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1.
Mol Plant ; 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34793984

RESUMO

Osmotic stress caused by drought and salinity is a significant environmental threat that limits plant growth and agricultural yield. Redox regulation plays an important role in plant stress responses, but the mechanisms by which plants perceive and transduce redox signals are still underexplored. Here, we report a critical function for the thiol peroxidase GPX1 in osmotic stress response in rice, where it serves the role of a redox sensor and transducer. GPX1 is quickly oxidized and forms an intramolecular disulfide bond upon exposure to osmotic stress, which is required for the activation of bZIP68, a VRE-like basic leucine zipper (bZIP) transcription factor involved in ABA-independent osmotic stress response pathway. The disulfide exchange between GPX1 and bZIP68 induces homo-tetramerization of bZIP68 and thus positively regulates osmotic stress response by regulating osmotic-responsive gene expression. Furthermore, we discovered that the nuclear translocation process of GPX1 is regulated by its acetylation under osmotic stress. Our findings therefore not only uncover the redox regulation of GPX1-bZIP68 module during osmotic stress, but also highlight the coordination of protein acetylation and redox signaling in plant osmotic stress responses.

2.
Cell Death Discov ; 7(1): 332, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732697

RESUMO

Numerous studies have shown that carbon ion radiotherapy (CIRT) induces anti-cancer immune responses in melanoma patients, yet the mechanism remains elusive. The abundance of myeloid-derived suppressor cells (MDSC) in the tumour microenvironment is associated with therapeutic efficacy and disease outcome. This study analysed the changes in the immune contexture in response to the carbon ion treatment. The murine melanoma B16, MelanA, and S91 tumour models were established in syngeneic immunocompetent mice. Then, the tumours were irradiated with carbon ion beams, and flow cytometry was utilised to observe the immune contexture changes in the bone marrow, peripheral blood, spleen, and tumours. The immune infiltrates in the tumour tissues were further assessed using haematoxylin/eosin staining and immunohistochemistry. The immunoblot detected the expression of proteins associated with the JAK/STAT signalling pathway. The secretion of immune-related cytokines was examined using ELISA. Compared to conventional radiotherapy, particle beams have distinct advantages in cancer therapy. Here, the use of carbon ion beams (5 GyE) for melanoma-bearing mice was found to reduce the population of MDSC in the bone marrow, peripheral blood, and spleen of the animals via a JAK2/STAT3-dependent mechanism. The percentage of CD3+, CD4+, CD8+ T cells, macrophages, and natural killer cells increased after radiation, resulting in reduced tumour growth and prolonged overall survival in the three different mouse models of melanoma. This study, therefore, substantiated that CIRT boosts anti-tumour immune responses via the inhibition of MDSC.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34820768

RESUMO

Although it is often assumed that spatial attention exists in the form of a unitary focus, the split-attention hypothesis proposes that attention can be simultaneously divided into two spatially noncontiguous positions and that the space in between can be ignored. However, whether split attention occurs directly based on the generation of attentional benefit or whether it requires a gradual divide from a unitary focus over time has not been clarified. In the present study, by using two spatial salient cues to direct the attention allocation of participants, we aimed to investigate whether attention requires time to divide from a unitary focus and whether the appearance time of split attention varies when the task difficulty level increases between experiments. The results showed that attention required time to divide from a unitary focus, and the position between the two cued positions was not excluded by attention when the stimulus-onset asynchrony (SOA) was 60 ms. However, as the task difficulty increased between experiments, the appearance time of split attention was earlier. These findings suggest that the appearance time of split attention has a certain flexibility and can be changed according to the task requirement, thus implying that split attention and unitary attention present some common attention mechanisms and that a split or unitary mode can be flexibly selected for an attention system.

4.
Iran J Public Health ; 50(9): 1825-1831, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34722378

RESUMO

Background: We aimed to investigate the effect of copper stainless steel on apoptosis of vascular smooth muscle cells in coronary artery. Methods: The study was carried out in 2019 at Hubei University of Medicine, Xiangyang, China. The rat coronary artery smooth muscle cell was used for cell resuscitation and culture. MTT method was used to visualize cell growth curve and to detect the cell survival and growth. The incubated cells were randomly divided into copper-containing stainless-steel group, ordinary stainless-steel group, and control group. The cells were made into single cell suspension, which were intervened by experimental group and incubated in incubator with CO2 for 48 hours. TUNEL method was used to detect the apoptosis. The number of apoptotic cells in five high power fields (×200) was counted. The expression of Fas protein in three groups of cells was detected by Western blot. Results: The growth curves of rat coronary artery smooth muscle cells showed that the OD value of the cells reached the plateau 7 days after inoculation, indicating that the cells grew well. TUNEL staining showed the apoptosis in all three groups. The apoptotic index in copper-containing group was significantly higher than that in common stainless-steel group (P <0.01). The results of the Fas protein expression level through Western blot showed that the level in the copper-containing group was significantly higher than that in the common stainless-steel group (P<0.01). Conclusion: Copper-containing stainless steel can promote apoptosis of coronary artery smooth muscle cells. The material could prevent stent restenosis.

5.
Int J Mol Sci ; 22(22)2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34829996

RESUMO

Hydrogen sulfide (H2S) is an important signaling molecule that regulates diverse cellular signaling pathways through persulfidation. Our previous study revealed that H2S is involved in the improvement of rice drought tolerance. However, the corresponding enzymatic sources of H2S and its regulatory mechanism in response to drought stress are not clear. Here, we cloned and characterized a putative l-cysteine desulfhydrase (LCD) gene in rice, which encodes a protein possessing H2S-producing activity and was named OsLCD1. Overexpression of OsLCD1 results in enhanced H2S production, persulfidation of total soluble protein, and confers rice drought tolerance. Further, we found that nitrate reductase (NR) activity was decreased under drought stress, and the inhibition of NR activity was controlled by endogenous H2S production. Persulfidation of NIA2, an NR isoform responsible for the main NR activity, led to a decrease in total NR activity in rice. Furthermore, drought stress-triggered inhibition of NR activity and persulfidation of NIA2 was intensified in the OsLCD1 overexpression line. Phenotypical and molecular analysis revealed that mutation of NIA2 enhanced rice drought tolerance by activating the expression of genes encoding antioxidant enzymes and ABA-responsive genes. Taken together, our results showed the role of OsLCD1 in modulating H2S production and provided insight into H2S-regulated persulfidation of NIA2 in the control of rice drought stress.

6.
Opt Express ; 29(18): 28124-28133, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34614951

RESUMO

Optical underwater target imaging and detection have been a tough but significant challenge in deep-sea exploration. Distant reflected signals drown in various underwater noises due to strong absorption and scattering, resulting in degraded image contrast and reduced detection range. Single-photon feature operating at the fundamental limit of the classical electromagnetic waves can broaden the realm of quantum technologies. Here we experimentally demonstrate a thresholded single-photon imaging and detection scheme to extract photon signals from the noisy underwater environment. We reconstruct the images obtained in a high-loss underwater environment by using photon-limited computational algorithms. Furthermore, we achieve a capability of underwater detection down to 0.8 photons per pulse at Jerlov type III water up to 50 meters, which is equivalent to more than 9 attenuation lengths. The results break the limits of classical underwater imaging and detection and may lead to many quantum-enhanced applications, like air-to-sea target tracking and deep-sea optical exploration.

7.
Opt Express ; 29(17): 27683-27695, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34615180

RESUMO

We propose an on-chip all-optical multilevel amplitude regenerator scheme over a Mach Zehnder interferometer (MZI) configuration, enabling multiple amplitude-noise suppression on 16-QAM signals. Joint parameter optimization is carried out based on the general nonlinear model of the proposed scheme to significantly reduce the phase distortion caused by the nonlinear interferometer, which is the key to perform the phase preserving operation. The full function of the phase-preserving amplitude regeneration (PPAR) is verified by an experiment on an on-chip nonlinear waveguide with the length of the 2.31 cm. Furthermore, we perform thoughtful investigations on the oscillatory behavior achieved by the silicon MZI regenerator, enabling the full PPAR on 16-QAM signals through the optimized multiple power plateaus. A maximum 1.6 dB improvement of signal quality is achieved by the proposed on-chip amplitude regenerator at the input signal-to-noise ratio (SNR) of 25 dB. The impact from the two-photon absorption (TPA) effect as an positive role in the regenerator is also well discussed.

8.
AMB Express ; 11(1): 142, 2021 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-34693461

RESUMO

Microorganisms play an essential role in sulfide removal. Alkaline absorption solution facilitates the sulfide's dissolution and oxidative degradation, so haloalkaliphile is a prospective source for environmental-friendly and cost-effective biodesulfurization. In this research, 484 sulfide oxidation genes were identified from the metagenomes of the soda-saline lakes and a haloalkaliphilic heterotrophic bacterium Halomonas salifodinae IM328 (=CGMCC 22183) was isolated from the same habitat as the host for expression of a representative sequence. The genetic manipulation was successfully achieved through the conjugation transformation method, and sulfide: quinone oxidoreductase gene (sqr) was expressed via pBBR1MCS derivative plasmid. Furthermore, a whole-cell catalyst system was developed by using the engineered strain that exhibited a higher rate of sulfide oxidation under the optimal alkaline pH of 9.0. The whole-cell catalyst could be recycled six times to maintain the sulfide oxidation rates from 41.451 to 80.216 µmol·min-1·g-1 dry cell mass. To summarize, a whole-cell catalyst system based on the engineered haloalkaliphilic bacterium is potentiated to be applied in the sulfide treatment at a reduced cost.

9.
J Agric Food Chem ; 69(44): 13200-13216, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34709825

RESUMO

Nontarget data acquisition for target analysis (nDATA) workflows using liquid chromatography-high-resolution accurate mass (LC-HRAM) spectrometry, spectral screening software, and a compound database have generated interest because of their potential for screening of pesticides in foods. However, these procedures and particularly the instrument processing software need to be thoroughly evaluated before implementation in routine analysis. In this work, 25 laboratories participated in a collaborative study to evaluate an nDATA workflow on high moisture produce (apple, banana, broccoli, carrot, grape, lettuce, orange, potato, strawberry, and tomato). Samples were extracted in each laboratory by quick, easy, cheap, effective, rugged, and safe (QuEChERS), and data were acquired by ultrahigh-performance liquid chromatography (UHPLC) coupled to a high-resolution quadrupole Orbitrap (QOrbitrap) or quadrupole time-of-flight (QTOF) mass spectrometer operating in full-scan mass spectrometry (MS) data-independent tandem mass spectrometry (LC-FS MS/DIA MS/MS) acquisition mode. The nDATA workflow was evaluated using a restricted compound database with 51 pesticides and vendor processing software. Pesticide identifications were determined by retention time (tR, ±0.5 min relative to the reference retention times used in the compound database) and mass errors (δM) of the precursor (RTP, δM ≤ ±5 ppm) and product ions (RTPI, δM ≤ ±10 ppm). The elution profiles of all 51 pesticides were within ±0.5 min among 24 of the participating laboratories. Successful screening was determined by false positive and false negative rates of <5% in unfortified (pesticide-free) and fortified (10 and 100 µg/kg) produce matrices. Pesticide responses were dependent on the pesticide, matrix, and instrument. The false negative rates were 0.7 and 0.1% at 10 and 100 µg/kg, respectively, and the false positive rate was 1.1% from results of the participating LC-HRAM platforms. Further evaluation was achieved by providing produce samples spiked with pesticides at concentrations blinded to the laboratories. Twenty-two of the 25 laboratories were successful in identifying all fortified pesticides (0-7 pesticides ranging from 5 to 50 µg/kg) for each produce sample (99.7% detection rate). These studies provide convincing evidence that the nDATA comprehensive approach broadens the screening capabilities of pesticide analyses and provide a platform with the potential to be easily extended to a larger number of other chemical residues and contaminants in foods.


Assuntos
Resíduos de Praguicidas , Praguicidas , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Contaminação de Alimentos/análise , Frutas/química , Resíduos de Praguicidas/análise , Praguicidas/análise , Espectrometria de Massas em Tandem , Verduras , Fluxo de Trabalho
10.
Cell Death Dis ; 12(11): 1029, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34716300

RESUMO

Breast cancer is a major threat to women's health and estrogen receptor-positive (ER+) breast cancer exhibits the highest incidence among these cancers. As the primary estrogen, estradiol strongly promotes cellular proliferation and radiotherapy, as a standard treatment, exerts an excellent therapeutic effect on ER+ breast cancer. Therefore, we herein wished to explore the mechanism(s) underlying the inhibitory effects of radiation on the proliferation of ER+ breast cancer cells. We used the ER+ breast cancer cell lines MCF7 and T47D, and their complementary tamoxifen-resistant cell lines in our study. The aforementioned cells were irradiated at different doses of X-rays with or without exogenous estradiol. CCK8 and clone-formation assays were used to detect cellular proliferation, enzyme-linked immunosorbent assay (ELISA) to determine estradiol secretion, western immunoblotting analysis and quantitative real-time PCR to evaluate the expression of proteins, and immunofluorescence to track endoplasmic reticulum stress-related processes. Finally, BALB/C tumor-bearing nude mice were irradiated with X-rays to explore the protein expression in tumors using immunohistochemistry. We found that ionizing radiation significantly reduced the phosphorylation of estrogen receptors and the secretion of estradiol by ER+ breast cancer cells. CYP19A (aromatase) is an enzyme located in the endoplasmic reticulum, which plays a critical role in estradiol synthesis (aromatization), and we further demonstrated that ionizing radiation could induce endoplasmic reticulum stress with or without exogenous estradiol supplementation, and that it downregulated the expression of CYP19A through ER-phagy. In addition, ionizing radiation also promoted lysosomal degradation of CYP19A, reduced estradiol synthesis, and inhibited the proliferation of tamoxifen-resistant ER+ breast cancer cells. We concluded that ionizing radiation downregulated the expression of CYP19A and reduced estradiol synthesis by inducing endoplasmic reticulum stress in ER+ breast cancer cells, thereby ultimately inhibiting cellular proliferation.

11.
Clin Trials ; 18(6): 673-680, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34693772

RESUMO

BACKGROUND: Contemporary Phase I oncology trials often include efficacy expansion in various tumor indications post dose finding. Preliminary anti-tumor activity from efficacy expansion can aid Go/No-Go decision for Phase 2 or Phase 3 initiation. Tumor cohorts in efficacy expansion are commonly analyzed independently in practice, which are often underpowered due to small sample size. Pooled analysis is also sometimes conducted, but it ignores the heterogeneity of the anti-tumor activity across cohorts. METHODS: We propose an optimal one-stage design and analysis strategy for the efficacy expansion to assess whether the treatment is effective. Allowing heterogeneous anti-tumor effects across tumor cohorts, inactive cohorts are pruned, and the potentially active cohorts are pooled together to gain study power. For a prospective design with a target power, the total sample size across all cohorts is minimized; or for an ad hoc analysis with pre-specified sample size for each cohort, the pruning criteria are optimized to achieve maximum power. The global type I error is controlled after proper multiplicity adjustment, and a penalty adjusted significance level is used for the pooled test. RESULTS: Simulation studies show that the proposed optimal design has desirable operating characteristics in increasing the overall power and detecting more true positive tumor cohorts. CONCLUSION: The proposed optimal design and analysis strategy provides a practical approach to design and analyze heterogeneous efficacy expansion cohorts in a basket setting with global type I and type II error being controlled.

12.
J Affect Disord ; 295: 1040-1048, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34706412

RESUMO

BACKGROUND: Developing machine learning based depression prediction method with information from long-term recordings is important and challenging to clinical diagnosis of depression. METHODS: We developed a novel two-stage feature selection algorithm conducted on the high-dimensional (over thirty thousand) features constructed by a context-aware analysis on the data set of DAIC-WOZ, including audio, video, and semantic features. The prediction performance was compared with seven reference models. The preferred topics and feature categories related to the retained features were also analyzed respectively. RESULTS: Parsimonious subsets (tens of features) were selected by the proposed method in each case of prediction. We obtained the best performance in depression classification with F1-score as 0.96 (0.67), Precision as 1.00 (0.63), and Recall as 0.92 (0.71) on the development set (test set). We also achieved promising results in depression severity estimation with RMSE as 4.43 (5.11) and MAE as 3.22 (3.98), having a marginal difference with the best reference model (random forest with 'Selected-Text' features). Five most important topics related to depression were revealed. The audio features were predominant to the other feature categories in depression classification while the contributions of the three feature categories to severity estimation were almost equal. LIMITATIONS: More depression samples in the database we used should be further included. The second stage of feature selection is relatively time-consuming. CONCLUSION: This pipeline of depression recognition as well as the preferred topics and feature categories are expected to be useful in supporting the diagnosis of psychological distress conditions.


Assuntos
Algoritmos , Depressão , Bases de Dados Factuais , Depressão/diagnóstico , Aprendizado de Máquina
13.
Front Pharmacol ; 12: 706249, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497512

RESUMO

Realgar has been used as a type of mineral drug that contains arsenic for thousands of years. Previous studies have shown that Realgar-induced acute kidney injury is associated with abnormal metabolism, but the underlying mechanism is poorly understood. The aim of this study is to investigate the metabolic changes in serum and kidney tissues of mice exposed to Realgar by using a metabolomic approach and explore the molecular mechanisms of acute kidney injury induced by Realgar. Forty mice were randomly divided into four groups: Control group, 0.5-, 1.0, and 2.0 g/kg Realgar group. After 1 week, the body weight and kidney weight of the mice were measured. The serum and kidney samples were used for LC-MS spectroscopic metabolic profiling. Principal component analysis (PCA), correlation analysis, and pathway analysis were used to detect the nephrotoxic effects of Realgar. Body weight decreased significantly in the 2.0 g/kg group, and the kidney weight index also showed a dose-dependent increase in Realgar. The PCA score plot showed the serum and kidney tissue metabolic profile of mice exposed to 2.0 g/kg Realgar separated from the control group, while the lower-doses of 0.5 g/kg and 1.0 g/kg Realgar shown a similar view to the Control group. Thirty-three metabolites and seventeen metabolites were screened and identified in the serum and kidney of mice in a dose-dependent manner. respectively. Correlation analysis showed a strong correlation among these metabolites. Amino acid metabolism, lipid metabolism, glutathione metabolism, and purine metabolism pathways were found to be mainly associated with Realgar nephrotoxicity. This work illustrated the metabolic alterations in Realgar-induced nephrotoxic mice through a metabolomic approach.

14.
J Immunol Res ; 2021: 6666428, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34514001

RESUMO

Liver ischemia-reperfusion injury (IRI) is an inevitable process during liver transplantation, hemorrhagic shock, resection, and other liver surgeries. It is an important cause of postoperative liver dysfunction and increased medical costs. The protective effects of the vagus nerve on hepatic IRI have been reported, but the underlying mechanism has not been fully understood. We established a hepatic vagotomy (Hv) mouse model to study the effect of the vagus on liver IRI and to explore the underlying mechanism. Liver IRI was more serious in mice with Hv, which showed higher serum ALT and AST activities and histopathological changes. Further experiments confirmed that Hv significantly downregulated the expression of IL-22 protein and mRNA in the liver, blocking the activation of the STAT3 pathway. The STAT3 pathway in the livers of Hv mice was significantly activated, and liver injury was clearly alleviated after treatment with exogenous IL-22 recombinant protein. In conclusion, Hv can aggravate hepatic IRI, and its mechanism may be related to inhibition of IL-22 expression and downregulation of the STAT3 pathway in the liver.

15.
Chem Commun (Camb) ; 57(77): 9894-9897, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34494043

RESUMO

Herein, we report the first example of controllable magnetoresistance in a semiconducting carbonized phthalonitrile resin. This special phenomenon is explained using the different ratios of graphite-like (sp2) and diamond-like (sp3) bonds and localization length (a0) as well as the density of states at the Fermi-level (N(EF)).

16.
Trends Plant Sci ; 26(12): 1207-1209, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34493443

RESUMO

Hydrogen sulfide (H2S) signaling regulates plant responses to adverse conditions via persulfidation of proteins. Recently, Chen et al. proposed that mechanistic interplay between H2S-linked persulfidation- and phosphorylation-based regulation of SNF1-RELATED PROTEIN KINASE 2.6 (SnRK2.6) modulates these pathways, providing a missing link to explain how plants coordinate abscisic acid (ABA) and H2S signaling in drought responses.

17.
Environ Microbiol ; 23(11): 6463-6482, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34587356

RESUMO

Soda-saline lakes are polyextreme environments inhabited by many haloalkaliphiles, including one of the most abundant Spiribacter species. However, its mechanisms of adaptation are not ecophysiologically characterized. Based on a large-scale cultivation strategy, we obtained a representative isolate of this Spiribacter species whose relative abundance was the highest (up to 15.63%) in a wide range of salinities in the soda-saline lakes in Inner Mongolia, China. This species is a chemoorganoheterotrophic haloalkaliphile. It has a small and streamlined genome and utilizes a wide variety of compatible solutes to resist osmotic pressure and multiple monovalent cation/proton antiporters for pH homeostasis. In addition to growth enhancement by light under microaerobic conditions, cell growth, organic substrate consumption and polyhydroxybutyrate biosynthesis were also improved by inorganic sulfide. Both quantitative RT-PCR and enzymatic assays verified that sulfide:quinone oxidoreductase was upregulated during this process. Metatranscriptomic analysis indicated that all genes related to environmental adaptation were transcribed in natural environments. Overall, this study has identified a novel abundant haloalkaliphile with multiple and highly integrated adaptive strategies and found that inorganic sulfide was able to improve the adaptation of a heterotroph to polyextreme environments.

18.
J Chromatogr A ; 1654: 462477, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34433124

RESUMO

Platycodon grandiflorum (PG), as a well-known medicine food homology species, possess various pharmacological effects and health benefits. Aiming to facilitate in-depth and global characterization of the chemical compositions of PG, a profiling method based on ultra-high performance liquid chromatography coupled with ion mobility quadrupole time-of-flight mass spectrometry (UPLC/IM-QTOF-MS) was conducted. Consequently, as many as 187 compounds were plausibly or unambiguously identified. Most importantly, phospholipids (PLs) were first observed and identified in PG. Due to their widely confirmed bioactivities, an analysis scheme was developed by hydrophilic interaction liquid chromatography and electrospray ionization tandem mass spectrometry combined with the online Paternò-Büchi reaction (HILIC-PB-MS/MS). The fatty acyl chains and C=C locations of 180 PLs molecular species, which fell into four classes, were unprecedently characterized. This exposure strategy of multi-type constituents greatly enriches the chemical profiling of PG, and helps promoting the further development of therapeutic agents and nutraceutical products from PG.


Assuntos
Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Platycodon , Espectrometria de Massas por Ionização por Electrospray , Química Farmacêutica/métodos , Suplementos Nutricionais/análise , Plantas Medicinais/química , Platycodon/química
19.
Mol Med Rep ; 24(5)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34435648

RESUMO

The present study aimed to investigate the protective effect of carvacrol on liver injury in mice with type 2 diabetes mellitus (T2DM) and to assess its potential molecular mechanism. Mice were divided into three groups (n=15/group): Non­diabetic db/m+ mice group, db/db mice group and db/db mice + carvacrol group. In the db/db mice + carvacrol group, db/db mice were administered 10 mg/kg carvacrol daily by gavage for 6 weeks. Fasting blood glucose and insulin levels were separately examined. Pathological changes were observed using hematoxylin and eosin, Masson's trichrome, periodic acid Schiff and reticular fiber staining. In addition, immunohistochemistry, immunofluorescence and western blotting were used to examine the expression levels of Toll­like receptor 4 (TLR4), NF­κB, NALP3, AKT1, phosphorylated (p)­AKT1, insulin receptor (INSR), p­INSR, mTOR, p­mTOR, insulin receptor substrate 1 (IRS1) and p­IRS1 in the liver tissues. The results revealed that carvacrol improved blood glucose and insulin resistance of T2DM db/db mice. After treatment with carvacrol for 6 weeks, the serum levels of TC, TG and LDL­C were markedly reduced, whereas HDL­C levels were significantly increased in db/db mice. Furthermore, carvacrol administration significantly decreased serum ALT and AST levels in db/db mice. Serum BUN, Cre and UA levels were markedly higher in db/db mice compared with those in the control group; however, carvacrol treatment markedly reduced their serum levels in db/db mice. Furthermore, histological examinations confirmed that carvacrol could protect the liver of db/db mice. Carvacrol could ameliorate liver injury induced by T2DM via mediating insulin, TLR4/NF­κB and AKT1/mTOR signaling pathways. The present findings suggested that carvacrol exerted protective effects on the liver in T2DM db/db mice, which could be related to insulin, TLR4/NF­κB and AKT1/mTOR signaling pathways.

20.
Cell Biol Toxicol ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34296331

RESUMO

Despite effective anticancer effects, the use of doxorubicin (Dox) is limited due to its side effects as cardiotoxicity. Corosolic acid (CRA) is a pentacyclic triterpene acid isolated from Lagerstroemia speciosa L. (Banaba) leaves, and it has also been shown to improve myocardial hypertrophy and myocardial infarction which expected to be used in clinical pharmaceuticals. The purpose of this study was to explore whether CRA can improve myocardial injury caused by Dox and to clarify potential mechanisms. C57 BL/6J mice and AMPKα2 knockout mice were given a single intraperitoneal (i.p.) injection of Dox (5 mg/kg) every week for 4 weeks, while normal saline (NS) was used as control. Mice were given CRA (10 mg/kg or 20 mg/kg) or equal volumes of normal saline daily after the first time i.p. injection of Dox. After 4 weeks, echocardiography, gravimetric, hemodynamic, histological, and biochemical analyses were conducted. After Dox injury, compared with the control group, CRA increased the survival rate of mice, improved the cardiac function, decreased the oxidative stress, and reduced the apoptosis. CRA may function by promoting transcription factor EB (TFEB) nuclear translocation and thus restoring autophagic flux. We also observed that CRA protected mitochondrial structure and function, which may benefit from oxidative stress reduction or TFEB activation. In vitro, the protective effect of CRA is reversed by TFEB deletion. Then, we evaluated the expression of AMPKα2/mTOR C1 signaling pathway, the main pathway of TFEB activation. In vivo and in vitro, CRA promoted TFEB nuclear translocation by activating AMPKα2/mTOR C1 signaling, while ablating AMPKα2 reversed these results and accompanied with a decrease in the ability of CRA to resist Dox-induced cardiotoxicity. Thus, we suggested that CRA activated TFEB in an AMPKα2-dependent manner to protect against Dox cardiotoxicity. This study confirms the role and mechanism of CRA in the treatment of Dox-induced cardiac injury. Dox-induced damage to autophagy includes autophagosomes maturation disorders and autophagolysosomes acidification defects, CRA restored autophagic flux, and promoted lysosomal degradation by activating TFEB in an AMPKα2-depended manner, stabilized mitochondrial function, ultimately protected against Dox-induced cardiotoxicity.

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