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1.
Small ; : e2401179, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38639026

RESUMO

Although the atmospheric stability of lead-free inorganic double perovskite (DP) solar cells (PSCs) looks promising, their further development is hampered by inadequate film quality and non-radiative carrier recombination at the interfaces. Herein, the incorporation of a newly developed intriguing class of 2D material Ti3C2Tx MXene nanosheets with the photo-absorbing Cu2AgBiI6 (CABI) active layer of a fully inorganic solar cell is reported. The highly conductive Ti3C2Tx nanosheets work as a multi-functional additive by tuning the band gap, reducing the non-radiative carrier recombination, and inhibiting carrier accumulation. In addition, the presence of Ti3C2Tx MXene increases the surface free energy of the perovskite film, which elevates the energy barrier for nucleation and realizes a highly crystalline CABI perovskite film. Primarily, the MXene modification accelerates the charge extraction and transport at the interfaces of the active layer, utilizing energy level alignment with the charge transport layers. Consequently, the photo-conversion efficiency (PCE) of the device with MXene is substantially enhanced to 1.50%. Moreover, the 2D Ti3C2Tx nanosheets increased the long-term stability of the devices by retaining 70% of the initial PCE after 1680 h. With regard to relieving the severe carrier recombination at the interfaces, this work sets a new paradigm toward imminent solar energy conversion.

2.
Angew Chem Int Ed Engl ; : e202400227, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38317632

RESUMO

2-tetrelavinylidenes (C=EH2 ; E=Si, Ge) are according to quantum chemical studies the least stable isomers on the [E,C,2H] potential energy hypersurface isomerizing easily via the trans-bent tetrelaacetylenes HE≡CH to the thermodynamically most stable 1-tetrelavinylidenes (E=CH2 ). Consequently, experimental studies on 2-tetrelavinylidenes (C=ER2 ) and their derivatives are lacking. Herein we report experimental and theoretical studies of the first N-heterocyclic carbene (NHC) supported 2-silavinylidene (NHC)C=SiBr(Tbb) (1-Si: NHC=C[N(Dipp)CH]2 , Dipp=2,6-diisopropylphenyl, Tbb=2,6-bis[bis(trimethylsilyl)methyl]-4-tert-butylphenyl) and the isovalent 2-germavinylidenes (NHC)C=GeBr(R) (1-Ge, 1-GeMind: R=Tbb, Mind (1,1,3,3,5,5,7,7-octamethyl-s-hydrindacene-4-yl)). The NHC-supported 2-tetrelavinylidenes were obtained selectively from the 1,2-dibromoditetrelenes (E)-(R)BrE=EBr(R) using the diazoolefin (NHC)CN2 as vinylidene transfer reagent. 1-E (E=Si, Ge) have a planar vinylidene core, a bent-dicoordinated vinylidene carbon atom (CVNL ), a very short E=CVNL bond and an almost orthogonal orientation of the NHC five-membered ring to the vinylidene core. Quantum chemical analysis of the electronic structures of 1-E suggest a significantly bent 1-tetrelaallene and tetrelyne character. NMR studies shed light into the dynamics of 1-E involving NHC-rotation around the CVNL -CNHC bond with a low activation barrier. Furthermore, the synthetic potential of 1-E is demonstrated by the synthesis and full characterization of the unprecedented NHC-supported bromogermynes BrGe=C(EBr2 Tbb)(NHC) (2-SiGe: E=Si; 2-GeGe: E=Ge).

3.
PLoS One ; 19(1): e0295522, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38166085

RESUMO

Influenza viral infection is a seasonal infection which causes widespread acute respiratory issues among humans globally. This virus changes its surface receptor composition to escape the recognition process by the host's immune cells. Therefore, the present study focussed to identify some other important viral proteins which have a significant role in establishment of infection and having apparent conserved structural composition. This could facilitate the permanent vaccine development process or help in designing a drug against IAV (influenza A virus) infection which will eliminate the seasonal flu shot vaccination process. The NS1 (Non-structural protein 1) protein of IAV maintains a conserved structural motif. Earlier studies have shown its significant role in infection establishment. However, the mechanism by which viruses escape the host's ND10 antiviral action remains elusive. The present study clearly showed that IAV infection and NS1 transfection in A549 cells degraded the main component of the ND10 anti-viral complex, PML and therefore, inhibited the formation of Daxx-sp100-p53-PML complex (ND10) at the mid phase of infection/transfection. PML degradation activated the stress axis which increased cellular ROS (reactive oxygen species) levels as well as mitochondrial dysfunction. Additionally, IAV/NS1 increased cellular stress and p53 accumulation at the late phase of infection. These collectively activated apoptotic pathway in the host cells. Along with the inactivation of several interferon proteins, IAV was found to decrease p-IKKε. A549 cells transfected with pcDNA3.1-NS1 showed a similar effect in the interferon axis and IKKε. Moreover, NS1 induced the disintegration of the host's ND10 complex through the changes in the SUMOylation pattern of the PML nuclear body. These findings suggest the possible mechanism of how NS1 helps IAV to establish infection in the host cells. However, it demands further detailed study before targeting NS1 to develop permanent vaccines or novel drugs against IAV in future.


Assuntos
Vírus da Influenza A , Humanos , Quinase I-kappa B/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Corpos Nucleares da Leucemia Promielocítica , Proteínas não Estruturais Virais/metabolismo , Interferons/metabolismo , Replicação Viral , Interações Hospedeiro-Patógeno
4.
Life Sci ; 329: 121911, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37429416

RESUMO

AIMS: Identification of the progress of non-alcoholic fatty liver disease (NAFLD) is crucial for their effective treatment. Circulating peripheral blood mononuclear cells (PBMC) could be a surrogate monitor instead of complicated and expensive biopsies. Changes in immuno-metabolic status in NAFLD patients may be reflected by an expression of different PBMC-specific molecular markers. It was hypothesized that impaired autophagy with enhanced inflammasome activation is a critical molecular event in PBMC that could contribute to systemic inflammation associated with NAFLD progression. MAIN METHODS: A cross-sectional study with a sample size of 50 subjects were undertaken from a governmental facility in Kolkata, India. Major anthropometric, biochemical, and dietary parameters were recorded. Cellular and serum samples of NAFLD patients were analyzed for oxidative stress, inflammation, inflammasome activation, and autophagic flux by western blot, flow cytometry, immunocytochemistry. KEY FINDINGS: Baseline anthropometric and clinical parameters were found associated with NAFLD severity. Elevated systemic inflammation was reflected by higher proinflammatory markers like iNOS, Cox-2, IL-6, TNF-α, IL-1ß, hsCRP in the serum of NAFLD subjects (p < 0.05). ROS-induced NLRP3 inflammasomes marker proteins were upregulated (p < 0.05) in PBMC along with NAFLD severity. Expression of autophagic markers such as LC3B, Beclin-1 and its regulator pAMPKα were found diminished (p < 0.05) with a concomitant rise of p62. Colocalization of NLRP3 with LC3B proteins in PBMC was found diminished along NAFLD severity. SIGNIFICANCE: Present data provide mechanistic evidence of impaired autophagy and intracellular ROS triggered inflammasome activation in PBMC, which could potentially exacerbate NAFLD severity.


Assuntos
Inflamassomos , Hepatopatia Gordurosa não Alcoólica , Humanos , Inflamassomos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Leucócitos Mononucleares/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Estudos Transversais , Inflamação , Autofagia
5.
Mol Ther Nucleic Acids ; 32: 203-228, 2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37078062

RESUMO

Phosphorodiamidate morpholino oligonucleotide (PMO)-based antisense reagents cannot enter cells without the help of a delivery technique, which limits their clinical applications. To overcome this problem, self-transfecting guanidinium-linked morpholino (GMO)-PMO or PMO-GMO chimeras have been explored as antisense agents. GMO facilitates cellular internalization and participates in Watson-Crick base pairing. Targeting NANOG in MCF7 cells resulted in decline of the whole epithelial to mesenchymal transition (EMT) and stemness pathway, evident through its phenotypic manifestations, all of which were promulgated in combination with Taxol due to downregulation of MDR1 and ABCG2. GMO-PMO-mediated knockdown of no tail gene resulted in desired phenotypes in zebrafish even upon delivery after 16-cell stages. In BALB/c mice, 4T1 allografts were found to regress via intra-tumoral administration of NANOG GMO-PMO antisense oligonucleotides (ASOs), which was associated with occurrence of necrotic regions. GMO-PMO-mediated tumor regression restored histopathological damage in liver, kidney, and spleen caused by 4T1 mammary carcinoma. Serum parameters of systemic toxicity indicated that GMO-PMO chimeras are safe. To the best of our knowledge, self-transfecting antisense reagent is the first report since the discovery of guanidinium-linked DNA (DNG), which could be useful as a combination cancer therapy and, in principle, can render inhibition of any target gene without using any delivery vehicle.

6.
Alcohol Clin Exp Res (Hoboken) ; 47(1): 18-35, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341762

RESUMO

We conducted a systematic review with meta-analytic elements using publicly available Gene Expression Omnibus (GEO) datasets to determine the role of epigenetic mechanisms in prenatal alcohol exposure (PAE)-induced hypothalamic-pituitary-adrenal (HPA) axis dysfunctions in offspring. Several studies have demonstrated that PAE has long-term consequences on HPA axis functions in offspring. Some studies determined that alcohol-induced epigenetic alterations during fetal development persist in adulthood. However, additional research is needed to understand the major epigenetic events leading to alcohol-induced teratogenesis of the HPA axis. Our network analysis of GEO datasets identified key pathways relevant to alcohol-mediated histone modifications, DNA methylation, and miRNA involvement associated with PAE-induced alterations of the HPA axis. Our analysis indicated that PAE perturbated the epigenetic machinery to activate corticotrophin-releasing hormone, while it suppressed opioid, glucocorticoid receptor, and circadian clock genes. These results help to further our understanding of the epigenetic basis of alcohol's effects on HPA axis development.


Assuntos
Sistema Hipotálamo-Hipofisário , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sistema Hipófise-Suprarrenal/metabolismo , Etanol/efeitos adversos , Epigênese Genética , Estresse Psicológico/metabolismo
7.
Bioorg Med Chem Lett ; 76: 129017, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36209968

RESUMO

Despite the enormous potential of siRNAs to transcriptionally downregulate disease causing proteins in many genetic diseases, efficient delivery and endosomal escape are the two bottlenecks that have resulted in only a handful of FDA approved drugs. In this report, we have successfully delivered siRNA against Nanog with the help of pentafluorobenzyl modified Internal Oligo-guanidinium transporter (IGT) that has previously shown promising results in peptide and antisense morpholino delivery. Nanog downregulation in prostate cancer cell line DU145 in serum containing media led to suppression of associated proteins such as KLF4, FAK and cMyc and also enhanced the chemosensitivity of Epirubicin, an anthracycline based drug, in DU145 cells by associated MDR-1 downregulation in vitro. These results show that IGT is a promising candidate for siRNA delivery and its conjugation with stable siRNAs could enhance the chemotherapeutic efficiency of siRNAs alone and in combination with small molecule-based drugs.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Epirubicina , Proteína Homeobox Nanog , Proteínas de Transporte de Cátions Orgânicos , Neoplasias da Próstata , RNA Interferente Pequeno , Humanos , Masculino , Linhagem Celular Tumoral , Epirubicina/farmacologia , Guanidina/metabolismo , Morfolinos , Proteína Homeobox Nanog/genética , Peptídeos/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , RNA Interferente Pequeno/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética
8.
J Pharm Bioallied Sci ; 14(Suppl 1): S486-S489, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36110708

RESUMO

Purpose: Recently, human amniotic membrane (AM) has been reported to have regenerative potential that facilitate repair in the field of oral and periodontal surgeries. Methods: Eighteen subjects with bilateral Miller's class I gingival recession defects were selected. Subjects were allocated randomly to treatment with coronally positioned flap + amnion allograft (test group) and coronally positioned flap alone (control group). The clinical parameters used in this study were width of attached gingiva (AG), clinical attachment level (CAL), pocket depth (PD), width of keratinized gingiva (WKG), length of gingival recession (RL), width of gingival recession (RW). Results: The mean width of attached gingiva at the control sites (A) was found to be 1.33 ± 0.50 mm (range 1.00-2.00), 2.00 ± 0.71 mm (range 2.00-3.00) and 2.22 ± 0.67 mm (range 2.00-3.00) on day 0, 90 and 180, respectively. Thus, it was increased by 0.67 mm and 0.89 mm on day 90 and 180 compared to that of the baseline, which are 50% and 67%, respectively. Conclusions: It can be concluded that combined coronally advanced flap and amniotic membrane have additional advantage in the outcome of periodontal therapy in the management of gingival recession.

9.
Angew Chem Int Ed Engl ; 61(42): e202205575, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36017770

RESUMO

An anionic Rh-Ga complex catalyzed the hydrodefluorination of challenging C-F bonds in electron-rich aryl fluorides and trifluoromethylarenes when irradiated with violet light in the presence of H2 , a stoichiometric alkoxide base, and a crown-ether additive. Based on theoretical calculations, the lowest unoccupied molecular orbital (LUMO), which is delocalized across both the Rh and Ga atoms, becomes singly occupied upon excitation, thereby poising the Rh-Ga complex for photoinduced single-electron transfer (SET). Stoichiometric and control reactions support that the C-F activation is mediated by the excited anionic Rh-Ga complex. After SET, the proposed neutral Rh0 intermediate was detected by EPR spectroscopy, which matched the spectrum of an independently synthesized sample. Deuterium-labeling studies corroborate the generation of aryl radicals during catalysis and their subsequent hydrogen-atom abstraction from the THF solvent to generate the hydrodefluorinated arene products. Altogether, the combined experimental and theoretical data support an unconventional bimetallic excitation that achieves the activation of strong C-F bonds and uses H2 and base as the terminal reductant.

10.
Bioconjug Chem ; 33(5): 907-917, 2022 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-35486710

RESUMO

Cell-penetrating peptides (CPPs) are structurally diverse sophisticated tools endowed with high arginine content, amphipathicity, and well-adopted suitable secondary structures. Despite its capability of breaching the lipid barriers, CPP has major limitations such as in vivo metabolic instability, poor bioavailability, and reduced endosomal escape tendency, which are yet to be improved. In this context, we first have introduced a new class of cellular transporter having a guanidinium-functionalized δ-azaproline (δ-azp)-containing peptide where the δ-azp structurally resembles the "proline" amino acid having an additional "N" at the δ-position. This non-natural peptidic backbone was found to impart proteolytic stability, as reported earlier by our group. Herein, we report the synthesis of a flexible azaproline-tetraguanidinium transporter named FAT along with a revised scalable methodology for δ-azp compared to our previously reported procedure. FAT shows a random-coil-like structure as determined by CD spectroscopy, and is hence structurally different from the polyproline PPII helix. Direct translocation is predicted to be the possible mode of the cellular entrance of FAT into CHO cells when the "Bodipy" fluorophore is covalently attached as the cargo. Simultaneously, two other macromolecular therapeutics, e.g., proapoptotic domain peptide (PAD, a 14-mer peptide) and programmed death ligand 1 (PDL1) morpholino (a 25-mer antisense oligo), were successfully conjugated with FAT and delivered into human carcinoma cells, and their efficacy was analyzed by MTT assay and western blot technique, respectively. Having obtained promising results in internalizing different types of cargos, FAT could be envisaged as a potential drug delivery agent as an alternative to natural CPPs for future application.


Assuntos
Carcinoma , Peptídeos Penetradores de Células , Animais , Antígeno B7-H1 , Peptídeos Penetradores de Células/química , Cricetinae , Cricetulus , Guanidina , Humanos , Morfolinos
11.
Chem Biodivers ; 19(5): e202100823, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35298074

RESUMO

Cananginones, a family of linear acetogenins found as secondary metabolites in the plant kingdom, show cytotoxicity against several types of cancer cells. We aimed to investigate the efficacy of cananginone and its mechanism as an anti-cancer agent. Our initial screening of Cananginone against HepG2, PC3, A549, and MCF7 cells showed anti-cancer activities and is more potent against MCF7 cells, consistent with the previous report. Next, cell-based assays have revealed that cananginone abrogates cancer stem cell renewal as well as Epithelial-Mesenchymal Transition (EMT) and increased the ROS level beyond the threshold level thus reducing the viability of cancer cells. In the connection of Hh-Gli to EMT, our study indicated that cananginone inhibits Gli1 in a non-canonical pathway. Presumably, this is the first report on the inhibitory activity of cananginone in the Hh pathway and is different from Hh-antagonists cyclopamine and GANT 61 considering the mechanism.


Assuntos
Neoplasias da Mama , Transição Epitelial-Mesenquimal , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Proteínas Hedgehog/metabolismo , Humanos , Proteína GLI1 em Dedos de Zinco/metabolismo
13.
J Am Chem Soc ; 143(36): 14780-14794, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34469138

RESUMO

Experimental and theoretical studies are reported of the first two-coordinated Si0-isocyanide compound (SIDipp)Si═C═N-ArMes (1: SIDipp (NHC) = C[N(Dipp)CH2]2, ArMes = 2,6-dimesitylphenyl), supported by an N-heterocyclic carbene (NHC). A Si atom economic two-step synthesis of 1 involves a 2e reduction of the isocyanide-stabilized silyliumylidene salt [SiBr(CNArMes)(SIDipp)][B(ArF)4] (2[B(ArF)4], ArF = B(C6H3-3,5-(CF3)2)4) with KC8. 2[B(ArF)4] was obtained from SiBr2(SIDipp) after bromide abstraction with an equimolar mixture of Na[B(ArF)4] and ArMesNC. Exact adherence to the stoichiometry is crucial in the latter reaction, since 2[B(ArF)4] reacts with SiBr2(SIDipp) via isocyanide exchange to afford the disilicon(II) salt [Si2Br3(SIDipp)2)][B(ArF)4] (3[B(ArF)4]), the reaction leading to an equilibrium that favors 3[B(ArF)4] (Keq(298 K) = 10.6, ΔH° = -10.6 kJ mol-1; ΔS° = -16.0 J mol-1 K-1). 3[B(ArF)4] was obtained selectively from the 2:1 reaction of SiBr2(SIDipp) with Na[B(ArF)4] and fully characterized. Detailed studies of 1 reveal an intriguing structure featuring a planar CNHC-Si-C-N skeleton with a V-shaped geometry at the dicoordinated Si0 center, a slightly bent Si═C═N core, a CNHC-Si-CCNR 3c-2e out of plane π-bond (HOMO), and an anticlinal conformation of the SIDipp and ArMes substituents leading to axial chirality and the presence of two enantiomers, (Ra)-1 and (Sa)-1. Compound 1 displays structural dynamics in solution, rapidly interconverting the enantiomers. The silacumulene 1 is a potent Si(SIDipp) transfer agent as demonstrated by the synthesis and full characterization of the NHC-supported germasilyne (Z)-(SIDipp)(Cl)Si═GeArMes (4) from 1 and Ge(ArMes)Cl.

14.
Nanoscale ; 13(19): 8864-8874, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33949417

RESUMO

Recently, several types of lead halide perovskites have been actively researched for resistive switching (RS) memory or artificial synaptic devices due to their current-voltage hysteresis along with the feasibility of fabrication, low-temperature processability and superior charge mobility. However, the toxicity and environmental pollution potential of lead halide perovskites severely restrict their large-scale commercial prospects. In the present work, the environmentally friendly and uniform CsSnCl3 perovskite films are introduced to act as an active layer in the flexible memristors. Ag/CsSnCl3/ITO devices demonstrate bipolar RS with excellent electrical properties such as forming free characteristics, good uniformity, low operating voltages, a high ON/OFF ratio (102) and a long retention time (>104 s). The RS mechanism has been well explained in the outline of electric field-induced formation and rupture of Ag filaments in the CsSnCl3 layer. The metallic nature of the conducting filament has been further confirmed by temperature-dependent variation of low and high resistance states. Additionally, various pulse measurements have been carried out to mimic some of the basic synaptic functions including postsynaptic current, paired-pulse facilitation, long-term potentiation and long-term depression under normal as well as bending conditions. Our work provides the opportunity for exploring artificial synapses based on lead-free halide perovskites for the development of next-generation flexible electronics.

15.
Sci Rep ; 10(1): 15443, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963259

RESUMO

In the context of failure of treatment for non alcoholic fatty liver disease (NAFLD)-mediated systemic damages, recognition of novel and successful characteristic drug to combat these anomalous situations is earnestly required. The present study is aimed to evaluate protective value of ethanol extract of Coccinia grandis leaves (EECGL), naturally occurring medicinal plant, on NAFLD-mediated systemic damage induced by high lipid diet along with monosodium glutamate (HM)-fed rats. Our study uncovered that EECGL significantly ameliorates HM-induced hyperlipidemia, increased lipogenesis and metabolic disturbances (via up regulation of PPAR-α and PPAR-γ), oxidative stress (via reducing the generation of reactive oxygen species and regulating the redox-homeostasis) and inflammatory response (via regulating the pro-inflammatory and anti-inflammatory factors with concomitant down regulation of NF-kB, iNOS, TNF-α and up regulation of eNOS). Furthermore, EECGL significantly inhibited HM-induced increased population of cells in sub G0/G1 phase, decreased Bcl2 expression and thereby loss of mitochondrial membrane potential with over expression of Bax, p53, p21, activation of caspase 3 and 9 indicated the apoptosis and suppression of cell survival. It is perhaps the first comprehensive study with a mechanistic approach which provides a strong unique strategy for the management of HM-induced systemic damage with effective dose of EECGL.


Assuntos
Cucurbitaceae/química , Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Glutamato de Sódio/toxicidade , Animais , Biomarcadores/análise , Regulação da Expressão Gênica , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Estresse Oxidativo , Ratos , Ratos Wistar
16.
Bioconjug Chem ; 31(10): 2367-2382, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-32986398

RESUMO

A nontoxic delivery vehicle is essential for the therapeutic applications of antisense phosphorodiamidate morpholino oligonucleotides (PMOs). Though guanidinium-rich or arginine-rich cellular transporter conjugated Vivo-PMO or PPMO has been developed for in vivo application, however, either their toxicity or stability has become an issue. Previously, we reported nonpeptidic internal guanidinium transporter (IGT) mediated delivery of PMO for gene silencing and got encouraging results. In this paper, we report the synthesis of IGT using a Hg-free method for scale up and N-terminal modification of IGT with a suitable hydrophobic or lipophilic group to improve the cell permeability, endosomal escape, and mitochondrial localization and to reduce toxicity in the MTT assay. For the delivery of PMO, IGT-PMO conjugate was synthesized to target NANOG in cells, a transcription factor required for cancer stem cell proliferation and embryonic development and is involved in many cancers. Our data shows IGT-PMO-facilitated NANOG inhibition, and thereby the prevention of EpCAM-N-Cadherin-Vimentin axis mediated epithelial to mesenchymal transition (EMT) in MCF-7 cells. Moreover, unlike taxol, NANOG inhibition influences the expression of stemness factor c-Myc, Hh-Gli signaling proteins, other cancer related factors, and their respective phenotypes in cancer cells. To the best of our knowledge, this is the first report to illustrate that the IGT-PMO-mediated NANOG inhibition increases the therapeutic potential of taxol and induces G0-G1 arrest in cancer cells to prevent cancer progression. However, it warrants further investigation in other cancer cells and preclinical platforms.


Assuntos
Antineoplásicos/administração & dosagem , Morfolinos/administração & dosagem , Proteína Homeobox Nanog/antagonistas & inibidores , Paclitaxel/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Portadores de Fármacos/química , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Morfolinos/farmacocinética , Morfolinos/farmacologia , Proteína Homeobox Nanog/genética , Paclitaxel/farmacocinética , Paclitaxel/farmacologia
17.
ACS Appl Mater Interfaces ; 12(37): 41718-41727, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32830960

RESUMO

Halide perovskite (HP) materials are actively researched for resistive switching (RS) memory devices due to their current-voltage hysteresis along with low-temperature processability, superior charge mobility, and simple fabrication. In this study, all-inorganic RbPbI3 perovskite has been doped with Cl in the halide site and incorporated as a switching media in the Ag/RbPbI3-xClx/ITO structure, since pure RbPbI3 is nonswitchable. Five compositions of the RbPbI3-xClx (x = 0, 0.3, 0.6, 0.9, and 1.2) films are fabricated, and the conductivity was found to be increasing upon increase in Cl concentration, as revealed by dielectric and I-V measurements. The device with a 20% chloride-substituted film exhibits a higher on/off ratio, extended endurance, long retention, and high-density storage ability. Finally, a plausible explanation of the switching mechanism from iodine vacancy-mediated growth of conducting filaments (CFs) is provided using conductive atomic force microscopy (c-AFM). The c-AFM measurements reveal that pure RbPbI3 is insulating in nature, whereas Cl-doped films demonstrate resistive switching behavior.

18.
Free Radic Res ; 54(7): 477-496, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32842814

RESUMO

Smokeless tobacco (SLT) or chewing tobacco has been a highly addictive practice in India across ages, posing major threat to the systemic health and possibly neurodegeneration. Earlier studies showed components of SLT could be harmful to neuronal health. However, mechanism of SLT in neurodegeneration remained unexplored. This study investigated the detrimental role of SLT on differentiated neuronal cell lines, PC12 and SH-SY5Y by using graded doses of water soluble lyophilised SLT. Reduced cell viability, compromised mitochondrial structure and functions were observed when neuronal cell lines were treated with SLT (6 mg/mL) for 24 h. There was reduction of oxidative phosphorylation and aerobic glycolysis as determined by diminution of ATP production (2.5X) and basal respiration (1.9X). Mitochondrial membrane potential was dropped by 3.5 times. Bid, a pro-apoptotic Bcl-2 family protein, has imperative role in regulating mitochondrial outer membrane permeabilization and subsequent cytochrome c release leading to apoptosis. This article for the first time indicated the involvement of Bid in SLT mediated neurotoxicity and possibly neurodegeneration. SLT treatment enhanced expression of cleaved-Bid in time dependent manner. The involvement of Bid was further confirmed by using Bid specific shRNA which reversed the effects of SLT and conferred significant protection from apoptosis up to 72 h. Thus, our results clearly indicated that SLT induced neuronal cell death occurred via production of ROS, alteration of mitochondrial morphology, membrane potential and oxidative phosphorylation, inactivation of survival pathway and activation of apoptotic markers mediated by Bid. Therefore, Bid could be a potential future therapeutic target for SLT induced neurodegeneration.


Assuntos
Neurônios/patologia , Tabaco sem Fumaça/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Citocromos c/metabolismo , Dano ao DNA , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação Oxidativa , Células PC12 , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Proteína Supressora de Tumor p53/metabolismo
19.
Langmuir ; 36(22): 6178-6187, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32418427

RESUMO

Biocompatible, nonconventional, multifunctional, purely aliphatic, light-emitting terpolymers, i.e., acrylonitrile-co-3-(N-isopropylacrylamido)propanenitrile-co-N-isopropylacrylamide (AN-co-NIPAMPN-co-NIPA, 1) and acrylonitrile-co-3-(N-hydroxymethylacrylamido)propanenitrile-co-N-hydroxymethylacrylamide (AN-co-NHMAMPN-co-NHMA, 2), were designed and synthesized via N-H-functionalized C-C + N-C-coupled in situ protrusions/grafting of fluorophore monomers, i.e., NIPAMPN and NHMAMPN, by solution polymerization of two highly hydrophobic nonemissive monomers in water. These scalable and reusable 1 and 2 were suitable for high-performance three-in-one applications, such as Fe(III) sensors, imaging of Madin-Darby canine kidney (MDCK) and human lung cancer (A549) cells, and security inks. The structures of 1 and 2, N-C-coupled in situ attachments/grafting of third fluorophore monomers, grafting events, and aggregation-enhanced emissions (AEEs), were analyzed by 1H and 13C NMR spectroscopy, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR) spectroscopy, ultraviolet-visible (UV-vis) spectroscopy, thermogravimetric (TG) analysis, high-resolution transmission electron microscopy (HRTEM), dynamic light scattering (DLS), fluorescence imaging, and fluorescence lifetime. The geometries, electronic structures, and absorption/emission properties of 1 and 2 at optimized compositions were examined by density functional theory (DFT), time-dependent DFT (TDDFT), and natural transition orbital (NTO) analyses. The limits of detection were 3.20 × 10-7 and 1.37 × 10-7 M for 1 and 2, respectively. The excellent biocompatibility of 1 and 2 was confirmed by >95% retention of MDCK and A549 cell morphologies.

20.
Chemistry ; 26(2): 502-516, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31599070

RESUMO

To circumvent costly fluorescent labeling, five nonconventional, multifunctional, intrinsically fluorescent aliphatic terpolymers (1-5) have been synthesized by C-C/C-N-coupled, solution polymerization of two non-emissive monomers with protrusions of fluorophore monomers generated in situ. These scalable terpolymers were suitable for sensing and high-performance exclusion of CuII , logic function, and bioimaging. The structures of the terpolymers, in situ attachment of fluorescent monomers, aggregation-induced enhanced emission, bioimaging ability, and super adsorption were investigated by 1 H and 13 C NMR, EPR, FTIR, X-ray photoelectron, UV/Vis, and atomic absorption spectroscopy, thermogravimetric analysis, high-resolution transmission electron microscopy, dynamic light scattering, solid-state fluorescence, fluorescence imaging, and fluorescence lifetime measurements, as well as by isotherm, kinetics, and thermodynamic studies. The geometries and electronic structures of the fluorophores and the absorption and emission properties of the terpolymers were examined by DFT, time-dependent DFT, and natural transition orbital analyses. For 1, 2, and 5, the limits of detection were determined to be 1.03×10-7 , 1.65×10-7 , and 1.77×10-7 m, respectively, and the maximum adsorption capacities are 1575.21, 1433.70, and 1472.21 mg g-1 , respectively.

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