handheld, battery-powered luminometer with performance on par with high-end benchtop instruments. By pairing robust and inexpensive Silicon Photomultiplier (SiPM) sensors with a low-profile shutter system, our design compensates for sensor non-idealities and thermal drift, achieving a limit of detection of 1.6E-19 moles of firefly luciferase. Using these devices, we performed two pilot cross-sectional serology studies to assess sars-cov-2 antibody levels: a cohort in the United States, as well as a field study in Bangladesh. Results from both studies were consistent with previous work and demonstrate the device's suitability for distributed applications in global health.

4.
Adv Sci (Weinh) ; 11(1): e2304545, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37990786

RESUMO

Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD. In this work, the pathological accumulation of HDAC6 in AD brains over age as well as the relationship of its regulatory activity - with amyloid pathogenesis and pathophysiological alterations is aimed to be enlightened using the newly developed HDAC6 inhibitor (HDAC6i) PB118 in microglia BV2 cell and 3D-AD human neural culture model. Results suggest that the structure-based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aß deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α-tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho-tau (p-tau) levels associated with AD. These findings indicate that HDAC6 plays key roles in the pathophysiology of AD and potentially serves as a suitable pharmacological target through chemical biology-based drug discovery in AD.


Assuntos
Doença de Alzheimer , Humanos , Desacetilase 6 de Histona , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Tubulina (Proteína)/metabolismo
5.
J Pept Sci ; 30(1): e3535, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37580909

RESUMO

Intracellular protein-protein interactions provide a major therapeutic target for the development of peptide-based anticancer therapeutic agents. MDM2 is the 491-residue protein encoded by the MDM2 oncogene. Being a ubiquitin-protein ligase, MDM2 represses the transcription ability of the tumor suppressor p53 by proteasome-mediated degradation. Under typical cellular circumstances, a sustained p53 expression level is maintained by negative regulation of MDM2, whereas under stress conditions, this is alleviated to increase the p53 level. Modulation of MDM2-p53 interaction via fabrication of an MDM2-interacting peptide could be a useful strategy to inhibit subsequent proteasomal degradation of p53 and initiation of p53 signaling leading to the initiation of p53-mediated apoptosis of tumor cells. Here, in this research work, a novel anticancer peptide mPNC-NLS targeting the nucleus and the MDM2 protein (p53 negative regulator) was designed to promote the p53 protein activity for the prevention of cancer. It induces effective apoptosis in both A549 and U87 cells and remains non-cytotoxic to normal lung fibroblast cells (WI38). Further, immunocytochemistry and Western blot results confirm that the designed mPNC-NLS peptide induces the apoptotic death of lung cancer cells via activation of p53 and p21 proteins and remarkably stifled the in vitro growth of 3D multicellular spheroids composed of A549 cells.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/farmacologia , Apoptose , Peptídeos/farmacologia , Peptídeos/metabolismo
6.
Inorg Chem ; 62(49): 20439-20449, 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38001041

RESUMO

High-valent metal-fluoride complexes are currently being explored for concerted proton-electron transfer (CPET) reactions, the driving force being the high bond dissociation energy of H-F (BDEH-F = 135 kcal/mol) that is formed after the reaction. Ni(III)-fluoride-based complexes on the pyridine dicarboxamide pincer ligand framework have been utilized for CPET reactions toward phenols and hydrocarbons. We have replaced the central pyridine ligand with an N-heterocyclic carbene carbene to probe its effect in both stabilizing the high-valent Ni(III) state and its ability to initiate CPET reactions. We report a monomeric carbene-diamide-based Ni(II)-fluoride pincer complex that was characterized through 1H/19F NMR, mass spectrometry, UV-vis, and X-ray crystallography analysis. Although carbenes and deprotonated carboxamides in the Ni(II)-fluoride complex are expected to stabilize the Ni(III) state upon oxidation, the Ni(III)/Ni(II) redox process occurred at very high potential (0.87 V vs Fc+/Fc, dichloromethane) and was irreversible. Structural studies indicate significant distortion in the imidazolium "NCN" carbene plane of Ni(II)-fluoride caused by the formation of six-membered metallacycles. The high-valent NiIII-fluoride analogue was synthesized by the addition of 1.0 equiv CTAN (ceric tetrabutylammonium nitrate) in dichloromethane at -20 °C which was characterized by UV-vis, mass spectrometry, and EPR spectroscopy. Density functional theory studies indicate that the Ni-carbene bond elongated, while the Ni-F bond shortened upon oxidation to the Ni(III) species. The high-valent Ni(III)-fluoride was found to react with the substituted phenols. Analysis of the KIE and linear free energy relationship correlates well with the CPET nature of the reaction. Preliminary analysis indicates that the CPET is asynchronous and is primarily driven by the E0' of the Ni(III)-fluoride complex.

7.
J Med Chem ; 66(23): 16075-16090, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-37972387

RESUMO

Recent studies have shown that the epigenetic protein histone deacetylase 11 (HDAC11) is highly expressed in the brain and critically modulates neuroimmune functions, making it a potential therapeutic target for neurological disorders. Herein, we report the development of PB94, which is a novel HDAC11 inhibitor. PB94 exhibited potency and selectivity against HDAC11 with IC50 = 108 nM and >40-fold selectivity over other HDAC isoforms. Pharmacokinetic/pharmacodynamic evaluation indicated that PB94 possesses promising drug-like properties. Additionally, PB94 was radiolabeled with carbon-11 as [11C]PB94 for positron emission tomography (PET), which revealed significant brain uptake and metabolic properties suitable for drug development in live animals. Furthermore, we demonstrated that neuropathic pain was associated with brain upregulation of HDAC11 and that pharmacological inhibition of HDAC11 by PB94 ameliorated neuropathic pain in a mouse model. Collectively, our findings support further development of PB94 as a selective HDAC11 inhibitor for neurological indications, including pain.


Assuntos
Neuralgia , Doenças Neuroinflamatórias , Animais , Camundongos , Encéfalo/metabolismo , Histona Desacetilases/metabolismo , Neuralgia/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico
8.
Angew Chem Int Ed Engl ; 62(45): e202312519, 2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37721455

RESUMO

The development of Alzheimer's disease (AD) drugs has recently witnessed substantial achievement. To further enhance the pool of drug candidates, it is crucial to explore non-traditional therapeutic avenues. In this study, we present the use of a photolabile curcumin-diazirine analogue, CRANAD-147, to induce changes in properties, structures (sequences), and neurotoxicity of amyloid beta (Aß) species both in cells and in vivo. This manipulation was achieved through irradiation with LED light or molecularly generated light, dubbed as "molecular light", emitted by the chemiluminescence probe ADLumin-4. Next, aided by molecular chemiluminescence imaging, we demonstrated that the combination of CRANAD-147/LED or CRANAD-147/ADLumin-4 (molecular light) could effectively slow down the accumulation of Aßs in transgenic 5xFAD mice in vivo. Leveraging the remarkable tissue penetration capacity of molecular light, phototherapy employing the synergistic effect of a photolabile Aß ligand and molecular light emerges as a promising alternative to conventional AD treatment interventions.


Assuntos
Doença de Alzheimer , Curcumina , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/química , Curcumina/farmacologia , Curcumina/uso terapêutico , Diazometano , Camundongos Transgênicos , Fototerapia , Modelos Animais de Doenças
9.
In Silico Pharmacol ; 11(1): 19, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37525849

RESUMO

In India, breast cancer is the most common cause of mortality for women and has the potential to spread to other body organs. As a transcription factor, interactions with the estrogen receptor (ER) alpha are primarily responsible for the development of malignant tumors. Aromatase inhibitors are the most often used treatment for ER(+) breast cancer. Various synthetic compounds have been developed over the years to block the aromatase receptor, however, the majority of them are hazardous and cause multidrug resistance. So, combating these natural drugs can be prioritized. The current study was conducted to investigate the anticancer potential of Lagenaria siceraria phytoconstituents against breast cancer target protein (PDB ID: 3EQM) based on a literature review. In this study, 34 Lagenaria siceraria ligands were chosen, and the structure of the human aromatase receptor was acquired from the protein data bank. For those natural chemicals, molecular docking, drug-likeness, toxicity, and molecular dynamics were used to evaluate and analyse their anti-breast cancer activity. Five substances, 2,3-Diphenyl quinoxaline, 17-Acetoxy pregnolone, Benzyl-d-glucoside, Ergostenol acetate, and Stigmast-7-en-3-ol, shown higher binding affinity than Tamoxifen, signaling their potential use in breast cancer treatment.

10.
Front Public Health ; 11: 1209068, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37448657

RESUMO

Background: Knowing the relationship between the factors related to home environment and early childhood development (ECD) in Bangladeshi children aged 3 to 4 years would help to find out appropriate interventions for the children with lower ECD outcomes. Therefore, we aimed to understand the relationship between the home environment factors and ECD in rural Bangladeshi children aged 3 to 4 years. Methods: We used data from the Multiple Indicator Cluster Survey (MICS) 2019, and included 7,326 rural children aged 3 to 4 years. The ECD index (ECDI) included four domains: literacy-numeracy, learning, physical and socio-emotional development. If a child met at least three of these four domains, the child was indicated as developmentally "on track". Results: The findings show that 27.4% of rural children missed to reach developmentally on-track while 72.2% of children did not attain the literacy-numeracy domain of ECD. The home environment factors including parental participation in children's activities, was found to be associated with ECD. For instance, reading books to child had 26% (aOR = 1.26, 95% CI = 1.08-1.48), and telling stories to child had 29% (aOR = 1.29, 95% CI = 1.09-1.53) more developmentally on-track in overall ECDI. Similar associations between home environment factors and specific ECD domains were also obtained. We also identified that children aged 4 years, girls, and children of mothers with higher socio-economic status (SES) were higher developmentally on-track than their counterparts. Conclusion: Home environment factors like reading books and telling stories to children were found to be significantly associated with ECD in rural areas of Bangladesh. Our study's findings would assist in implementing the essential public health intervention to enhance the ECD program especially in the rural Bangladeshi context.


Assuntos
Desenvolvimento Infantil , Ambiente Domiciliar , Criança , Feminino , Humanos , Pré-Escolar , Bangladesh/epidemiologia , Mães , Aprendizagem
11.
Environ Res ; 232: 116071, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37209979

RESUMO

Existing water and wastewater treatment techniques are becoming increasingly difficult to employ due to the discovery of new toxins, the rapid development of population and industrial activities, and the limited quantity of water resources. Treatment of wastewater is a critical need in modern civilization due to a scarcity of water resources and rising industrial activity. Some of the techniques utilized include adsorption, flocculation, filtration, and others, although they are only used for primary wastewater treatment. However, the development and deployment of modern wastewater management with high efficiency and low capitalization are critical in terms of mitigating the environmental consequences of waste. The employment of different nanomaterials in the treatment of wastewater has opened up a world of possibilities for heavy metal and pesticide removal, as well as the treatment of microbes and organic contaminants in wastewater. Nanotechnology is a rapidly evolving technology because of certain nanoparticle's outstanding physiochemical and biological capabilities as contrasted to bulk counterparts. Secondly, it has been established that this is a cost-effective treatment strategy with significant potential in wastewater management, transcending the limitations imposed by currently existing technology. Advances in nanotechnology to reduce water contamination have been presented in this review, including the use of various nanomaterials such as nanocatalysts, nanoadsorbents, and nanomembranes in the treatment of wastewater containing organic contaminants, hazardous metals, and virulent pathogens.


Assuntos
Nanopartículas , Nanoestruturas , Poluentes Químicos da Água , Purificação da Água , Águas Residuárias , Purificação da Água/métodos , Filtração , Adsorção
12.
Eur J Med Chem ; 254: 115327, 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37098307

RESUMO

Targeting histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic approach for anti-inflammation and related biological pathways, including inflammatory events associated with the brain. In this study, in order to develop brain-permeable HDAC6 inhibitors for anti-neuroinflammation, we report here the design, synthesis, and characterization of a number of N-heterobicyclic analogues that can inhibit HDAC6 with high specificity and strong potency. Among our analogues, PB131 exhibits potent binding affinity and selectivity against HDAC6, with an IC50 value of 1.8 nM and more than 116-fold selectivity over other HDAC isoforms. In addition, PB131 shows good brain penetration, binding specificity, and reasonable biodistribution through our positron emission tomography (PET) imaging studies of [18F]PB131 in mice. Furthermore, we characterized the efficacy of PB131 on regulating neuroinflammation using the mouse microglia model BV2 cells in vitro and the LPS-induced inflammation mouse model in vivo. These data not only indicate the anti-inflammatory activity of our novel HDAC6 inhibitor PB131, but also strengthen the biological functions of HDAC6 and further extend the therapeutic approach inhibiting HDAC6. Our findings show that PB131 displays good brain permeability, high specificity, and strong potency toward inhibiting HDAC6 and is a potential HDAC6 inhibitor for inflammation-related disease treatment, especially neuroinflammation.


Assuntos
Encéfalo , Inibidores de Histona Desacetilases , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Encéfalo/metabolismo , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/química , Distribuição Tecidual
13.
Waste Manag ; 164: 143-153, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37059038

RESUMO

The extensive distribution of microplastics and their abundance around the world has raised a global concern because of the lack of proper disposal channels as well as poor knowledge of their implications on human health. Sustainable remediation techniques are required owing to the absence of proper disposal methods. The present study explores the deterioration process of high-density polyethylene (HDPE) microplastics using various microbes along with the kinetics and modeling of the process using multiple non-linear regression models. Ten different microbial strains were used for the degradation of microplastics for a period of 30 days. Effect of process parameters on the degradation process was studied with the selected five microbial strains that presented the best degradation results. The reproducibility and efficacy of the process were tested for an extended period of 90 days. Fourier-transform infrared spectroscopy (FTIR) and field emission-scanning electron microscopy (FE-SEM) were used for the analysis of microplastics. Polymer reduction and half-life were evaluated. Pseudomonas putida achieved the maximum degradation efficiency of 12.07% followed by Rhodococcus ruber (11.36%), Pseudomonas stutzeri (8.28%), Bacillus cereus (8.26%), and Brevibacillus borstelensis (8.02%) after 90 days. Out of 14 models tested, 5 were found capable of modeling the process kinetics and based on simplicity and statistical data, Modified Michaelis-Menten model (F8; R2 = 0.97) was selected as superior to others. This study successfully establishes the potential of bioremediation of microplastics as the viable process.


Assuntos
Microplásticos , Poluentes Químicos da Água , Humanos , Polietileno/química , Plásticos , Reprodutibilidade dos Testes , Cinética , Poluentes Químicos da Água/análise , Espectroscopia de Infravermelho com Transformada de Fourier
14.
Bioresour Technol ; 369: 128399, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36503834

RESUMO

Activated carbon derived from peat-based biomass was sulfurized and magnetized forming magnetically-engineered sulfurized peat-based activated carbon (MEPBAC) and used for adsorption of caffeine (CFN) and sulfamethoxazole (SMX) from aqueous media. Modification increased the surface area (724 m2/g) and introduced sulphur-groups and Fe-based nano-structures in MEPBAC. Sulphur-groups enhanced adsorption efficiency, whereas Fe-based nano-structures facilitated easy magnetic separation of MEPBAC after intended use leading to high reusability with consistent removal efficiency (∼95 %). Response surface methodology was employed for design of experiments and process optimization. The results revealed that the maximum removal (SMX 94 %; CFN 97 %) could be achieved at an adsorbent dose of 1.4 and 1.6 g/L, respectively (pH 11, 311 K). Adsorption kinetics was best explained by a pseudo-second-order kinetic model. Adsorption data of SMX was fitted better to Langmuir (linear) and Freundlich (non-linear) isotherms, whereas that of CFN was fitted well with Freundlich (linear) and Langmuir (non-linear) isotherms (R2 ≥ 0.99).


Assuntos
Carvão Vegetal , Poluentes Químicos da Água , Termodinâmica , Carvão Vegetal/química , Poluentes Químicos da Água/química , Concentração de Íons de Hidrogênio , Sulfametoxazol , Adsorção , Cinética , Preparações Farmacêuticas
15.
J Med Chem ; 65(20): 13866-13878, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36240440

RESUMO

Protein-protein interactions play a crucial role in microtubule dynamics. Microtubules are considered as a key target for the design and development of anticancer therapeutics, where inhibition of tubulin-tubulin interactions plays a crucial role. Here, we focused on a few key helical stretches at the interface of α,ß-tubulin heterodimers and developed a structural mimic of these helical peptides, which can serve as potent inhibitors of microtubule polymerization. To induce helicity, we have made stapled analogues of these sequences. Thereafter, we modified the lead sequences of the antimitotic stapled peptides with halo derivatives. It is observed that halo-substituted stapled peptides follow an interesting trend for the electronegativity of halogen atoms in interaction patterns with tubulin and a correlation in the toxicity profile. Remarkably, we found that para-fluorophenylalanine-modified stapled peptide is the most potent inhibitors, which perturbs microtubule dynamics, induces apoptotic death, and inhibits the growth of melanoma.


Assuntos
Antimitóticos , Tubulina (Proteína) , Tubulina (Proteína)/química , Moduladores de Tubulina/farmacologia , Antimitóticos/farmacologia , p-Fluorfenilalanina , Peptídeos/farmacologia , Microtúbulos , Halogênios
16.
Acta Pharm Sin B ; 12(10): 3891-3904, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36213537

RESUMO

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [18F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6. PET studies of [18F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals, with more pronounced changes identified in the cortex and hippocampus. The translatability of this radiotracer for AD in a potential human use was supported by additional studies, including similar uptake profiles in non-human primates, an increase of HDAC6 in AD-related human postmortem hippocampal tissues by Western blotting protein analysis, and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals. Collectively, our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.

17.
Environ Sci Pollut Res Int ; 29(58): 88089-88100, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35829886

RESUMO

The present study investigated the performance of a chromium-based advanced oxidation process using chromium (as Cr3+ or Cr6+) and H2O2 for the treatment of synthetic and simulated textile wastewaters. With the Cr3+/H2O2 system, the maximum total organic carbon (TOC) and color removals from the synthetic dye wastewater (Remazol Brilliant Violet 5R dye concentration = 100 mg/L) were 75% and 99%, respectively, within 30 min duration ([Cr3+]:[H2O2] = 1:30, stoichiometric H2O2 dose = 2.01 ml/L and pH = 7). Whereas the same catalyst and oxidant combination resulted in chemical oxygen demand (COD) and color removals of ~ 46%, and 84%, respectively, after 3 h of reaction at the optimized reaction conditions (i.e., [Cr3+]:[H2O2] = 1:50, stoichiometric H2O2 dose = 11.6 ml/L and pH = 7) from the simulated textile wastewater (initial pH = 10.2, and COD = 1820 mg/L). Further, the addition of stoichiometric H2O2 dose to the pretreated wastewater and pH adjustment increased the overall COD removal to 77%. Both oxidation and precipitation reactions were found responsible for organics removal from the wastewater. The other alternative involving activated carbon adsorption as second step, was not found as effective as the above scheme. The data on COD removal from simulated textile wastewater could be fit adequately in the retarded first-order kinetic model. Based on the COD and color removal results and preliminary cost analysis, this can be suggested that the Cr3+/H2O2 oxidation process followed by pH adjustment and further H2O2 treatment was the best option for the removal of COD and color from the simulated combined textile wastewater.


Assuntos
Águas Residuárias , Poluentes Químicos da Água , Peróxido de Hidrogênio , Eliminação de Resíduos Líquidos/métodos , Cromo , Hidrogênio , Têxteis , Oxirredução , Indústria Têxtil
18.
Chemosphere ; 304: 135243, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35679977

RESUMO

The human health-related issues originating from the consumption of arsenic and fluoride-containing drinking water are major challenges worldwide. Amongst the different technologies available, electrocoagulation and adsorption are two promising technologies for simultaneous remediation of contaminants from groundwater. The present study evaluates and compares the environmental impacts of aluminium hydroxide/oxide nanoparticles (AHNP) adsorption and aluminium electrode electrocoagulation processes by performing their LCA. The Environmental impacts of both technologies were evaluated using Gabi software with the help of two mid-point methods (CML 2001 and TRACI). Evaluations are based on the treatment of 720 L of arsenic(III) and fluoride contaminated water from initial concentrations of 0.5 and 10 mg/L, respectively, to their WHO permissible limits. The management of spent materials has been considered for environmental impacts. The LCA analysis has shown that dissolution of aluminium electrode and electricity consumption in the electrochemical process are the significant contributors to environmental impacts in GWP, AP, ODP, ADP fossil, FAETP and HTP categories. Adsorption (GWP 35.2 kg CO2 eq.) has almost eight times higher environmental impacts than electrocoagulation (GWP 4.5 kg CO2 eq.) because in-situ generated coagulant has higher adsorption capacity than pre-precipitated adsorbents. The scenario analysis was performed with four different sources of electricity. The economic evaluation concludes that the combined cost of material and energy involved in the adsorption process (INR 0.7 per litre) is almost seven times higher than that of the electrocoagulation process (INR 0.1 per litre). Hence electrocoagulation is a more environment-friendly, low-cost technology to treat groundwater for community purposes.


Assuntos
Arsênio , Água Subterrânea , Poluentes Químicos da Água , Purificação da Água , Adsorção , Alumínio/análise , Animais , Arsênio/análise , Dióxido de Carbono/análise , Eletrocoagulação/métodos , Fluoretos/análise , Humanos , Estágios do Ciclo de Vida , Poluentes Químicos da Água/análise , Purificação da Água/métodos
19.
RSC Med Chem ; 13(2): 196-201, 2022 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-35308028

RESUMO

Cell proliferation is a crucial step that might promote cancer if deregulated. Therefore, this vital segment is critically controlled by a complicated cell-cycle process in normal cells that is regulated by some regulatory proteins. It has been observed that p16 protein, playing a crucial role in cell-cycle progression/regulation, remains inactivated in different cancer cells. This inactivity of p16 protein leads to the enhancement of cancer cell proliferation by allowing uncontrolled cancer cell division. Hence, the activity of p16 protein needs to be restored using new viral vectors, small molecules as well as peptides to control/suppress this type of abnormal cell proliferation. In this work, we have taken an interesting approach to increase the efficiency and bio-availability of p16 peptide (functional part of p16 protein) to be an aggressive anti-leukemia therapeutic agent by conjugating a nuclear-localized signal (NLS) sequence and a short peptide (AVPI) with it. Moreover, this newly designed NLS attached hybrid peptide greatly affects XIAP expressing but p16 lower expressing human chronic myelogenous leukemia (CML) cell proliferation by targeting both nuclear (CDK4/cyclin D) and cellular factors (XIAP) and promoting the caspase-3 dependent apoptosis pathway.

20.
Chemosphere ; 287(Pt 3): 132220, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34543895

RESUMO

The present study investigated the effects of metal loaded spent adsorbent as catalyst for the catalytic pyrolysis of pine needle biomass. Metal active sites (Ni, Fe, Cu, Zn and Mo) were introduced in alumina matrix by wet impregnation process. Non-catalytic and catalytic semi-batch pyrolysis study was carried out at conditions: 550 °C temperature, 50 °C min-1 heating rate and 200 mL min-1 N2 flow rate. Results indicated significant deoxygenation potential 3.33-35.57% of the applied catalysts towards oxygenated compounds by converting them into their corresponding hydrocarbon (27.70-36.41%) and phenolic (40.41-46.04%) derivatives. Among all the catalysts, Ni/Al and Fe/Al produced the highest quality bio-oil by enriching their carbon content to 62.93 and 60.14% and heating value to 31.41 and 26.86 MJ kg-1, respectively. Moreover, significant enhancement in their hydrocarbons (36.41 and 36.01% for Ni/Al and Fe/Al, respectively) and phenolic compounds (46.04 and 41.67% for Ni/Al and Fe/Al, respectively) from 9.15% hydrocarbons and 13.32% phenols in non-catalytic bio-oil had also been observed. Presence of CO and CO2 in the evolved gases also represented the occurrence of deoxygenation reactions during catalytic breakdown. Hydrocarbon and phenol-rich bio-oil can find its application either as a replacement for petroleum fuel or an industrial-grade chemical. Thus, catalysts derived from spent aluminum hydroxide nanoparticle adsorbent can act as an effective substitute for the currently utilized high-cost catalysts in catalytic pyrolysis of biomass.


Assuntos
Nanopartículas , Pirólise , Hidróxido de Alumínio , Biocombustíveis , Biomassa , Catálise , Temperatura Alta , Hidrocarbonetos , Fenóis , Óleos de Plantas , Polifenóis
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