RESUMO
The present research comes up with a novel DNA-loaded poly-L-lysine (PLL)/hyaluronan (HA) nanocarrier (DNA-loaded PLL/HA NCs) for gene delivery applications, as a promising candidate for gene delivery into diverse cells. A straightforward approach was employed to prepare such a nanosystem through masking DNA-loaded PLL molecules by HA. Fourier-transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), field emission-scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM) were used to analyse the interaction of the molecules as well as the physicochemical properties of the NCs. The NCs showed a negative charge of -24 ± 3 mV, with an average size of 138 ± 6 nm, in an ellipsoid-shape with smooth surfaces. The DNA loading efficiency (LE) measured by DNA absorbance was around 95 %. The MTT assay showed that the developed NCs are non-toxic to the cells. Furthermore, the uptake of the DNA-loaded PLL/HA NCs by the human embryonic kidney (HEK)-293T cells was evaluated by a flow cytometry method, and demonstrated high potential cellular uptake over 90% for transferring the gene to HEK-293T cells at the optimised conditions. Therefore, the DNA-loaded PLL/HA NCs are the potent strategy for developing nanosystems for gene delivery applications.
Assuntos
Ácido Hialurônico , Polilisina , DNA/química , DNA/genética , Humanos , Ácido Hialurônico/química , Microscopia Eletrônica de Transmissão , Polilisina/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
A new series of imidazo[1,2-b]pyrazole derivatives 4a-o was designed, synthesized, and screened for in vitro α-glucosidase inhibitory activity. All compounds showed high inhibitory activity in the range of IC50 = 95.0 ± 0.5-372.8 ± 1.0 µM as compared to standard drug acarbose (IC50 = 750 ± 1.5 µM) and were also found to be non-cytotoxic. Among the synthesized compounds, the most potent compound was compound 4j with eightfold higher inhibitory activity compared to acarbose. Like acarbose, compound 4j inhibited α-glucosidase in a competitive mode. Molecular modeling studies of the most potent compounds 4j, 4f, 4o, and 4c were also conducted.
Assuntos
Técnicas de Química Sintética , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pirazóis/química , alfa-Glucosidases/química , Sítios de Ligação , Relação Dose-Resposta a Droga , Ativação Enzimática , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Cinética , Estrutura Molecular , Ligação Proteica , Pirazóis/síntese química , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
Twenty three fused carbazole-imidazoles 6a-w were designed, synthesized, and screened as new α-glucosidase inhibitors. All the synthesized fused carbazole-imidazoles 6a-w were found to be more active than acarbose (IC50â¯=â¯750.0⯱â¯1.5⯵M) against yeast α-glucosidase with IC50 values in the range of 74.0⯱â¯0.7-298.3⯱â¯0.9⯵M. Kinetic study of the most potent compound 6v demonstrated that this compound is a competitive inhibitor for α-glucosidase (Ki valueâ¯=â¯75⯵M). Furthermore, the in silico studies of the most potent compounds 6v and 6o confirmed that these compounds interacted with the key residues in the active site of α-glucosidase.
Assuntos
Carbazóis/química , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Imidazóis/química , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Técnicas In Vitro , Cinética , Conformação Proteica , Saccharomyces cerevisiae/enzimologia , alfa-Glucosidases/químicaRESUMO
An efficient, one-pot and four-component synthesis of a new series of 2,3-disubstituted isoindolin-1-ones is described and their Jack bean urease inhibitory activities are evaluated. Heating a mixture of 1,1-bis(methylthio)-2-nitroethene, a 1,2-diamine, a 2-formylbenzoic acid and a primary amine in EtOH for 3.5â¯h afforded the corresponding 2,3-disubstituted isoindolin-1-ones in good to excellent yields. All sixteen synthesized isoindolin-1-one derivatives 5a-p showed urease inhibitory activity. Among them, 5c showed the most urease inhibitory activity (IC50â¯=â¯10.07⯱â¯0.28⯵M) being over 2-fold more potent than thiourea (IC50â¯=â¯22.01⯱â¯0.10⯵M) and 10-fold than hydroxyurea (IC50â¯=â¯100.00⯱â¯0.02⯵M) as the standard inhibitors, respectively. Also, results from molecular docking studies were in good agreement with those obtained from in vitro tests.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Ftalimidas/farmacologia , Urease/antagonistas & inibidores , Canavalia/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Ftalimidas/síntese química , Ftalimidas/química , Relação Estrutura-Atividade , Urease/metabolismoRESUMO
Humans have a complicated symbiotic relationship with their gut microbiome, which is postulated to impact host health and disease broadly. Epigenetic alterations allow host cells to regulate gene expression without altering the DNA sequence. The gut microbiome, offering environmental hints, can influence responses to stimuli by host cells with modifications on their epigenome and gene expression. Recent increasing data suggest that regulatory non-coding RNAs (miRNAs, circular RNAs, and long lncRNA) may affect host-microbe interactions. These RNAs have been suggested as potential host response biomarkers in microbiome-associated disorders, including diabetes and cancer. This article reviews the current understanding of the interplay between gut microbiota and non-coding RNA, including lncRNA, miRNA, and circular RNA. This can lead to a profound understanding of human disease and influence therapy. Furthermore, microbiome engineering as a mainstream strategy for improving human health has been discussed and confirms the hypothesis about a direct cross-talk between microbiome composition and non-coding RNA.
Assuntos
Microbioma Gastrointestinal , MicroRNAs , Microbiota , RNA Longo não Codificante , Humanos , Microbioma Gastrointestinal/genética , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: X-linked mental retardation-hypotonic facies syndrome-1 (MRXFH1), caused by a mutation in the ATRX gene, is a rare syndromic form of X-linked mental retardation (XLMR) that is mainly characterized by severe intellectual disability, dysmorphic facies, and skewed X-inactivation pattern in carrier women. METHOD: In this study, due to the genetic heterogeneity of the disease, we performed exome sequencing (ES) on a 15-year-old boy with primary microcephaly and intellectual disability. Also, Sanger sequencing, cosegregation analysis, and structural modeling were done to identify and verify the causative variant in the proband and other affected individuals in the family. In addition, we collected data from previously reported cases to compare with our patients' phenotypes. RESULTS: ES revealed a previously reported missense variant in the ATRX gene (c.5182G > C, p.Ala1728Pro), segregating with the new clinical characteristic including primary microcephaly in the pedigree. This variant meets the criteria of being likely pathogenic based on the ACMG variant interpretation guideline. CONCLUSIONS: The findings of this study extend the spectrum of phenotypes associated with the identified variant and provide further details on its clinical features.
Assuntos
Deficiência Intelectual , Deficiência Intelectual Ligada ao Cromossomo X , Microcefalia , Surdez , Exoma , Feminino , Transtornos do Crescimento , Humanos , Hipogonadismo , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Microcefalia/genética , Mutação , Proteína Nuclear Ligada ao X/genéticaRESUMO
In an attempt to find novel α-glucosidase inhibitors, an efficient, straightforward reaction to synthesize a library of fully substituted 6-amino-pyrazolo[1,5-a]pyrimidines 3 has been investigated. Heating a mixture of α-azidochalcones 1 and 3-aminopyrazoles 2 under the mild condition afforded desired compounds with a large substrate scope in good to excellent yields. All obtained products were evaluated as α-glucosidase inhibitors and exhibited excellent potency with IC50 values ranging from 15.2 ± 0.4 µM to 201.3 ± 4.2 µM. Among them, compound 3d was around 50-fold more potent than acarbose (IC50 = 750.0 ± 1.5 µM) as standard inhibitor. Regarding product structures, kinetic study and molecular docking were carried out for two of the most potent ones.
Assuntos
Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Linhagem Celular Tumoral , Inibidores de Glicosídeo Hidrolases/síntese química , Humanos , Simulação de Acoplamento Molecular , Pirazóis/síntese química , Piridinas/síntese química , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/metabolismo , alfa-Glucosidases/metabolismoRESUMO
A facile sonochemical route for the synthesis of benzo[1,3]thiazine derivatives via a one pot, multicomponent, intramolecular CH activation reaction from isocyanides, aniline and benzoyl (acetyl) isothiocyanate adduct catalyzed by copper (I) iodide in acetone at 30⯰C have been reported. The advantages of the described method include using simple and readily available starting materials and performing under mild copper-catalytic reaction conditions and also obtaining pure product with high yield without applying column chromatography. Furthermore, using the sonochemical methodology as an efficient method led to reduce the reaction times.
RESUMO
A new series of 6-amino-pyrido[2,3-d]pyrimidine-2,4-dione derivatives 3a-3s were prepared via a facile and efficient reaction from α-azidochalcones and 6-amiouracils. The reactions were performed under mild conditions to produce the corresponding compounds in good to excellent yields. Obtained derivatives 3a-3s were evaluated for α-glucosidase inhibitory activity and all of them exhibited excellent in vitro yeast α-glucosidase inhibition with IC50 values ranging from 78.0⯱â¯2.0 to 252.4⯱â¯1.0⯵M. For example, the most active compound 3o was around 10-fold more potent than acarbose, a standard drug (IC50â¯=â¯750.0⯱â¯1.5⯵M). Kinetic study of compound 3o revealed that it inhibited α-glucosidase in a competitive mode. Molecular modeling studies of the most active compounds 3o, 3i, 3e and 3m were also performed.