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1.
J Ethnopharmacol ; : 113916, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33571615

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: 25 flavors of the turquoise pill, a traditional Tibetan medicine for the treatment of various types of hepatitis, has not been investigated on its safety, especially the component mineral turquoise, which is believed to be essential but worried for its potential toxicity. AIM OF THE STUDY: To explore the potential acute toxicity and function of 25 flavors of the turquoise pill and turquoise, the possible mechanism of the effects of turquoise and 25 flavors of the turquoise pill were systematically studied based on 1H NMR metabolomics. MATERIALS AND METHODS: The rats were administered with turquoise and 25 flavors of the turquoise pill by gavage for 7 days, and samples of serum, liver, and kidney were collected. The potential toxicity and function of turquoise and 25 flavors of the turquoise pill on the liver and kidney of SD rats were evaluated by 1H NMR metabonomics, histopathology, and biochemical indexes. RESULTS: The results demonstrated that 25 flavors of the turquoise pill could scavenge free oxygen radicals, strengthen aerobic respiration and inhibit glycolysis in the liver. It did not cause oxidative stress in the kidney with no obvious damage. By modulation of branched-chain amino acids (BCAAs), 25 flavors of the turquoise pill can improve the utilization of glucose and promote aerobic respiration of the kidney. CONCLUSION: Considering the high dosage and short duration used in this study relative to their typical clinical usage, administration of 25 flavors of the turquoise pill and its component mineral turquoise are safe to livers and kidneys.

2.
J Ethnopharmacol ; 265: 113192, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32889033

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Wu-Zi-Yan-Zong-Wan (WZYZW) is a commonly used Chinese medicinal recipe for oligozoospermia. Oligozoospermia is a common disease that harms human fertility, there is no effective therapeutic medicine at present. However, the underlying pharmacological mechanism remains unclear. METHODS: Oligozoospermia rats model induced by Tripterygium glycosides (TG) was established to inspect the efficiency of WZYZW in the treatment of oligozoospermia by traditional pharmacodynamics combined with NMR-based metabolomics. Multivariate statistics were used to extracted the underlying biomarkers and metabolic pathways of WZYZW in the treatment of oligozoospermia. RESULTS: The results showed that TG disturbed many metabolites and metabolic pathways such as oxidative stress (choline, O-phosphocholine, betaine and ascorbate), energy metabolism in mitochondria (glucose, lactate, succinate, fumarate, 3-hydroxybutyrate and alanine), mitochondrial apoptosis markers (Bax and Bcl-2) and amino acids metabolisms (arginine, branched-chain amino acids, taurine and myo-inositol). CONCLUSIONS: WZYZW could significantly reverse the disturbed metabolites to their normal status by their abilities of anti-oxidation, anti-apoptosis, balancing the osmotic pressure regulatory molecules and regulating the amino acids metabolism. This study provides pharmacological basis and guidance for the clinical usage of WZYZW.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Metabolômica , Oligospermia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Diterpenos , Compostos de Epóxi , Espectroscopia de Ressonância Magnética , Masculino , Oligospermia/metabolismo , Pressão Osmótica/efeitos dos fármacos , Fenantrenos , Ratos , Ratos Sprague-Dawley
3.
Environ Res ; : 110584, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33285157

RESUMO

Heat waves (HWs) and urban heat islands (UHIs) can potentially interact. The mechanisms behind their synergy are not fully disclosed. Starting from the localized UHI phenomenon, this study aims i) to reveal their associated impacts on human thermal comfort through three different definitions of HW events, based on air temperature (airT), wet-bulb globe temperature (WBGT) and human-perceived temperature (AppT) respectively, and ii) to understand the role of air moisture and wind. The analysis was conducted in four districts (NH, JD, MH and XJH) with different urban development patterns and geographic conditions, in the megacity of Shanghai with a subtropical humid climate. Results evidenced the localized interplay between HWs and UHIs. The results indicate that less urbanized districts were generally more sensitive to the synergies. JD district recorded the highest urban heat island intensity (UHII) amplification, regardless of the specific HW definition. Notably, during AppT-HWs, the increment was observed in terms of maximum (1.3 °C), daily average (0.8 °C), diurnal (0.4 °C) and nocturnal UHII (1.0 °C). Nevertheless, localized synergies between HWs and UHIs at different stations also exhibited some commonalities. Under airT-HW, the UHII was amplified throughout the day at all stations. Under WBGT-HW, diurnal UHII (especially at 11:00-17:00 LST) was consistently amplified at all stations. Under AppT-HW conditions, the nocturnal UHII was slightly amplified at all stations. Air moisture and wind alleviated the synergistic heat exacerbation to the benefit of thermal comfort. The extent depended on geographic condition, diurnal and nocturnal scenarios, temperature type and HW/normal conditions. Stronger HW-UHI synergies indicate the necessity to develop specific urban heat emergency response plans, able to capture and intervene on the underlying mechanisms. This study paves to way to their identification.

4.
Neural Plast ; 2020: 8824760, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33335546

RESUMO

In Parkinson's disease, the excess of beta oscillations in cortical-basal ganglia (BG) circuits has been correlated with normal movement suppression. In this paper, a physiologically based resonance model, generalizing an earlier model of the STN-GPe circuit, is employed to analyze critical dynamics of the occurrence of beta oscillations, which correspond to Hopf bifurcation. With the experimentally measured parameters, conditions for the occurrence of Hopf bifurcation with time delay are deduced by means of linear stability analysis, center manifold theorem, and normal form analysis. It is found that beta oscillations can be induced by increasing synaptic transmission delay. Furthermore, it is revealed that the oscillations originate from interaction among different synaptic connections. Our analytical results are consistent with the previous experimental and simulating findings, thus may provide a more systematic insight into the mechanisms underlying the transient beta bursts.

5.
Cell Death Differ ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208891

RESUMO

Hepatocyte cell death and liver inflammation have been well recognized as central characteristics of nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive. The kinase receptor-interacting protein 1 (RIP1) is a multitasking molecule with distinct functions in regulating apoptosis, necroptosis, and inflammation. Dissecting the role of RIP1 distinct functions in different pathophysiology has absorbed huge research enthusiasm. Wild-type and RIP1 kinase-dead (Rip1K45A/K45A) mice were fed with high-fat diet (HFD) to investigate the role of RIP1 kinase activity in the pathogenesis of NASH. Rip1K45A/K45A mice exhibited significantly alleviated NASH phenotype of hepatic steatosis, liver damage, fibrosis as well as reduced hepatic cell death and inflammation compared to WT mice. Our results also indicated that both in vivo lipotoxicity and in vitro saturated fatty acids (palmitic acid) treatment were able to induce the kinase activation of RIP1 in liver macrophages. RIP1 kinase was required for mediating inflammasome activation, apoptotic and necrotic cell death induced by palmitic acid in both bone marrow-derived macrophage and mouse primary Kupffer cells. Results from chimeric mice established through lethal irradiation and bone marrow transplantation further confirmed that the RIP1 kinase in hematopoietic-derived macrophages contributed mostly to the disease progression in NASH. Consistent with murine models, we also found that RIP1 kinase was markedly activated in human NASH, and the kinase activation mainly occurred in liver macrophages as indicated by immunofluorescence double staining. In summary, our study indicated that RIP1 kinase was phosphorylated and activated mainly in liver macrophages in both experimental and clinical NASH. We provided direct genetic evidence that the kinase activity of RIP1 especially in hematopoietic-derived macrophages contributes to the pathogenesis of NASH, through mediating inflammasome activation and cell death induction. Macrophage RIP1 kinase represents a specific and potential therapeutic target for NASH.

6.
BMC Complement Med Ther ; 20(1): 329, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33138805

RESUMO

BACKGROUND: Inflammation is a response to tissue injuries, which is indispensable and important for human health, but excessive inflammation can potentially cause damage to the host organisms. Camellia nitidissima Chi, one traditional medicinal and edible plant in China, was reported to exhibit anti-inflammation capability. Hence, this study was conducted to isolate the bioactive compounds from the flowers of C. nitidissima Chi and evaluate their anti-inflammatory activity. METHODS: The phytochemicals from the flowers of C. nitidissima Chi were isolated and purified by silica gel, Sephadex LH-20 gel, C18 reversed silica gel, semi-preparative HPLC, and identified by the spectrum technologies. The anti-inflammatory activity of isolated compounds was evaluated using cultured macrophage RAW 264.7 cells. Whereafter the potential metabolic mechanism of the anti-inflammatory activity of the bioactive compound was investigated by a 1H-NMR based metabolomics approach. The metabolites in 1H-NMR spectra were identified by querying the Human Metabolome Database and Madison Metabolomics Consortium Database online. And the multivariate statistical analysis was performed to evaluate the variability of metabolites among samples and between sample classes. RESULTS: The compound isolated from the flowers of C. nitidissima Chi was identified as 3-cinnamoyltribuloside (3-CT). 3-CT could inhibit the NO production and the mRNA expression of iNOS involved in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Moreover, 3-CT could inhibit the expression of a series of inflammatory cytokines, including TNF-α, IL-1ß, and IL-6, both at the mRNA level and protein level. The 1H-NMR based metabolomics approach was applied to investigate the potential metabolic mechanism of the anti-inflammatory activity of 3-CT. Thirty-five metabolites were identified and assigned. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the 1H-NMR data showed 3-CT could balance the significant changes in many endogenous metabolites (e.g., choline, glucose, phenylalanine) induced by LPS in RAW 264.7 cells, which related to cholinergic anti-inflammatory pathway, oxidative stress, energy metabolism, and amino acids metabolism. CONCLUSION: 3-CT, isolated from the flowers of C. nitidissima Chi, had potent anti-inflammatory activity in LPS-activated RAW 264.7 cells. Furthermore, our results indicated that 3-CT had effects on the cholinergic anti-inflammatory pathway, oxidative stress, energy metabolism, and amino acids metabolism in LPS-activated RAW 264.7 cells.

7.
Redox Biol ; 37: 101694, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32896721

RESUMO

Metabolism serves mammalian feeding and active behavior, and is controlled by circadian clock. The molecular mechanism by which clock factors regulate metabolic homeostasis under oxidative stress is unclear. Here, we have characterized that the daily oxygen consumption rhythm was deregulated in Per1 deficient mice. Per1 deficiency impaired daily mitochondrial dynamics and deregulated cellular GPx-related ROS fluctuations in the peripheral organs. We identified that PER1 enhanced GPx activity through PER1/GPX1 interaction in cytoplasm, consequently improving the oxidative phosphorylation efficiency of mitochondria. Per1 expression was specifically elevated in the fasting peripheral organs for protecting mitochondrial from oxidation stress. These observations reveal that Per1-driven mitochondrial dynamics is a critical effector mechanism for the regulation of mitochondrial function in response to oxidation stress.

8.
J Nutr Biochem ; 85: 108440, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32799135

RESUMO

Oxidative stress and the production of intracellular reactive oxygen species (ROS) have been implicated in the pathogenesis of sepsis. In excess, oxidative stress is not deemed an unbalanced biochemical reaction in the critically ill rats, but it is a key pathological factor in driving systemic inflammatory response that can result in multiple organ failure in sepsis. Thus, we aimed to explore whether antioxidant nutrients could reduce or delay the oxidative stress condition of sepsis rats, and then play a prospective role in the oxidative stress condition of critical disease. In this investigation, the ability of exogenous and endogenous antioxidant nutrients (ascorbate, taurine and glutathione) to prevent sepsis-induced changes in liver injury was examined using a rat model of sepsis induced by cecal ligation and puncture (CLP), and the underlying mechanisms were also investigated. The effects of three antioxidants on sepsis were assessed based on biochemical assays in combination with an NMR-based metabolomics approach and correlation network analysis. Our results suggested that ascorbate, taurine and glutathione had broadly similar protective effects on reducing oxidative stress. Compared with CLP rats, antioxidant-treated rats exhibited alleviated (P<.05) organ dysfunction and improved liver pathology. Moreover, taurine showed a better efficacy compared with ascorbate and glutathione, evidenced by significantly reversed metabolomics profiles toward normal state. Under conditions of sepsis, antioxidants suppressed inflammatory responses by restraining key signaling pathways, including the redox-sensitive transcription factor pathways of NF-κB and MAPK. Collectively, our findings suggested that antioxidant nutrients exerted beneficial effects on septic rats via protecting mitochondrial.

9.
J Hazard Mater ; 398: 122825, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-32768809

RESUMO

The toxicity of low-level arsenic (As)-contaminated soil is not well understood. An integrated proteomic and metabolomic approach combined with morphological examination was used to investigate the potential biological toxicity of As-contaminated soil based on an exposure experiment with the earthworm Eisenia fetida. The results showed that the earthworm hindgut accumulated high As concentrations resulting in injury to the intestinal epithelia, chloragogenous tissues and coelom tissues. Furthermore, As-contaminated soil induced a significant increase in betaine levels and a decrease in dimethylglycine and myo-inositol levels in the earthworms, suggesting that the osmoregulatory metabolism of the earthworms may have been disturbed. The significantly altered levels of asparagine and dimethylglycine were proposed as potential biomarkers of As-contaminated soil. The upregulation of soluble calcium-binding proteins and profilin, the downregulation of sodium/potassium-transporting ATPase, and the proteins changes identified by gene ontology enrichment analysis confirmed that the earthworms suffered from osmotic stress. In addition, the significant changes in glycine-tRNA ligase activity and coelomic tissue injury revealed that As accumulation may disturb the earthworm immune system. This work provided new insight into the proteomic and metabolic toxicity of low-level As-contaminated soil ecosystems in earthworms, extended our knowledge of dual omics and highlighted the mechanisms underlying toxicity.

10.
ACS Appl Mater Interfaces ; 12(28): 31645-31651, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32551489

RESUMO

Rectifying semiconductor junctions are crucial to electronic devices. They convert alternating current into a direct one by allowing unidirectional charge flows. Analogous to the current-flow rectification for itinerary electrons, here, a polar rectification that is based on the localized oxygen vacancies (OVs) in a Ti/fatigued-SrTiO3 (fSTO) Schottky junction is first demonstrated. The fSTO with OVs is produced by an electrodegradation process. The different movabilities of localized OVs and itinerary electrons in the fSTO yield a unidirectional electric polarization at the interface of the junction under the coaction of external and built-in electric fields. Moreover, the fSTO displays a pre-ferroelectric state located between paraelectric and ferroelectric phases. The pre-ferroelectric state has three sub-states and can be easily driven into a ferroelectric state by an external electric field. These observations open up opportunities for potential polar devices and may underpin many useful polar-triggered electronic phenomena.

11.
BMC Microbiol ; 20(1): 117, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410647

RESUMO

BACKGROUND: Xanthomonas oryzae pv. oryzae (Xoo) can cause destructive bacterial blight in rice. As an antibacterial, resveratrol may inhibit Xoo growth. This study focused on the potential structural-activity relationship of resveratrol and its derivatives against Xoo growth, and 1H-NMR-based metabolomic analysis was applied to investigate the global metabolite changes in Xoo after resveratrol treatment. RESULTS: Resveratrol showed the strongest inhibitory effects on Xoo growth compared with its derivatives, which lacked double bonds (compounds 4-6) or hydroxyls were substituted with methoxyls (compounds 7-9). The IC50 of resveratrol against Xoo growth was 11.67 ± 0.58 µg/mL. Results indicated that the double bond of resveratrol contributed to its inhibitory effects on Xoo growth, and hydroxyls were vital for this inhibition. Interestingly, resveratrol also significantly inhibited Xoo flagellum growth. Based on 1H-NMR global metabolic analysis, a total of 30 Xoo metabolites were identified, the changes in the metabolic profile indicated that resveratrol could cause oxidative stress as well as disturb energy, purine, amino acid, and NAD+ metabolism in Xoo, resulting in the observed inhibitory effects on growth. CONCLUSIONS: This study showed that the double bond of resveratrol contributed to its inhibitory effects on Xoo growth, and hydroxyls were also the important active groups. Resveratrol could cause oxidative stress of Xoo cells, and disturb the metabolism of energy, purine, amino acid and NAD +, thus inhibit Xoo growth.

12.
mSphere ; 5(2)2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295866

RESUMO

Candida albicans adapts to various conditions in different body niches by regulating gene expression, protein synthesis, and metabolic pathways. These adaptive reactions not only allow survival but also influence the interaction with host cells, which is governed by the composition and structure of the fungal cell wall. Numerous studies had shown linkages between mitochondrial functionality, cell wall integrity and structure, and pathogenicity. Thus, we decided to inhibit single complexes of the respiratory chain of C. albicans and to analyze the resultant interaction with macrophages via their phagocytic activity. Remarkably, inhibition of the fungal bc1 complex by antimycin A increased phagocytosis, which correlated with an increased accessibility of ß-glucans. To contribute to mechanistic insights, we performed metabolic studies, which highlighted significant changes in the abundance of constituents of the plasma membrane. Collectively, our results reinforce the strong linkage between fungal energy metabolism and other components of fungal physiology, which also determine the vulnerability to immune defense reactions.IMPORTANCE The yeast Candida albicans is one of the major fungal human pathogens, for which new therapeutic approaches are required. We aimed at enhancements of the phagocytosis efficacy of macrophages by targeting the cell wall structure of C. albicans, as the coverage of the ß-glucan layer by mannans is one of the immune escape mechanisms of the fungus. We unambiguously show that inhibition of the fungal bc1 complex correlates with increased accessibilities of ß-glucans and improved phagocytosis efficiency. Metabolic studies proved not only the known direct effects on reactive oxygen species (ROS) production and fermentative pathways but also the clear downregulation of the ergosterol pathway and upregulation of unsaturated fatty acids. The changed composition of the plasma membrane could also influence the interaction with the overlying cell wall. Thus, our work highlights the far-reaching relevance of energy metabolism, indirectly also for host-pathogen interactions, without affecting viability.

13.
J Ethnopharmacol ; 254: 112403, 2020 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-32109546

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrodiae Rhizoma (GR), a well-known and commonly-used TCM (Traditional Chinese Medicine) for treating headache, dizziness, tetanus, epilepsy, and etc., has been proven to relieve chronic atrophic gastritis (CAG). Due to its complex ingredients, the active fractions responsible for the treatment of CAG remain largely unknown. AIM OF THE STUDY: To explore the underlying material and interpret its underlying mechanism, the therapeutic effect of extract from different polar parts of Gastrodiae Rhizoma on autoimmune CAG was studied based on the 1H NMR metabolomics. MATERIALS AND METHODS: The rat model of CAG was established by autoimmune method. The modeled CAG rats were then treated with 4 polar parts (T1-4 in descending polarity, corresponding to water, n-butanol, ethyl acetate and petroleum ether extracts, respectively) of Gastrodiae Rhizoma for 21 consecutive days. The stomach and serum samples were collected and then subjected to histopathology observation, biochemical measurement (MDA, SOD, GSH, NO, XOD and pepsin), 1H NMR metabolic profiling and multivariate/univariate statistical analysis. RESULTS: The results showed that T1 had the best therapeutic effect, T2 the second, and T3 and T4 the poorest with no obvious therapeutic effect, demonstrating that the effective components of Gastrodiae Rhizoma should be compounds of high polarity. T1 achieved good therapeutic effects due to the anti-inflammatory and anti-oxidant activities, and by rectifying the disturbed energy and amino acid metabolism in CAG model. CONCLUSION: This integrated metabolomics approach proved the validity of the therapeutic effect of extract from different polar parts of Gastrodiae Rhizoma on autoimmune CAG, providing new insights into the underlying mechanisms, and demonstrating the feasibility of metabolomics to evaluate efficacy of herbal drug, which is often difficult by traditional means.

14.
Nat Commun ; 10(1): 5091, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704924

RESUMO

Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U13C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.


Assuntos
Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Succinatos/farmacologia , Alquilação , Animais , Antimetabólitos/farmacologia , Cisteína/efeitos dos fármacos , Cisteína/genética , Cisteína/metabolismo , Desoxiglucose/farmacologia , Regulação para Baixo , Endotoxemia/imunologia , Glucose/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/antagonistas & inibidores , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Inflamação/imunologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/imunologia , Fosforilação Oxidativa/efeitos dos fármacos , Células RAW 264.7 , Sesquiterpenos/farmacologia
15.
J Nat Prod ; 82(12): 3221-3226, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31736307

RESUMO

Nine new alkaloids, (+)-1, (-)-1, 2, (+)-3, (-)-3, and 4-7, along with five known compounds (8-12), were obtained from the branches and leaves of Elaeocarpus angustifolius. The alkaloids were structurally characterized by NMR and MS data. The absolute configurations of (+)-1, (-)-1, (+)-3, and (-)-3 were determined by comparing their experimental and computed electronic circular dichroism spectra. (±)-8,9-Dehydroelaeocarpine (5), (±)-9-epielaeocarpine cis-N-oxide trifluoroacetate (6), and (±)-elaeocarpine trifluoroacetate (9) exerted weak inhibitory activities against butyrylcholinesterase with IC50 values of 39, 29, and 35 µM, respectively, while that of tacrine, the positive control, was 0.07 ± 0.01 µM. This is the first report of the cholinesterase inhibitory activities of Elaeocarpus alkaloids.


Assuntos
Alcaloides/isolamento & purificação , Elaeocarpaceae/química , Folhas de Planta/química , Alcaloides/química , Alcaloides/farmacologia , Bioensaio , Inibidores da Colinesterase/farmacologia , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Estrutura Molecular , Análise Espectral/métodos
16.
Microbiologyopen ; 8(12): e930, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31532062

RESUMO

A balanced and optimized metabolic pathway is the basis for efficient production of a target metabolite. Traditional strategies mostly involve the manipulation of promoters or ribosome-binding sites, which can encompass long sequences and can be complex to operate. In this work, we found that by changing only the three nucleotides of the initiation codons, expression libraries of reporter proteins RFP, GFP, and lacZ with a large dynamic range and evenly distributed expression levels could be established in Escherichia coli (E. coli). Thus, a novel strategy that uses combinatorial modulation of initial codons (CMIC) was developed for metabolic pathway optimization and applied to the three genes crtZ, crtY, and crtI of the zeaxanthin synthesis pathway in E. coli. The initial codons of these genes were changed to random nucleotides NNN, and the gene cassettes were assembled into vectors via an optimized strategy based on type II restriction enzymes. With minimal labor time, a combinatorial library was obtained containing strains with various zeaxanthin production levels, including a strain with a titer of 6.33 mg/L and specific production value of 1.24 mg/g DCW-a striking 10-fold improvement over the starting strain. The results demonstrated that CMIC was a feasible technique for conveniently optimizing metabolic pathways. To our best knowledge, this is the first metabolic engineering strategy that relies on manipulating the initiation codons for pathway optimization in E. coli.


Assuntos
Vias Biossintéticas , Códon de Iniciação , Escherichia coli/genética , Escherichia coli/metabolismo , Engenharia Metabólica , Zeaxantinas/biossíntese , Regulação Bacteriana da Expressão Gênica , Biblioteca Gênica , Ordem dos Genes , Genes Reporter , Plasmídeos/genética , Regiões Promotoras Genéticas , Análise de Sequência de DNA
17.
J Cell Mol Med ; 23(10): 6622-6634, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31397978

RESUMO

DT-13 combined with topotecan (TPT) showed stronger antitumour effects in mice subcutaneous xenograft model compared with their individual effects in our previous research. Here, we further observed the synergistically effect in mice orthotopic xenograft model. Metabolomics analysis showed DT-13 combined with TPT alleviated metabolic disorders induced by tumour and synergistically inhibited the activity of the aerobic glycolysis-related enzymes in vivo and in vitro. Mechanistic studies revealed that the combination treatment promoted epidermal growth factor receptor (EGFR) degradation through non-muscle myosin IIA (NM IIA)-induced endocytosis of EGFR, further inhibited the activity of hexokinase II (HK II), and eventually promoted the aerobic glycolysis inhibition activity more efficiently compared with TPT or DT-13 monotherapy. The combination therapy also inhibited the specific binding of HK II to mitochondria. When using the NM II inhibitor (-)002Dblebbistatin or MYH-9 shRNA, the synergistic inhibition effect of DT-13 and TPT on aerobic glycolysis was eliminated in BGC-823 cells. Immunohistochemical analysis revealed selective up-regulation of NM IIA while specific down-regulation of p-CREB, EGFR, and HK II by the combination therapy. Collectively, these findings suggested that this regimen has significant clinical implications, warranted further investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Glicólise/efeitos dos fármacos , Saponinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Topotecan/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma/enzimologia , Carcinoma/genética , Carcinoma/metabolismo , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Sinergismo Farmacológico , Endocitose/efeitos dos fármacos , Receptores ErbB/metabolismo , Feminino , Hexoquinase/antagonistas & inibidores , Hexoquinase/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , RNA Interferente Pequeno , Saponinas/farmacologia , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Topotecan/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Aging Dis ; 10(4): 854-870, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31440390

RESUMO

Sepsis is a severe disease frequently occurred in the Intenisive Care Unit (ICU), which has a very high morbidity and mortality, especially in patients aged over 65 years. Owing to the aging effect and the ensuing deterioration of body function, the elder patients may have atypical responses to sepsis. Diagnosis and pathogenesis of sepsis in this population are thus difficult, which hindered effective treatment and management in clinic. To investigated age effects on sepsis, 158 elderly septic patients and 71 non-septic elderly participants were enrolled, and their plasma samples were collected for transcriptomics (RNA-seq) and metabolomics (NMR and GC-MS) analyses, which are both increasingly being utilized to discover key molecular changes and potential biomarkers for various diseases. Protein-protein interaction (PPI) analysis was subsequently performed to assist cross-platform integration. Real time polymerase chain reaction (RT-PCR) was used for validation of RNA-seq results. For further understanding of the mechanisms, cecal ligation and puncture (CLP) experiment was performed both in young and middle-aged rats, which were subjected to NMR-based metabolomics study and validated for several key inflammation pathways by western blot. Comprehensive analysis of data from the two omics approaches provides a systematic perspective on dysregulated pathways that could facilitate the development of therapy and biomarkers for elderly sepsis. Additionally, the metabolites of lactate, arginine, histamine, tyrosine, glutamate and glucose were shown to be highly specific and sensitive in distinguishing septic patients from healthy controls. Significant increases of arginine, trimethylamine N-oxide and allantoin characterized elderly patient incurred sepsis. Further analytical and biological validations in different subpopulations of septic patients should be carried out, allowing accurate diagnostics and precise treatment of sepsis in clinic.

19.
J Pharm Biomed Anal ; 176: 112800, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31394304

RESUMO

The Herpetospermum caudigerum Wall (HCW) is a traditional Tibetan medicine and is widely used in clinical practice. However, the shell of the HCW (SHCW) has rarely been studied, and some researchers have suggested that the SHCW may be toxic. Therefore, in this study, SHCW was administered to rats at two doses (0.1 and 0.33 g/kg) once a day for 21 days. The hepatic stimuli induced by SHCW in rats were investigated for the first time by 1H-NMR-based metabolomics combined with histopathological observation and biochemical detection. Histopathological sections showed a certain degree of hepatocyte edema and hepatic sinus congestion in the liver tissue of the rats in the drug-administered group. Serum biochemical indicators revealed a significant increase in ALT, AST, and MDA, and a significant decrease in SOD. Metabolomic results showed that the metabolites in rats were changed after gavage administration of extracts from SHCW. By multivariate statistical analysis and univariate analysis, it was found that SHCW could cause the disorder of energy metabolism, oxidative stress and amino acid metabolism in rats, leading to liver damage. This comprehensive metabolomics approach demonstrates its ability to describe the global metabolic state of an organism and provides a powerful and viable tool for exploring drug-induced toxicity or side effects.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Cucurbitaceae/toxicidade , Medicina Tradicional Tibetana/efeitos adversos , Metabolômica/métodos , Extratos Vegetais/toxicidade , Espectroscopia de Prótons por Ressonância Magnética , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Etanol/química , Humanos , Testes de Função Hepática/métodos , Masculino , Extratos Vegetais/isolamento & purificação , Ratos
20.
Environ Pollut ; 251: 910-920, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31234257

RESUMO

The toxic sensitivity in different physiological levels of chromium (Cr) contaminated soils with environmentally equivalent concentrations (EEC) was fully unknown. The earthworm Eisenia fetida was exposed to a Cr-contaminated soil at the EEC level (referred to as Cr-CS) to characterize the induced toxicity at the whole body, organ, tissue, subcellular structure and metabolic levels. The results showed that the survival rate, weight and biodiversity of the gut microorganisms (organ) had no significant difference (p > 0.05) between control and Cr-CS groups. Qualitative histopathological and subcellular evaluations from morphology showed earthworms obvious injuries. The organelle injuries combined with the metabolic changes provided additional evidence that the Cr-CS damaged the nucleus and probably disturbed the nucleic acid metabolism of earthworms. 2-hexyl-5-ethyl-3-furansulfonate, dimethylglycine, betaine and scyllo-inositol were sensitive and relatively quantitative metabolites that were recommended as potential biomarkers for Cr-CS based on their significant weights in the multivariate analysis model. In addition, the relative abundance of Burkholderiaceae, Enterobacteriaceae and Microscillaceae of the earthworm guts in the Cr-CS group significantly increased, particularly for Burkholderiaceae (increased by 13.1%), while that of Aeromonadaceae significantly decreased by 5.6% in contrast with the control group. These results provided new insights into our understanding of the toxic effects of the EEC level of Cr contaminated soil from different physiological levels of earthworms and extend our knowledge on the composition and sensitivity of the earthworm gut microbiota in Cr contaminated soil ecosystems. Furthermore, these toxic responses from gut microorganisms to metabolites of earthworms provided important data to improve the adverse outcome pathway and toxic mechanism of the Cr-CS if the earthworm genomics and proteomics would be also gained in the future.


Assuntos
Cromo/toxicidade , Poluição Ambiental/análise , Oligoquetos/metabolismo , Oligoquetos/microbiologia , Poluentes do Solo/toxicidade , Solo/química , Animais , Bacteroidetes/crescimento & desenvolvimento , Burkholderiaceae/crescimento & desenvolvimento , Cromo/análise , Enterobacteriaceae/crescimento & desenvolvimento , Organelas/efeitos dos fármacos , Poluentes do Solo/análise
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