RESUMO
Neuropathic pain arises from impairments or malfunctions within the nervous system, resulting in atypical transmission and interpretation of pain signals. In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM-NLCs, which were administered at 20 mg/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)-1ß and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase-1 (HO-1) and nuclear factor E2-related factor (Nrf2). Treatment with AGM and AGM-NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM-NLCs, all-trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO-1 expressions were significantly upregulated after AGM-NLCs administration. Overall, the results demonstrated that AGM-NLCs offer promising antinociceptive and anti-inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone.
Assuntos
Acetamidas , Portadores de Fármacos , Lipídeos , Fator 2 Relacionado a NF-E2 , Nanoestruturas , Neuralgia , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Acetamidas/farmacologia , Acetamidas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Nanoestruturas/química , Portadores de Fármacos/química , Hiperalgesia/tratamento farmacológico , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , NaftalenosRESUMO
Bupleurum marginatum Wall.ex DC [Apiaceae] (BM)is widely grown in southwestern China, and the whole plant is used as Traditional Chinese Medicine (TCM). Polysaccharides are main natural products in lots of TCM and have been studied for their effects of reducing oxidative stress, anti-inflammation and immune regulation. Herein, we investigated the extraction techniques of Bupleurum marginatum Wall.ex DC polysaccharides (BMP), the identification of their key components, and their ability to inhibit liver fibrosis in both cellular and animal models. Component identification indicated that monosaccharides in BMP mainly consisted of glucose, galactose, mannose, rhamnose, arabinose, and xylose. In vivo analysis revealed that BMP provided significant protective effects on N-Nitroso dimethylamine (NDMA)-induced liver fibrosis rats through reducing hepatomegaly, reducing tissue inflammation, and reducing collagen deposition. BMP also improved the hepatobiliary system and liver metabolism in accord to reduce the serum levels of ALT, AST, ALP, r-GT, and TBIL. In addition, BMP could reduce the level of inflammation and fibrosis through inhibition of IL-1ß and TGF-ß1. Cellular studies showed that the BMP could provide therapeutic effects on lipopolysaccharide (LPS)-induced cellular fibrosis model, and could reduce the level of inflammation and fibrosis by decreasing the level of TGF-ß1, IL-1ß, and TNF-α. Our study demonstrated that BMP may provide a new therapy strategy of liver injury and liver fibrosis.
RESUMO
A new triterpenoid saponin (1), along with five known compounds (2-6), was isolated from Bupleurum marginatum Wall. ex DC, of which compounds 2-4 were obtained for the first time from this plant. The structures were confirmed by the analysis of 1D, 2D NMR, and HR-ESIMS data, and comparison with previous spectral data. Anti-liver fibrotic activities of the isolates were determined as proliferation inhibition of LPS-induced activation of HSC-T6 in vitro.
Assuntos
Bupleurum , Saponinas , Triterpenos , Saponinas/farmacologia , Saponinas/química , Saponinas/isolamento & purificação , Bupleurum/química , Triterpenos/farmacologia , Triterpenos/química , Triterpenos/isolamento & purificação , Estrutura Molecular , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Cirrose Hepática/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Animais , Ressonância Magnética Nuclear BiomolecularRESUMO
CONTEXT: Alzheimer's disease (AD) is a chronic progressive neurodegenerative syndrome, which adversely disturbs cognitive abilities as well as intellectual processes and frequently occurs in the elderly. Inhibition of cholinesterase is a valuable approach to upsurge acetylcholine concentrations in the brain and persuades the development of multi-targeted ligands against cholinesterases. METHODS: The current study aims to determine the binding potential accompanied by antioxidant and anti-inflammatory activities of stilbenes-designed analogs against both cholinesterases (Acetylcholinesterase and butyrylcholinesterase) and neurotrophin targets for effective AD therapeutics. Docking results have shown that the WS6 compound exhibited the least binding energy - 10.1 kcal/mol with Acetylcholinesterase and - 7.8 kcal/mol with butyrylcholinesterase. The WS6 also showed a better binding potential with neurotrophin targets that are Brain-derived Neurotrophic Factor, Neurotrophin 4, Nerve Growth Factor, and Neurotrophin 3. The tested compounds particularly WS6 revealed significant antioxidant and anti-inflammatory activities through the comparative docking analysis with Fluorouracil and Melatonin as control drugs of antioxidants while Celecoxib and Anakinra as anti-inflammatory. The bioinformatics approaches including molecular docking calculations followed by the pharmacokinetics analysis and molecular dynamic simulations were accomplished to explore the capabilities of designed stilbenes as effective and potential leads. Root mean square deviation, root mean square fluctuations, and MM-GBSA calculations were performed through molecular dynamic simulations to extract the structural and residual variations and binding free energies through the 50-ns time scale.
Assuntos
Doença de Alzheimer , Butirilcolinesterase , Humanos , Idoso , Acetilcolinesterase , Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Simulação de Acoplamento MolecularRESUMO
PCR is indispensable in basic science and biotechnology for in-orbit life science research. However, manpower and resources are limited in space. To address the constraints of in-orbit PCR, we proposed an oscillatory-flow PCR technique based on biaxial centrifugation. Oscillatory-flow PCR remarkably reduces the power requirements of the PCR process and has a relatively high ramp rate. A microfluidic chip that could perform dispensing, volume correction, and oscillatory-flow PCR of four samples simultaneously using biaxial centrifugation was designed. An automatic biaxial centrifugation device was designed and assembled to validate the biaxial centrifugation oscillatory-flow PCR. Simulation analysis and experimental tests indicated that the device could perform fully automated PCR amplification of four samples in one hour, with a ramp rate of 4.4 ∘C/s and average power consumption of less than 30 W. The PCR results were consistent with those obtained using conventional PCR equipment. Air bubbles generated during amplification were removed by oscillation. The chip and device realized a low-power, miniaturized, and fast PCR method under microgravity conditions, indicating good space application prospects and potential for higher throughput and extension to qPCR.
Assuntos
Técnicas Analíticas Microfluídicas , Microfluídica , Reação em Cadeia da Polimerase/métodos , Centrifugação , Técnicas de Amplificação de Ácido Nucleico , Dispositivos Lab-On-A-ChipRESUMO
Mechanical force loading is essential for maintaining bone homeostasis, and unloading exposure can lead to bone loss. Osteoclasts are the only bone resorbing cells and play a crucial role in bone remodeling. The molecular mechanisms underlying mechanical stimulation-induced changes in osteoclast function remain to be fully elucidated. Our previous research found Ca2+-activated Cl- channel Anoctamin 1 (Ano1) was an essential regulator for osteoclast function. Here, we report that Ano1 mediates osteoclast responses to mechanical stimulation. In vitro, osteoclast activities are obviously affected by mechanical stress, which is accompanied by the changes of Ano1 levels, intracellular Cl- concentration and Ca2+ downstream signaling. Ano1 knockout or calcium binding mutants blunts the response of osteoclast to mechanical stimulation. In vivo, Ano1 knockout in osteoclast blunts loading induced osteoclast inhibition and unloading induced bone loss and. These results demonstrate that Ano1 plays an important role in mechanical stimulation induced osteoclast activity changes.
Assuntos
Canais de Cloreto , Osteoclastos , Anoctamina-1/genética , Anoctamina-1/metabolismo , Canais de Cloreto/genética , Osteoclastos/metabolismo , Transdução de Sinais/fisiologiaRESUMO
The continuous expansion of nucleic acid detection applications has resulted in constant developments in rapid, low-consumption, and highly automated nucleic acid extraction methods. Nucleic acid extraction using magnetic beads across an immiscible phase interface offers significant simplification and parallelization potential. The gas-liquid immiscible phase valve eliminates the requirement for complicated cassettes and is suitable for automation applications. By analyzing the process of magnetic beads crossing the gas-liquid interface, we utilized a low magnetic field strength to drive large magnetic bead packages to cross the gas-liquid interface, providing a solution of high magnetic bead recovery rate for solid-phase extraction with a low-surfactant system based on gas-liquid immiscible phase valve. The recovery rate of magnetic beads was further improved to 90%-95% and the carryover of the reagents was below 1%. Consequently, a chip and an automatic system were developed to verify the applicability of this method for nucleic acid extraction. The Hepatitis B virus serum standard was used for the extraction test. The extraction of four samples was performed within 7 minutes, with nucleic acid recovery maintained above 80% and good purity. Thus, through analysis and experiments, a fast, highly automated, and low-consumption nucleic acid recovery method was proposed in this study.
Assuntos
Ácidos Nucleicos , Ácidos Nucleicos/análise , Ácidos Nucleicos/isolamento & purificaçãoRESUMO
Two new triterpenoid saponins (1 and 2), together with two known saponins (3 and 4) were isolated from Bupleurum marginatum Wall. ex DC. Their structures were elucidated by the comprehensive spectroscopic analysis. Compounds 1 and 2 represented the rare example of an oleanane-type triterpenoid with two sugar moieties at C-3 and C-28. The cytotoxic activity of four compounds was evaluated against normal heptocell BRL-3A in vitro.
RESUMO
Advanced materials with high performance and distinctive function are one of the main driving forces for the development of human society. The selection of appropriate materials and adequately utilizing their features to apply them in a specific area rationally are of great significance but remain challenging. Herein, an aggregation-induced emission (AIE)-active nanocomposite (NC) hydrogel is developed by introducing a pH-responsive AIE luminogen (AIEgen) into a Laponite XLS/polyacrylamide-based NC hydrogel (Laponite is a trademark of the company BYK Additives Ltd.). The AIEgen can protonate to interact with the negatively charged clay through the electrostatic interaction, which results in a drastic fluorescence enhancement due to the restriction of intramolecular motion by the rigid clay to the protonated AIEgen. This behavior facilitates the input of fluorescent information with a high contrast ratio in the hydrogel by acid stimulation. Moreover, by utilizing the excellent resilience of the hydrogel, hierarchically inputting and displaying the information in the original and stretched states of the hydrogel film is realized, which achieves information-storage expansion and dual-encryption via switching between stretching and restoring the film. This work showcases fully and synergistically utilizing the superiorities of various advanced materials to achieve superior applications and should guide the future development of advanced materials in emerging areas.
RESUMO
[This corrects the article DOI: 10.1371/journal.pone.0247249.].
RESUMO
Mahonia bealei is one of the important members of the genus Mahonia and Traditional Chinese Medicine (TCM). Several compounds isolated from this plant have exhibited useful biological activities. Polysaccharides, an important biomacromolecule have been underexplored in case of M. bealei. In this study, hot water extraction and ethanol precipitation were used for the extraction of polysaccharides from the stem of M. bealei, and then extract was purified using ultrafiltration membrane at 50,000 Da cut off value. Characterization of the purified M. bealei polysaccharide (MBP) was performed using Fourier Transform Infrared Spectroscopy (FT-IR), along with Scanning Electron Microscopy (SEM), X-ray crystallography XRD analysis and Thermal gravimetric analysis (TGA). The purified polysaccharide MBP was tested for antioxidant potential by determining its reducing power, besides determining the DPPH, ABTS, superoxide radical, and hydroxyl radical scavenging along with ferrous ion chelating activities. An increased antioxidant activity of the polysaccharide was reported with increase in concentration (0.5 to 5 mg/ml) for all the parameters. Antimicrobial potential was determined against gram positive and gram-negative bacteria. 20 µg/ml MBP was found appropriate with 12 h incubation period against Escherichia coli and Bacillus subtilis bacteria. We conclude that polysaccharides from M. bealei possess potential ability of biological importance; however, more studies are required for elucidation of their structure and useful activities.
Assuntos
Berberis , Mahonia , Antioxidantes/química , Sequestradores de Radicais Livres , Mahonia/química , Polissacarídeos/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , ÁguaRESUMO
Liver fibrosis is a dynamic and highly integrated pathological process resulting from repeated liver injury healing accompanied by inflammation and extracellular matrix deposition. Treatment is necessary at the early stage of reversible liver fibrosis to prevent further deterioration to liver cirrhosis and liver cancer. Currently, the inhibition of liver fibrosis are mainly focused on prevention the activation of hepatic stellate cells and inhibition of inflammatory pathways involved in liver fibrosis. Previous research in our lab found that natural phenanthrenes derived from Traditional Chinese Medicine Baiyangjie could inhibit liver fibrosis through inhibiting TGF-ß1, TNF-α and promoting the secretion of MMP-9. Herein, in order to optimize the structure of phenanthrenes to maximize their anti-fibrosis activities, a series of phenanthrene derivatives were designed and synthesized in an expeditious manner. Their ability to inhibit LPS-initiated cellular liver fibrosis in HSC-T6 cells were examined and the results indicated that compounds A-1 and B-1 provided the best cellular anti-fibrosis activities. Further studies implied that they inhibited the LPS-initiated cellular liver fibrosis through inhibition the secretion of TNF-α, IL-1ß, TGF-ß1 and α-SMA. From these data, a picture emerges wherein a novel idea using phenanthrenes A-1 and B-1 as potential candidates to treat liver fibrosis for further animal studies.
Assuntos
Fenantrenos , Fator de Crescimento Transformador beta1 , Animais , Fibrose , Células Estreladas do Fígado , Lipopolissacarídeos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Estrutura Molecular , Fenantrenos/farmacologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the extracellular amyloid plaques in the brain. Recent studies have shown that ferroptosis, a recently identified cell death pathway associated with the accumulation of lipid hydroperoxides, is closely related to the occurrence and exacerbation of AD. The application of ferroptosis inhibitors can alleviate the development of AD in both cellular and animal models. Herein, a series of dual-functional hydroxylated chalcone derivatives by integrating the heterocyclic dimethylaminopyrimidine in the core structure were designed and synthesized beyond our previous research to optimize their inhibition activities towards Aß protein aggregation and ferroptosis simultaneously. The inhibitory ability of the novel synthesized chalcone derivatives were greatly improved. The results indicated that the introduction of the dimethylaminopyrimidine structure provided improved effect on Aß protein aggregation inhibitory activity in both solution and cellular models. Trihydroxy chalcone derivative A-N-5 provided the best inhibition activities against Aß protein aggregation in cellular models. The trihydroxy compound A-N-5 did not show cytotoxicity at the concentration lower than 100 µM (with IC50 > 1 mM), but had a significant effect on promoting cell proliferation. Results indicated that compound A-N-5 could potentially promote neuronal cell growth in the damaged brain tissue. The compound could also inhibit ferroptosis induced by RSL or erastin and reduce the lipid peroxidation levels induced by Aß1-42 protein aggregation. Molecular docking was also conducted to explain the better inhibitory effect of novel compounds to inhibit Aß protein aggregation compared to the previous designed molecules without incorporation of the dimethylaminopyrimidine. In summary, the trihydroxy compound A-N-5 showed the best inhibition activities against Aß aggregation as well as ferroptosis with low cytotoxicity as a promising molecular skeleton candidate for further development of lead compound for in vivo test to treat AD.
Assuntos
Doença de Alzheimer , Chalcona , Chalconas , Doenças Neurodegenerativas , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Chalcona/química , Chalconas/farmacologia , Chalconas/uso terapêutico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/metabolismo , Relação Estrutura-AtividadeRESUMO
Hydrogels have been utilized extensively in the field of cutaneous wound treatment. The introduction of nanomaterials (NMs), which are a big category of materials with diverse functionalities, can endow the hydrogels with additional and multiple functions to meet the demand for a comprehensive performance in wound dressings. Therefore, NMs-functionalized hydrogels (NMFHs) as wound dressings have drawn intensive attention recently. Herein, an overview of reports about NMFHs for the treatment of cutaneous wounds in the past five years is provided. Firstly, fabrication strategies, which are mainly divided into physical embedding and chemical synthesis of the NMFHs, are summarized and illustrated. Then, functions of the NMFHs brought by the NMs are reviewed, including hemostasis, antimicrobial activity, conductivity, regulation of reactive oxygen species (ROS) level, and stimulus responsiveness (pH responsiveness, photo-responsiveness, and magnetic responsiveness). Finally, current challenges and future perspectives in this field are discussed with the hope of inspiring additional ideas.
Assuntos
Hidrogéis , Nanoestruturas , Hidrogéis/uso terapêutico , Pele , Hemostasia , Administração CutâneaRESUMO
Abstract The extract of Belamcanda chinensis leaves (BCLE) is a traditional Chinese herbal medicine for the treatment of diabetes-related hyperlipidemia in Hainan province, South China. In this study, the lipid-decreasing effects of BCLE on obese diabetes were investigated on KK-Ay mice. The component F2 ameliorated lipid disorder, as indicated by decreased levels of body weight, liver index, levels of TC, TG and LDL-c in the serum and liver. The enhancement effect of F2 on liver SOD and the inhibitory effect of F2 on MDA demonstrated that F2 exhibited significant antioxidant activity on liver injury. F2 also prevented vacuolar degeneration and reduced pathological tissue injury in liver. In addition, the component F1 decreased the levels of TG, LDL-c and MDA in the liver. These findings suggest that F2 may have therapeutic potential in the prevention and therapy of hyperlipemia and liver disease associated with obesity-related diabetes.
RESUMO
Endogenous and exogenous neurotoxins are important factors leading to neurodegenerative diseases. In the 1980s, the discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) contributes to Parkinson's disease (PD) symptoms led to new research investigations on neurotoxins. An abnormal metabolism of endogenous substances, such as condensation of bioamines with endogenous aldehydes, dopamine (DA) oxidation, and kynurenine pathway, can produce endogenous neurotoxins. Neurotoxins may damage the nervous system by inhibiting mitochondrial activity, increasing oxidative stress, increasing neuroinflammation, and up-regulating proteins related to cell death. This paper reviews the biological synthesis of various known endogenous neurotoxins and their toxic mechanisms.
Assuntos
Síndromes Neurotóxicas/patologia , Neurotoxinas/efeitos adversos , Estresse Oxidativo , Animais , Humanos , Síndromes Neurotóxicas/etiologiaRESUMO
This study was designed to preparecarboxyl-functionalized poly (N-isopropylacrylamide) PNIPAM microgels having excellent catalytic properties.Recently, researchers are trying to fabricate cost effective and efficient hybrid catalytic materials for the synthesis of nitrogenous compounds along with enhanced optical properties. For the same motive, synthesis of carboxyl-functionalized PNIPAM microgels was performed by using polymerization of soap-free emulsion of N-isopropyl acrylamide, which is NIPAM along with acrylic acid (AA). The thiol group was introduced through the imide bond mediated by carbodiimide, between carboxyl-functionalized microgels through carboxyl group and aminoethanethiol (AET). Copper, Palladium and Cu/Pd nanoparticles were incorporated successfully into thiol-functionalized PNIPAM microgels through metals thiol linkage. The synthesized microgels and hybrid encompassing metallic nanoparticles were characterized in detail by using Transmission electron microscopy (TEM), Scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron (XPS) and Fourier transformed infrared spectroscopy for structural interpretation. The thermal properties of the pure and hybrid microgels were inspected by TG analysis. The prepared nanocomposites PNIPAM-Cu, PNIPAM-Pd and PNIPAM-Cu/Pd exhibited decent catalytic properties for the degradation of 4-Nitrophenol and methylene blue, but the bimetallic Cu/Pd have remarkable catalytic properties. The catalytic reaction followed pseudo-first-order reaction with rate constants 0.223 min-1, 0.173 min-1 for 4-Nitrophenol and methylene blue in that order. In this study,we were able to establish that Cu/Pd hybrid is an efficient catalyst for 4-Nitrophenol and methylene blue as compared to its atomic analogue.
RESUMO
The biological damage caused by the environmental factors such as radiation and its control methods are one of the frontiers of life science research that has received widespread attention. Ionizing radiation can directly interact with target molecules (such as DNA, proteins and lipids) or decomposed by radiation from water, leading to changes in oxidative events and biological activities in cells. Liver is a radiation-sensitive organ, and its radiosensitivity is second only to bone marrow, lymph, gastrointestinal tissue, gonads, embryos and kidneys. In addition, as a key organ of mammals, liver performs a series of functions, including the production of bile, the metabolism of nutrients, the elimination of waste, the storage of glycogen, and the synthesis of proteins. Therefore, liver is prone to various pathophysiological changes. In this review, the effects of radiation on liver injury, its pathogenesis, bystander effect and the natural traditional Chinese medicine to protect the radiation induced liver damage are discussed.
Assuntos
Fígado , Radiação Ionizante , Animais , DNA , Dano ao DNA , OxirreduçãoRESUMO
DC-SIGN receptor articulated by macrophages and dendritic cells is encoded by CD209 gene and plays a role to activate and proliferate the T-lymphocytes in response of virus attack. The dysfunctional activity of DC-SIGN receptor because of missense SNPs can lead to cause dengue haemorrhage fever, HIV-1 infection etc. Out of 11 transcripts of CD209, all missense SNPs of canonical transcript were retrieved from Ensembl database and evaluated by their deleteriousness by using Polyphen-2, PMut, SIFT, MutPred, PROVEAN and PhD-SNP together with stimulation of its complete 3D structure. 10 nsSNPs were chosen depending on both the significance value of nsSNP and their prediction among SNPs evaluating servers which are based on different algorithms. Moreover, the position and native role of 10 nsSNPs in wild 3D model has been described which assist to acknowledge their importance. This study urges the researcher's community to experimentally validate these SNPs and their association in causing the diseases like dengue fever, Tuberculosis etc.
Assuntos
Moléculas de Adesão Celular/genética , Biologia Computacional/métodos , Lectinas Tipo C/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Moléculas de Adesão Celular/química , Simulação por Computador , Predisposição Genética para Doença , Humanos , Ligação de Hidrogênio , Lectinas Tipo C/química , Modelos Moleculares , Conformação Proteica , Estabilidade Proteica , Receptores de Superfície Celular/química , SoftwareRESUMO
By HPLC-MSn and HRMS analyses, the structures of 52 polyoxypregnane glycosides were rapidly inferred from Dregea sinensis Hemsl on the basis of their sodium-cationized molecules [M + Na]+ and predominant diagnostic ions resulting from the saccharic chain on C3 and the neutral loss of substituent on C11 and C12. Compounds 1 and 7 significantly inhibited LPS-stimulated splenocyte proliferation in vitro.[Formula: see text].