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1.
J Mater Chem B ; 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34784408

RESUMO

Efficient antibacterial therapy holds great promise for human health. However, it is often limited by the insufficient activity of antibacterial agents. Herein, we demonstrate that the localized surface plasmon resonance (LSPR) excitation of gold nanostars (AuNSs) can dramatically improve the antibacterial activity of a Zn-metal-organic frameworks (Zn-MOFs) nanosheet, which exhibits higher ability to generate reactive oxygen species (ROS) (∼2.5-fold) for bacterial inactivation under light irradiation. Mechanistic investigations demonstrate that the enhancement is closely related to a plasmon-induced "dual excited synergistic effect". On the one hand, the Zn-MOFs nanosheets as photosensitive agents can be excited to generate ROS with bacterial toxicity. More importantly, abundant plasmonic hot electrons are generated on the surface of AuNSs upon LSPR excitation, which are then transferred from AuNSs into the Zn-MOFs due to the energy matching. As a result, the Zn-MOFs nanosheet presents an electron-rich condition, which activates the adsorbed O2 molecule into a transition state followed by its decomposition into ROS for bacterial inactivation. This study highlights the superiority of LSPR excitation on improving the antibacterial activity of MOFs and provides a novel strategy for effective antibacterial therapy.

2.
PLoS One ; 16(11): e0259436, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34735495

RESUMO

Diabetic nephropathy is one of the common microvascular complications of diabetes. Iron death is a recently reported way of cell death. To explore the effects of iron death on diabetic nephropathy, iron death score of diabetic nephropathy was analyzed based on the network and pathway levels. Furthermore, markers related to iron death were screened. Using RNA-seq data of diabetic nephropathy, samples were clustered uniformly and the disease was classified. Differentially expressed gene analysis was conducted on the typed disease samples, and the WGCNA algorithm was used to obtain key modules. String database was used to perform protein interaction analysis on key module genes for the selection of Hub genes. Moreover, principal component analysis method was applied to get transcription factors and non-coding genes, which interact with the Hub gene. All samples can be divided into two categories and principal component analysis shows that the two categories are significantly different. Hub genes (FPR3, C3AR1, CD14, ITGB2, RAC2 and ITGAM) related to iron death in diabetic nephropathy were obtained through gene expression differential analysis between different subtypes. Non-coding genes that interact with Hub genes, including hsa-miR-572, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-208a-3p, hsa-miR-153-3p and hsa-miR-29c-3p, may be related to diabetic nephropathy. Transcription factors HIF1α, KLF4, KLF5, RUNX1, SP1, VDR and WT1 may be related to diabetic nephropathy. The above factors and Hub genes are collectively involved in the occurrence and development of diabetic nephropathy, which can be further studied in the future. Moreover, these factors and genes may be potential target for therapeutic drugs.

3.
BMC Dev Biol ; 21(1): 15, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34715791

RESUMO

BACKGROUND: Tetraploid cotton plants serve as prime natural fiber source for the textile industry. Although various omics studies have revealed molecular basis for fiber development, a better understanding of transcriptional regulation mechanism regulating lint fiber initiation is necessary to meet global natural fiber demand. RESULTS: Here, we aimed to perform transcriptome sequencing to identify DEGs (differentially expressed genes) in ovules of the cotton variety Xu142 and its fibreless mutant Xu142fl during early lint fiber initiation period. Totally, 5516 DEGs including 1840 upregulated and 3676 downregulated were identified. GO enrichment analysis revealed that the downregulated DEGs were mainly associated with biological processes such as transcription related biosynthesis and metabolism, organic cyclic compound biosynthesis and metabolism, photosynthesis, and plant cell wall organization, with molecular functions involving transcription related binding, organic cyclic compound binding, and dioxygenase activity, while the upregulated DEGs were associated with DNA replication and phospholipid biosynthetic related processes. Among the 490 DEGs annotated as transcription factor genes, 86.5% were downregulated in the mutant including the Malvaceae-specific MMLs, expression patterns of which were confirmed during the central period of lint fiber initiation. Investigation of the 16 genes enriched in the cell wall organization revealed that 15 were EXPA coding genes. CONCLUSIONS: Overall, our data indicate that lint fiber initiation is a complicated process involving cooperation of multiple transcription factor families, which might ultimately lead to the reorganization of the cell wall and terminated cell division of the differentiating fiber initials.

4.
Anal Bioanal Chem ; 413(28): 6951-6962, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34676432

RESUMO

Epithelial-mesenchymal transition (EMT) is implicated in the pathological processes of cancer metastasis and drug resistance. Anti-cancer drugs may also potentially lead to EMT, resulting in their reduced therapeutic effect. Therefore, the combination of these anti-cancer drugs with anti-EMT agents has been promoted in clinic. Screening anti-EMT drugs and evaluation of EMT process are highly dependent on EMT biomarkers on cell membrane. At present, the detection of EMT biomarker is mainly by Western blot method, which is time-consuming and complicated. In this work, for effectively screening anti-EMT drugs by evaluation of the EMT process, a type of aptamer probe based on aggregation-induced emission (AIE) was designed. The aptamer SYL3C was employed to target the EMT biomarker EpCAM on cell membrane. Two fluorophores, FAM and tetraphenylethene (TPE, an AIE dye), were modified at the two ends of SYL3C, respectively. This aptamer probe (TPE-SYL3C-FAM) can monitor the EpCAM expression, which can be recovered by anti-EMT drugs. By observation of the change in TPE emission intensity, the anti-EMT effect of drugs can be evaluated. The FAM emission was used as internal reference to reduce environmental interferences. This probe can be potentially used to screen anti-EMT agents as anti-cancer adjuvant drugs with high throughput.

5.
Fundam Clin Pharmacol ; 35(6): 1032-1044, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34545633

RESUMO

Epilepsy, which is caused by abnormal neuronal firing in the brain, is a common neurological disease and affects motor and cognitive functions. Excessive levels of glutamate and insufficient levels of inhibitory GABA are involved in its pathophysiology. Valproic acid (Val), a GABAergic agonist, is one of the first-line antiepileptic drugs, but it shows many adverse side effects at the clinical dose. Clavulanic acid (CA), a ß-lactamase inhibitor, has been demonstrated to increase glutamate transporter-1 expression. This study evaluated the effects of CA and Val in an epilepsy rat model. Male Wistar rats received intraperitoneal injections of pentylenetetrazol (PTZ, 35 mg/kg, every other day, IP, for 13 days) to induce kindling epilepsy. After four times of PTZ injection, rats received daily treatment with CA (1 or 10 mg/kg, IP), Val (50 or 100 mg/kg, IP), or the combination of CA (1 mg/kg) and Val (50 mg/kg) for 7 consecutive days. Motor, learning, and memory functions were measured. Rats with PTZ-induced kindling exhibited seizures, motor dysfunction, cognitive impairment, and cell loss and reduction of neurogenesis in the hippocampus. Neither 1 mg/kg CA nor 50 mg/kg Val treatment was effective in alleviating behavioral and neuronal deficits. However, treatment with 10 mg/kg CA, 100 mg/kg Val, and the combination of 1 mg/kg CA and 50 mg/kg Val improved these behavioral and neuronal deficits. Particularly, the combination of CA and Val showed synergistic effects on seizure suppression, suggesting the potential for treating epilepsy and related neuronal damage and motor and cognitive deficits.

6.
Bioorg Chem ; 115: 105241, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34426157

RESUMO

Cellular autophagy is an intracellular degradation pathway, which transports damaged, deformed, senescent or non-functional proteins and organelles to lysosome for digestion and degradation. Cellular autophagy is deeply evolutionarily conservedfromyeasttomammaliancells, and many homologous proteins of the autophahgy regulators are found in several species. This physiological process maintains the steady state of cells. Furtheremore, autophagy dysfunction is closely related to various diseases, such as neurodegenerative diseases, inflammation-related diseases, cardiovascular diseases, metabolic diseases, etc. The LC3 and p62 protein protein interaction (PPI) promotes the formation of autophagosomes and delivers polyubiquitinated "cargoes" to autophagic degradation. Therefore, LC3-p62 PPI plays an integral role in the formation of autophagosomes and effectively inhibits autophagy. However, there are still few studies on the LC3-p62 PPI inhibitors for its unclear molecular mechanism. Furthermore, most of these inhibitors are macromolecules with poorly active, and small molecules are particularly scarce. In this article, the computation method was used to identify the hot spot and design peptides as the binder of LC3-p62 PPI. Findings from this work provide a reference for the follow-up research of discovering small molecule inhibitors targeting LC3-p62 PPI.

7.
Australas J Dermatol ; 62(4): e524-e531, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34426977

RESUMO

BACKGROUND/OBJECTIVES: Increased rates of histopathological misdiagnosis of melanoma have been associated with incisional punch more so than shave biopsy when compared with complete excisional biopsy. It is unknown how the increasing utilisation of shave biopsy may impact melanoma diagnosis. The extent to which the provision of clinical information to the pathologist may improve diagnostic accuracy remains unclear. This study assessed the impact of both initial biopsy technique and provision of adequate clinical information to pathologists on the accuracy of histopathological diagnosis of melanoma and disease progression. METHODS: We conducted a retrospective cohort with nested case-control study of all histopathological false-negative and false-positive melanoma diagnoses from January 2014 to May 2019 from the Victorian Melanoma Service electronic database. Cases were assessed for the initial biopsy type, provision of clinical information on pathology request forms and disease progression associated with false-negative diagnosis. RESULTS: Partial shave biopsy had higher odds of false-negative (OR 5.19, 95% CI 2.89-9.32; P < 0.001) and false-positive diagnoses (OR 1.95, 95% CI 1.45-2.63; P < 0.001) of melanoma when compared with elliptical excisional biopsy. These odds ratios were comparable with those found with incisional punch biopsy. Providing the suspected clinical diagnosis to pathologists also reduced the odds of false-negative diagnosis with melanoma progression by 3.8-fold (P = 0.02). CONCLUSION: The choice of initial biopsy technique and providing the suspected clinical diagnosis to pathologists are important for correct histopathological diagnosis of cutaneous melanoma and prevention of further disease progression.

8.
Eur J Med Chem ; 223: 113663, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198150

RESUMO

Acetylcholinesterase (AChE) inhibitors are currently the first-line drugs approved by the FDA for the treatment of Alzheimer's disease (AD). However, a short effective-window limits their therapeutic benefits. Clinical studies have confirmed that the combination of AChE inhibitors and neuroprotective agents exhibits better anti-AD effects. We have previously reported that the dual AChE/GSK3ß (Glycogen synthase kinase 3ß) modulators have both neuroprotective effects and cognitive impairment-improvement effects. In this study, we characterized a new backbone of the AChE/GSK3ß inhibitor 11c. It was identified as a highly potent AChE inhibitor and was found superior to donepezil, the first-line drug for the treatment of AD. In vivo studies confirmed that 11c significantly inhibited the activity of AChE in the brain but had little effect on the activity of AChE in the intestine. This advantage of 11c was expected to reduce the peripheral side effects caused by donepezil. Furthermore, biomarker studies have shown that 11c also improved the levels of acetylcholine and synaptophysin in the brain and exhibited neuroprotective effects. Preliminary in vivo and in vitro research results underline the exciting potential of compound 11c in the treatment of AD.


Assuntos
Acetilcolina/metabolismo , Acetilcolinesterase/química , Encéfalo/metabolismo , Inibidores da Colinesterase/química , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Niacinamida/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Intestinos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Niacinamida/metabolismo , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
9.
Mol Inform ; 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34323388

RESUMO

Glycogen synthase kinase 3 beta (GSK-3ß) is considered as a promising drug target for the treatment of Alzheimer's disease (AD). In the present study, two compound libraries were selected for virtual screening based on pharmacophore models of GSK-3ß to discover new inhibitors. Nine potential hits were retained for biological investigation and four of these compounds showed GSK-3ß inhibitory activity (with the IC50 values in sub-micromolar range on GSK-3ß). Compounds 6 and 9 have good safety. They do not have any significant in vitro cytotoxicity against PC12 and SH-SY5Y neuroblastoma cells at concentrations up to 90 µM. Based on the inhibitory activity and druggability properties, compound 8 is the preferred molecule, and it is a promising lead for the development of the GSK-3ß inhibitors for reducing the abnormal hyperphosphorylation of tau protein and relieving AD.

10.
Eur J Pharmacol ; 908: 174354, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34284013

RESUMO

Forsythiaside B is the major ingredient of Callicarpa kwangtungensis Chun, and has been proven to protect myocardium from ischemia-reperfusion injury to achieve myocardial protection. However, the effect of forsythiaside B on adverse myocardial fibrosis remains unclear. In the present study, the myocardial fibrosis animal models were established induced by isoproterenol (ISO) to investigate whether forsythiaside B exhibited antifibrotic actions. Forsythiaside B was found to significantly improve the cardiac ejection fraction and fractional shortening rate of myocardial fibrosis mice compared with the normal saline group. In addition, forsythiaside B could lower the level of TGF-ß1, the expression of α-SMA and collagen III. Forsythiaside B down-regulated the expression of Smad4 and the phosphorylation level of Smad3, which indicates that forsythiaside B could suppress myocardial fibrosis by inhibiting the TGF-ß1/Smad signaling pathway. These results demonstrated that forsythiaside B could prevent myocardial fibrosis in ISO-induced mice, and may be a potentially rational therapeutic approach for the treatment of myocardial fibrosis.

11.
Appl Microbiol Biotechnol ; 105(13): 5607-5616, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34228183

RESUMO

Nitrosamine compounds, represented by N-nitrosodimethylamine, are regarded as potentially genotoxic impurities (PGIs) due to their hazard warning structure, which has attracted great attention of pharmaceutical companies and regulatory authorities. At present, great research gaps exist in genotoxicity assessment and carcinogenicity comparison of nitrosamine compounds. In this work, a collection of GFP-fused yeast cells representing DNA damage repair pathways were used to evaluate the genotoxicity of eight nitrosamine compounds (10-6-105 µg/mL). The high-resolution expression profiles of GFP-fused protein revealed the details of the DNA damage repair of nitrosamines. Studies have shown that nitrosamine compounds can cause extensive DNA damage and activate multiple repair pathways. The evaluation criteria based on the total expression level of protein show a good correlation with the mammalian carcinogenicity data TD50, and the yeast cell collection can be used as a potential reliable criterion for evaluating the carcinogenicity of compounds. The assay based on DNA damage pathway integration has high sensitivity and can be used as a supplementary method for the evaluation of trace PGIs in actual production. KEY POINTS: • The genotoxicity mechanism of nitrosamines was systematically studied. • The influence of compound structure on the efficacy of genotoxicity was explored. • GFP-fused yeast cells have the potential to evaluate impurities in production.


Assuntos
Técnicas Biossensoriais , Nitrosaminas , Animais , Dano ao DNA , Mutagênicos/toxicidade , Nitrosaminas/toxicidade , Saccharomyces cerevisiae/genética
12.
Food Funct ; 12(18): 8248-8259, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34319319

RESUMO

Diabetes mellitus (DM), characterized by abnormal carbohydrate, lipid, and protein metabolism, is a metabolic disorder caused by a shortage of insulin secretion or decreased sensitivity of target cells to insulin. In addition to changes in lifestyle, a low-calorie diet is recommended to reduce the development of DM. Steviol glycosides (SGs), as natural sweeteners, have gained attention as sucrose alternatives because of their advantages of high sweetness and being low calorie. Most SGs with multiple bioactivities are beneficial to regulate physiological functions. Though SGs have been widely applied in food industry, there is little data on their glucosylated derivatives that are glucosylated steviol glycosides (GSGs). In this review, we have discussed the metabolic fate of GSGs in contrast to SGs, and the molecular mechanisms of glycoside metabolites against diabetes-related metabolic disorders are also summarized. SGs are generally extracted from the Stevia leaf, while GSGs are mainly manufactured using enzymes that transfer glucose units from a starch source to SGs. Results from this study suggest that SGs and GSGs share same bioactive metabolites, steviol and steviol glucuronide (SVG), which exhibit anti-hyperglycemic effects by activating glucose-induced insulin secretion to enhance pancreatic ß-cell function. In addition, steviol and SVG have been found to ameliorate the inflammatory response, lipid imbalance, myocardial fibrosis and renal functions to modulate diabetes-related metabolic disorders. Therefore, both SGs and GSGs may be used as potential sucrose alternatives and/or pharmacological alternatives for preventing and treating metabolic disorders.

13.
Neurochem Res ; 46(9): 2439-2450, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34170454

RESUMO

Extensive studies have shown that oxidative stress is a crucial pathogenic factor in Alzheimer's disease (AD). Nuclear factor E2-related factor 2 (Nrf2) is a master cytoprotective regulator against oxidative stress, and thus represents an attractive therapeutic target in AD. The goal of our study is to investigate the contribution of Nrf2 in Rhynchophylline (Rhy)-induced neuroprotection in AD. The data showed that intraperitoneal administration of Rhy (10 or 20 mg/kg) could ameliorate Aß1-42-induced cognitive impairment, evidenced by performance improvement in memory tests. The result of Antioxidant response element (ARE)-luciferase activity assay indicated that Rhy treatment improved ARE promoter activity. The results of reactive oxygen species (ROS), malondialdehyde (MDA) and glutathione (GSH) assessment in the frontal cortex and hippocampus showed that Rhy treatment could attenuate Aß1-42-induced oxidative stress to some extent, evidenced by reversion of these cytokines compared to Aß1-42 + Veh group. Rhy treatment also restored expression of Nrf2 and its downstream protein heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (NOQ1), and recombinant glutamate cysteine ligase, modifier subunit (GCLM) in the frontal cortex and hippocampus of Aß1-42-treated mice. In addition, to investigate whether activation of Nrf2-mediated pathway is responsible for the neuroprotection of Rhy, Nrf2 siRNA was used in human neuroblastoma cells (SH-SY5Y). Interestingly, the results showed that the protective effects of Rhy, including anti-oxidative, anti-apoptosis and elevation of Nrf2 and its downstream proteins, were abolished in Nrf2 siRNA-transfected cells. These findings indicate that Rhynchophylline is protective against Aß1-42-induced neurotoxicity via Nrf2-ARE activation, and suggest that Rhy may serve as a potential candidate and promising Nrf2 activator for management of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Memória/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Oxindóis/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Camundongos Endogâmicos ICR , Fragmentos de Peptídeos
14.
J Ethnopharmacol ; 278: 114334, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34126213

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Jiao Sanxian, a customary term for the three Traditional Chinese Medicines of charred hawthorn (Crataegi Fructus), charred malt (Hordei Fructus Germinatus) and Liu Shenqu (Massa Medicata Fermentata), is a classic prescription for the treatment of functional dyspepsia (FD). This prescription is called "Jiao Sanxian" in China because people believe that it is a miracle medicine for enhancing digestion and improving stagnation of digestive system. Even though Jiao Sanxian is widely used in clinical treatment, the underlying mechanism has not been clarified to date. AIM OF THE STUDY: The present study is aimed to explore the efficacy and mechanism of Jiao Sanxian in improving the symptoms of FD in rats by using multiple pharmacological methods. MATERIALS AND METHODS: The Sprague Dawley (SD) rats were divided into control, model, Jiao Sanxian decoction low-dosage (JSXD LD), Jiao Sanxian decoction medium-dosage (JSXD MD), and Jiao Sanxian decoction high-dosage (JSXD HD) group at random. A FD model was established with reserpine, and animals were given intragastric administration. During this period, weight and food intake of animals were recorded. Samples of rat gastric antrum, spleen, and duodenum were collected for pathological staining and immunohistochemical determination of Ghrelin protein expression after 19 days of treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of related brain gut peptides in serum. Moreover, 16S rRNA sequencing was used to valuate the influence of intestinal flora structure of the cecal contents of experimental rats. And plasma metabolomics by Ultra Performance Liquid Chromatography coupled with Quadrupole-Time-of-Flight mass spectrometry (UPLC-Q/TOF-MS) were performed to further reveal the mechanism of action. RESULTS: Jiao Sanxian decoction (JSXD) group with different dosage could increase body weight and food intake, improve histopathological changes, and alter disordered brain gut peptides in FD rats. 16S rRNA sequencing results described that JSXD improved the disorder of structural composition, biodiversity and function of gut microbiota in FD rats. Metabolomics illustrated 26 metabolites with JSXD treatment underwent continuous changes, which revealed JSXD might exert digestive effect by ameliorating abnormal metabolic pathways. The most relevant metabolic pathways were arachidonic acid metabolism, pyruvate metabolism, glycerophospholipid metabolism, alanine, aspartate and glutamate metabolism. CONCLUSIONS: JSXD can improve functional dyspepsia in rats and the mechanism is related to regulate secretion of brain gut peptides, significantly improve the disorder of intestinal flora and ameliorated multi-metabolic pathways.

15.
J Nat Prod ; 84(7): 1889-1897, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34156846

RESUMO

Chemotherapy resistance is one of the main causes of lung cancer treatment failure, and a combination regimen may be an effective way to overcome this. Here we report 5 new (1-3, 7, and 9) and 15 known polyketides, isolated from an endozoic Aspergillus niger. The structures of the new compounds were determined by the interpretation of IR, HRESIMS, NMR, and ECD spectra. The ESI-MS/MS fragmentation of the isolated naphtho-γ-pyrone isomers in positive mode is discussed. The effects of isolated compounds in combination with cisplatin (DDP) on a DDP-resistant A549 cell line (A459/DDP) are investigated. The most active compound, 12, could reduce the ratio of GSH/GSSG, promote the generation of intracellular ROS, and cooperate with DDP to down-regulated levels of Nrf2, Akt, HO-1, and NQO1, suggesting that inhibition of Nrf2 and Akt pathways might be involved in the combined effect of 12 and DDP in A549/DDP cells.

16.
Exp Physiol ; 106(8): 1814-1828, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34086374

RESUMO

NEW FINDINGS: What is the central question of this study? Imbalance of activities between GABAergic and glutamatergic systems is involved in epilepsy. It is not known whether simultaneously increasing GABAergic and decreasing glutamatergic activity using valproic acid and ceftriaxone, respectively, leads to better seizure control. What is the central question of this study? Ceftriaxone suppressed seizure and cognitive deficits and restored neuronal density and the number of newborn cells in the hippocampus in a rat model of epilepsy. Combined treatment with ceftriaxone and valproic acid showed additive effects in seizure suppression. ABSTRACT: The pathophysiology of epilepsy is typically considered as an imbalance between inhibitory GABA and excitatory glutamate neurotransmission. Valproic acid (Val), a GABA agonist, is one of the first-line antiepileptic drugs in the treatment of epilepsy, but it exhibits adverse effects. Ceftriaxone (CEF) elevates expression of glutamate transporter-1, enhances the reuptake of synaptic glutamate, increases the number of newborn cells and exhibits neuroprotective effects in animal studies. In this study, we evaluated effects of the combination of CEF and Val on behavioural and neuronal measures in a rat epilepsy model. Male Wistar rats were injected i.p. with pentylenetetrazol (35 mg/kg, every other day for 13 days) to induce the epilepsy model. Ceftriaxone (10 or 50 mg/kg), Val (50 or 100 mg/kg) or the combination of CEF and Val were injected daily after the fourth pentylenetetrazol injection for seven consecutive days. Epileptic rats exhibited seizure and impairments in motor and cognitive functions. Treatment with CEF and Val reduced the seizure and enhanced motor and cognitive functions in a dose-dependent manner. The combination of CEF (10 mg/kg) and Val (50 mg/kg) improved behaviours considerably. Histologically, compared with control animals, epileptic rats exhibited lower neuronal density and a reduction in hippocampal newborn cells but higher apoptosis in the basolateral amygdala, all of which were restored by the treatment with CEF, Val or the combination of CEF and Val. The study findings demonstrated that the combination of low doses of CEF and Val has beneficial effects on seizure suppression, neuroprotection and improvement in motor and cognitive functions in epilepsy.

17.
Future Med Chem ; 13(13): 1105-1125, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33960203

RESUMO

Background: Alzheimer's disease is a multifactorial neurological disorder seen in elderly people. Loss of cholinergic transmission and unbalanced tryptophan metabolism kynurenine pathway have been demonstrated in neuropsychiatric diseases. Methods & results: Among the two series of synthesized compounds, compounds 5c and 5h were identified as effective dual BChE/IDO1 inhibitors, with well-balanced micromolar activity. Compounds 5c and 5h exhibited promising ability to ameliorate behavioral impairment by Morris water maze. The safety of miconazole analogs was also validated by PC12 and SH-SY5Y cell lines. Conclusion: These results highlight the ability of 5c and 5h to treat Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Miconazol/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Humanos , Masculino , Camundongos , Miconazol/síntese química , Miconazol/química , Modelos Moleculares , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos
18.
J Med Chem ; 64(10): 6856-6876, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33973470

RESUMO

Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aß deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aß1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/química , Peptídeos beta-Amiloides/farmacologia , Animais , Sítios de Ligação , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Desenho de Fármacos , Grelina/metabolismo , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
19.
ACS Appl Mater Interfaces ; 13(21): 25143-25152, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34019365

RESUMO

Dielectric energy storage materials are becoming increasingly popular due to their potential superiority, for example, excellent pulse performance as well as good fatigue resistance. Although numerous studies have focused on lead-free dielectric materials which possess outstanding energy storage characteristics, the results are still not satisfying in terms of achieving both large discharging energy density (Wd) and high discharging efficiency (η) under low electric fields, which is crucial to be conducted in miniatured electronic components. Here, we adopt the strategy of domain engineering to develop sodium bismuth titanate (Bi0.5Na0.5TiO3)-based ceramics employed in the low-field situation. Remarkably, a large Wd of 2.86 J/cm3 and an ultrahigh η of 90.3% are concurrently obtained in 0.94(Bi0.5Na0.5)0.65(Ba0.3Sr0.7)0.35TiO3-0.06 Bi(Zn2/3Nb1/3)O3 system when the electric field is as low as 180 kV/cm. Additionally, the ceramic shows brilliant thermal endurance (20-160 °C) and frequency stability (0.1-100 Hz) with high Wd (>1.48 J/cm3) together with an ultra-high η (>90%). What's more, the ceramic displays a fast charge-discharge time (t0.9 = 109.2 ns). The piezoresponse force microscopy (PFM) results reveal that the introduced Bi(Zn2/3Nb1/3)O3 disrupts the microdomains of (Bi0.5Na0.5)0.65(Ba0.3Sr0.7)0.35TiO3 ceramics and promotes the formation of nanodomains, leading to enhanced energy storage properties. The current work may arouse interest in developing low-field high-performing dielectric capacitors for energy storage application.

20.
Biomater Sci ; 9(10): 3621-3637, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34008587

RESUMO

Short half-life is one of the main causes of drug attrition in clinical development, which also leads to the failure of many leading compounds and hits to become drug candidates. Nowadays, nanomaterials have been applied to drug development to address this problem. In fact, the clinical application of nanoparticles (NPs) is severely limited due to their rapid elimination by the reticuloendothelial system (RES) in vivo. In this paper, we aim to summarize representative strategies on prolonging the circulation time for bridging the gap between excellent pharmaceutics and proper half-life and encourage clinical translation.


Assuntos
Nanopartículas , Meia-Vida
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