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1.
Theranostics ; 12(2): 929-943, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34976221

RESUMO

Background: Bone is a frequent site of metastases from breast cancer, but existing therapeutic options are not satisfactory. Although osteoblasts have active roles in cancer progression by assisting the vicious bone-destructive cycle, we employed a counterintuitive approach of activating pro-tumorigenic Wnt signaling and examined the paradoxical possibility of developing osteoblast-derived tumor-suppressive, bone-protective secretomes. Methods: Wnt signaling was activated by the overexpression of Lrp5 and ß-catenin in osteoblasts as well as a pharmacological agent (BML284), and the therapeutic effects of their conditioned medium (CM) were evaluated using in vitro cell cultures, ex vivo breast cancer tissues, and a mouse model of osteolysis. To explore the unconventional regulatory mechanism of the action of Wnt-activated osteoblasts, whole-genome proteomics analysis was conducted, followed by immunoprecipitation and gain- and loss-of-function assays. Results: While osteoblasts did not present any innate tumor-suppressing ability, we observed that the overexpression of Lrp5 and ß-catenin in Wnt signaling made their CM tumor-suppressive and bone-protective. The growth of breast cancer cells and tissues was inhibited by Lrp5-overexpressing CM (Lrp5 CM), which suppressed mammary tumors and tumor-driven bone destruction in a mouse model. Lrp5 CM also inhibited the differentiation and maturation of bone-resorbing osteoclasts by downregulating NFATc1 and cathepsin K. The overexpression of Lrp5 upregulated osteopontin that enriched Hsp90ab1 (Hsp90 beta) and moesin (MSN) in Lrp5 CM. Hsp90ab1 and MSN are atypical tumor-suppressing proteins since they are multi-tasking, moonlighting proteins that promote tumorigenesis in tumor cells. Importantly, Hsp90ab1 immuno-precipitated latent TGFß and inactivated TGFß, whereas MSN interacted with CD44, a cancer stem-cell marker, as well as fibronectin 1, an ECM protein. Furthermore, Hsp90ab1 and MSN downregulated KDM3A that demethylated histones, together with PDL1 that inhibited immune responses. Conclusion: In contrast to inducing tumor-enhancing secretomes and chemoresistance in general by inhibiting varying oncogenic pathways in chemotherapy, this study presented the unexpected outcome of generation tumor-suppressive secretomes by activating the pro-tumorigenic Wnt pathway. The results shed light on the contrasting role of oncogenic signaling in tumor cells and osteoblast-derived secretomes, suggesting a counterintuitive option for the treatment of breast cancer-associated bone metastasis.

2.
Oncol Rep ; 47(3)2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35014683

RESUMO

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the colony formation assay data shown in Fig. 2C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 38: 1295­1302, 20137; DOI: 10.3892/or.2017.5745].

3.
Oncol Rep ; 47(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34821372

RESUMO

Following the publication of the above paper, the authors submitted a request to the Editorial Office to publish a corrigendum in light of a concern regarding potential contamination of their cells during the course of performing the experiments; at the same time, it was drawn to the Editors' attention by a concerned reader that certain of the colony­formation assay data shown in Fig. 2C were strikingly similar to data appearing in different form in another article by different authors. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 37: 297-304, 2017; DOI: 10.3892/or.2016.5275].

4.
Hortic Res ; 8(1): 255, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34848682

RESUMO

The marvelously diverse Orchidaceae constitutes the largest family of angiosperms. The genus Cymbidium in Orchidaceae is well known for its unique vegetation, floral morphology, and flower scent traits. Here, a chromosome-scale assembly of the genome of Cymbidium ensifolium (Jianlan) is presented. Comparative genomic analysis showed that C. ensifolium has experienced two whole-genome duplication (WGD) events, the most recent of which was shared by all orchids, while the older event was the τ event shared by most monocots. The results of MADS-box genes analysis provided support for establishing a unique gene model of orchid flower development regulation, and flower shape mutations in C. ensifolium were shown to be associated with the abnormal expression of MADS-box genes. The most abundant floral scent components identified included methyl jasmonate, acacia alcohol and linalool, and the genes involved in the floral scent component network of C. ensifolium were determined. Furthermore, the decreased expression of photosynthesis-antennae and photosynthesis metabolic pathway genes in leaves was shown to result in colorful striped leaves, while the increased expression of MADS-box genes in leaves led to perianth-like leaves. Our results provide fundamental insights into orchid evolution and diversification.

5.
Front Plant Sci ; 12: 744792, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868129

RESUMO

Oryza longistaminata is an African wild rice species that possesses special traits for breeding applications. Self-incompatibility is the main cause of sterility in O. longistaminata, but here we demonstrated that its pollen vitality are normal. Lipid and carbohydrate metabolism were active throughout pollen development. In this study, we used I2-KI staining and TTC staining to investigate pollen viability. Aniline-blue-stained semithin sections were used to investigate important stages of pollen development. Tandem mass tags (TMT)-based quantitative analysis was used to investigate the profiles of proteins related to lipid and carbohydrate metabolism in 4-, 6-, and 8.5-mm O. longistaminata spikelets before flowering. Pollen was found to germinate normally in vitro and in vivo. We documented cytological changes throughout important stages of anther development, including changes in reproductive cells as they formed mature pollen grains through meiosis and mitosis. A total of 31,987 RNA transcripts and 8,753 proteins were identified, and 6,842 of the proteins could be quantified. RNA-seq and proteome association analysis indicated that fatty acids were converted to sucrose after the 6-mm spikelet stage, based on the abundance of most key enzymes of the glyoxylate cycle and gluconeogenesis. The abundance of proteins involved in pollen energy metabolism was further confirmed by combining quantitative real-time PCR with parallel reaction monitoring (PRM) analyses. In conclusion, our study provides novel insights into the pollen viability of O. longistaminata at the proteome level, which can be used to improve the efficiency of male parent pollination in hybrid rice breeding applications.

6.
CNS Neurosci Ther ; 2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-34964272

RESUMO

AIM: To understand the direct impact of bradykinin in autonomic control of circulation through baroreflex afferent pathway. METHODS: The mean arterial pressure (MAP) was monitored while bradykinin and its agonists were applied via nodose (NG) microinjection, the expression of bradykinin receptors (BRs) in the NG (1st -order) and nucleus tractus solitarius (NTS, 2nd -order) were tested in adult male, age-matched female, and ovariectomized rats under physiological and hypertensive conditions. Additionally, bradykinin-induced depolarization was also tested in identified baroreceptor and baroreceptive neurons using whole-cell patch-clamp technique. RESULTS: Under physiological condition, bradykinin-induced dose- and estrogen-dependent reductions of MAP with lower estimated EC50 in females. B2 R agonist mediated more dramatic MAP reduction with long-lasting effect compared with B1 R activation. These functional observations were consistent with the molecular and immunostaining evidences. However, under hypertensive condition, the MAP reduction was significantly less dramatic in N' -Nitro-L-Arginine-methyl ester (L-NAME) induced secondary and spontaneous hypertension rats in males compared with female rats. Electrophysiological data showed that bradykinin-elicited concentration-dependent membrane depolarization with discharges during initial phase in identified myelinated Ah-types baroreceptor neurons, not myelinated A-types; while, higher concentration of bradykinin was required for depolarization of unmyelinated C-types without initial discharges. CONCLUSION: These datasets have demonstrated for the first time that bradykinin mediates direct activation of baroreflex afferent function to trigger estrogen-dependent depressor response, which is due mainly to the direct activation/neuroexcitation of female-specific myelinated Ah-type baroreceptor neurons leading to a sexual dimorphism in parasympathetic domination of blood pressure regulation via activation of B2 R/B1 R expression in baroreflex afferent pathway.

8.
Front Vet Sci ; 8: 751861, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34917669

RESUMO

Newborn piglets are prone to diarrhea after weaning as a result of changes in their environment and feed. Enterotoxigenic Escherichia coli (ETEC) K88 strain is a typical pathogen that causes diarrhea in such stage of piglets. Hermetia illucens larvae are widely used in livestock and poultry production because of their high nutritional value and immunoregulatory effects. This study aimed to evaluate the protective effects of H. illucens feed in protecting against ETEC induced diarrhea in piglets and to unravel the mechanisms of immune modulation and intestinal barrier maintenance. The results showed that after ETEC infection, citric acid in the serum of the groups fed on H. illucens larvae increased significantly, which stimulated macrophages to secrete cytokines that promote B lymphocyte differentiation, ultimately increasing the production of IgA and IgG in serum. Concomitantly, citric acid also had a positive effect on the intestinal barrier damaged due to ETEC infection by inhibiting the production of inflammatory cytokines, reducing the Bcl-2/Bax ratio, and promoting the expression of tight junction proteins. Correlation analysis showed that the increase of citric acid levels might be related to Massilia. Thus, citric acid derived from H. illucens larvae can improve the immune performance of weaned piglets and reduce ETEC-induced damage to the intestinal barrier in weaned piglets.

9.
Wideochir Inne Tech Maloinwazyjne ; 16(4): 697-703, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34950264

RESUMO

Introduction: Treatment of highly complex anal fistula is still a profound test for a specialist colorectal surgeon. The reasons are directly related to recurrence and incontinence. Aim: To evaluate the clinical results of a combined method of intraoperative endoanal ultrasonography (IOEAUS) and transanal opening of the intersphincteric space (TROPIS). Material and methods: This study retrospectively included 48 patients with complex anal fistula, all of whom underwent new surgical methods. This operation mainly consists of two steps. Firstly, the type of anal fistula was determined by endoanal ultrasonography (EAUS) or magnetic resonance imaging (MRI) before the operation. Then the TROPIS procedure was performed with the help of EAUS, and the decision on whether a drainage seton should be placed depended on the condition of the tract. If there were secondary tracts, they were found and the same was done. Results: The median follow-up was 12 months. Two (4.1%) patients experienced recurrence. Four (8.3%) patients did not have primary healing. All 6 patients underwent the same procedure again, and three recovered completely. So total successful fistula healing was observed in 45 (93.7%). There were no major complications and no significant deterioration in anal function and incontinence postoperatively. Conclusions: Combined IOEAUS and TROPIS is an effective procedure in the treatment of highly complex anal fistula, and it may offer a new means for other operations.

10.
J Phys Chem Lett ; 12(51): 12187-12195, 2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-34918929

RESUMO

Hybrid methylammonium lead iodide (MAPbI3) perovskite nanoplatelets (NPLs) have emerged as promising optoelectronic materials because of their remarkable properties in defect tolerance, band gap tunability, and light emission. However, the detailed formation mechanism, in particular the atomic structure information in the initial nucleation stage, stands as a mystery because of the intrinsic vulnerability toward moisture, electron beams, etc. By virtue of the imaging technique under the extremely low electron dose of the cryogenic TEM, atomic structures of MAPbI3 NPLs are imaged, and a twist-to-untwist structural evolution is captured. According to theoretical calculation results, the twist-to-untwist evolution is a spontaneous process, and the band gap will be reduced, which is further verified by the red shift of photoluminescence peaks with aging time. Moreover, MA cation polarization is observed by quantitative analysis of the atomic-resolution image of single-crystalline MAPbI3 NPLs, which demonstrates the high ion mobility in the lattice of the hybrid halide perovskites.

11.
Cancers (Basel) ; 13(22)2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34830748

RESUMO

Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFß (LAP-TGFß) as an inhibitor of TGFß activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.

12.
Obes Facts ; 14(6): 658-674, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34818257

RESUMO

INTRODUCTION: Parents can act as important agents of change and support for healthy childhood growth and development. Studies have found that parents may not be able to accurately perceive their child's weight status. The purpose of this study was to measure parental perceptions of their child's weight status and to identify predictors of potential parental misperceptions. METHODS: We used data from the World Health Organization (WHO) European Childhood Obesity Surveillance Initiative and 22 countries. Parents were asked to identify their perceptions of their children's weight status as "underweight," "normal weight," "a little overweight," or "extremely overweight." We categorized children's (6-9 years; n = 124,296) body mass index (BMI) as BMI-for-age Z-scores based on the 2007 WHO-recommended growth references. For each country included in the analysis and pooled estimates (country level), we calculated the distribution of children according to the WHO weight status classification, distribution by parental perception of child's weight status, percentages of accurate, overestimating, or underestimating perceptions, misclassification levels, and predictors of parental misperceptions using a multilevel logistic regression analysis that included only children with overweight (including obesity). Statistical analyses were performed using Stata version 15 1. RESULTS: Overall, 64.1% of parents categorized their child's weight status accurately relative to the WHO growth charts. However, parents were more likely to underestimate their child's weight if the child had overweight (82.3%) or obesity (93.8%). Parents were more likely to underestimate their child's weight if the child was male (adjusted OR [adjOR]: 1.41; 95% confidence intervals [CI]: 1.28-1.55); the parent had a lower educational level (adjOR: 1.41; 95% CI: 1.26-1.57); the father was asked rather than the mother (adjOR: 1.14; 95% CI: 0.98-1.33); and the family lived in a rural area (adjOR: 1.10; 95% CI: 0.99-1.24). Overall, parents' BMI was not strongly associated with the underestimation of children's weight status, but there was a stronger association in some countries. DISCUSSION/CONCLUSION: Our study supplements the current literature on factors that influence parental perceptions of their child's weight status. Public health interventions aimed at promoting healthy childhood growth and development should consider parents' knowledge and perceptions, as well as the sociocultural contexts in which children and families live.

14.
Plant Physiol ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34618124

RESUMO

Petals of the monocot Phalaenopsis aphrodite (Orchidaceae) possess conical epidermal cells on their adaxial surfaces, and a large amount of cuticular wax is deposited on them to serve as a primary barrier against biotic and abiotic stresses. It has been widely reported that subgroup 9A members of the R2R3-MYB gene family, MIXTA and MIXTA-like in eudicots, act to regulate the differentiation of conical epidermal cells. However, the molecular pathways underlying conical epidermal cell development and cuticular wax biosynthesis in monocot petals remain unclear. Here, we characterized two subgroup 9A R2R3-MYB genes, PaMYB9A1 and PaMYB9A2 (PaMYB9A1/2), from P. aphrodite through the transient overexpression of their coding sequences and corresponding chimeric repressors in developing petals. We showed that PaMYB9A1/2 function to coordinate conical epidermal cell development and cuticular wax biosynthesis. In addition, we identified putative targets of PaMYB9A1/2 through comparative transcriptome analyses, revealing that PaMYB9A1/2 acts to regulate the expression of cell wall-associated and wax biosynthetic genes. Furthermore, a chemical composition analysis of cuticular wax showed that even-chain n-alkanes and odd-chain primary alcohols are the main chemical constituents of cuticular wax deposited on petals, which is inconsistent with the well-known biosynthetic pathways of cuticular wax, implying a distinct biosynthetic pathway occurring in P. aphrodite flowers. These results reveal that the function of subgroup 9A R2R3-MYB family genes in regulating the differentiation of epidermal cells is largely conserved in monocots and dicots. Furthermore, both PaMYB9A1/2 have evolved additional functions controlling the biosynthesis of cuticular wax.

15.
Ecotoxicol Environ Saf ; 226: 112862, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34624533

RESUMO

OBJECTIVE: To investigate the mechanisms of ATR-induced dopaminergic toxicity by microglia activation and the response of the Keap1/ Nrf2- ARE signaling pathway. METHODS: Wistar rats were treated with 50, 100 and 200 mg/kg ATR and BV-2 microglia cells were treated with 50, 100 µM ATR or 100 ng/mL LPS, respectively. Rats behavioral responses and histopathological changes were monitored. Immunohistochemical and immunofluorescence analysis detected Iba-1 and TH+ cells in rats. Keap1/Nrf2-ARE signaling-related proteins and inflammatory factors from BV-2 cells and rats were detected using ELISA, Western blot and Real-time PCR. RESULTS: After ATR treatment, the grip strength of Wistar rats was significantly decreased, and anxiety were clearly observed. TH+ neurons were reduced, however, the number of microglia cells and Iba-1 levels were increased clearly in SN. The release of ROS, TNF-α and IL-Iß were increased, and levels of SOD and GSH-Px were significantly decreased. Keap1 mRNA expression and protein levels were decreased, while nuclear Nrf2 mRNA expression and protein levels were both increased in vivo and in vitro. CONCLUSION: ATR could significantly activate microglia and exacerbate neurotoxicity and neuroinflammation, leading to accelerate dopaminergic neuron cell death by inhibiting Keap1/Nrf2-ARE signaling pathway.


Assuntos
Atrazina , Fator 2 Relacionado a NF-E2 , Animais , Neurônios Dopaminérgicos/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Microglia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais
16.
Biometals ; 34(6): 1353-1363, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34599705

RESUMO

Mercury (Hg) is highly toxic while selenium (Se) has been found to antagonize Hg. Both Hg and Se have been found to induce metallothioneins (MTs). In this study, the complexes formed by metallothionein-1 (MT-1) with HgCl2 and/or Na2SeO3 was studied using matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) and X-ray absorption spectrometry (XAS). MALDI-TOF-MS and XAS indicated the formation of Hg-S bond or Se-S bond when MT-1 reacted with HgCl2 or Na2SeO3, respectively. The bond lengths of Hg-S and coordination number in MT-Hg are 2.41 ± 0.02 Å and 3.10 and in MT-Se are 2.50 ± 0.03 Å and 2.69. A MT-Se-Hg complex was formed when MT-1 reacted with both HgCl2 and Na2SeO3, in which the neighboring atom of Hg is Se, while the neighboring atoms of Se are S and Hg. Our study is an important step towards a better understanding of the interaction of HgCl2 and/or Na2SeO3 with proteins like MT-1.

17.
J Cardiothorac Surg ; 16(1): 308, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663400

RESUMO

BACKGROUND: This study aimed to determine the underlying pathophysiologic mechanism of elevated carbohydrate antigen 19-9 (CA19-9) in pulmonary sequestration (PS) patients. MATERIALS AND METHODS: Four pulmonary sequestration patients, 12 pneumonia patients and 12 healthy adult volunteers were prospectively studied. Specimens from another 34 pulmonary sequestration patients were retrospectively analyzed. Serum CA19-9 levels of 4 patients were tested before and 1 week, 1 month and 3 months after surgery. The CA19-9 levels of 12 pneumonia patients and 12 healthy adult volunteers were tested as controls. The expression and localization of CA19-9 in diseased lesions and corresponding normal lung tissues were analyzed by Immunohistochemical (IHC). Hematoxylin-eosin (HE) staining was performed to observe the pathological changes in pulmonary sequestration tissues. RESULTS: Serum CA19-9 levels were significantly higher in the 4 patients (797.3 ± 316 IU/ml) than in the pneumonia patients (10.07 ± 5.01 IU/ml) and healthy volunteers (9.85 ± 4.12 IU/ml). In addition, serum CA19-9 levels decreased dramatically after the focus was removed. Positive staining of CA19-9 was found in 70% (24/34) of pulmonary sequestration tissues, and CA19-9 was mainly expressed in the bronchial mucus. In the 4 diseased lesions, deformed alveolar structure and inflammatory cell infiltration were observed, and the degree of damage was positively correlated with serum CA19-9 levels. CONCLUSIONS: CA19-9 could be generated by abnormal columnar epithelia in pulmonary sequestration tissues and was transported into circulation after alveoli damage. CA19-9 could serve as an adjuvant diagnostic marker in pulmonary sequestration.


Assuntos
Sequestro Broncopulmonar , Pneumopatias , Biomarcadores Tumorais , Antígeno CA-19-9 , Humanos , Pneumopatias/diagnóstico , Estudos Retrospectivos
18.
Kaohsiung J Med Sci ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34672426

RESUMO

To explore the relationship between the severity of hypertension and the imbalanced intestinal flora, inflammatory factors, adiponectin (ADPN) and vascular endothelial function in primary hypertension patients. According to the grading criteria for hypertension, in total of 60 patients with primary hypertension in our hospital from April to July, 2020 were divided into Grade 1 group (n = 20), Grade 2 group (n = 20), and Grade 3 group (n = 20). The feces of the research subjects were collected to extract the deoxyribonucleic acid (DNA) and detect its composition of intestinal flora. Subsequently, the peripheral blood was collected to determine the changes in inflammatory factors interleukin-2 (IL-2), IL-4, tumor necrosis factor-α (TNF-α) and IL-1ß, serum immunoglobulin G (IgG) and IgM, ADPN and vascular endothelial function-related endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and intercellular adhesion molecule-1 (ICAM-1). There were no significant differences in the gender, age, and body mass index (BMI), the proportion of smokers, diet habit, probiotics and antihypertensive medication use, and number of diabetic cases among groups (p > 0.05). We found an inverse association between blood pressure measures and microbial diversity, in particular microbial richness (p < 0.05). Among the four major kinds of intestinal flora, the composition of firmicutes (p < 0.05) and bacteroidetes (p < 0.05) showed obvious differences among the three groups, and they had consistent trends with the changes in the abundance of firmicutes and bacteroidetes. Intestinal flora imbalance is closely related to the severity of hypertension, inflammatory factors, ADPN, and vascular endothelial function.

19.
Ecotoxicol Environ Saf ; 227: 112886, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34673406

RESUMO

Atrazine (ATR) is a widely used herbicide that can induce the degeneration of dopaminergic (DAergic) neurons in the substantia nigra, resulting in a Parkinson's disease-like syndrome. Despite the high risk of environmental exposure, few studies have investigated strategies for the prevention of ATR neurotoxicity. Our previous studies demonstrated that ATR can impair mitochondrial function, leading to metabolic failure. Cells maintain mitochondrial quality through selective autophagic elimination, termed mitophagy. Soybean isoflavones (SI) possess multiple beneficial bioactivities, including preservation of mitochondria function, so it was hypothesized that SI can protect neurons against ATR toxicity by promoting mitophagy. Pretreatment of SH-SY5Y neurons with SI prevented ATR-induced metabolic failure and cytotoxicity as assessed by intracellular ATP, Na+-K+-ATPase activity, mitochondrial membrane potential, and cell viability assays. The neuroprotective efficacy of SI was superior to the major individual components genistein, daidzein, and glycitein. Ultrastructural analyses revealed that ATR induced mitochondrial damage, while SI promoted the sequestration of damaged mitochondria into autophagic vesicles. Soybean isoflavones also induced mitophagy as evidenced by upregulated expression of BNIP3/NIX, BEX2, and LC3-II, while co-treatment with the mitophagy inhibitor Mdivi-1 blocked SI-mediated neuroprotection and prevented SI from reversing ATR-induced BEX2 downregulation. Furthermore, BEX2 knockdown inhibited SI-induced activation of the BNIP3/NIX pathway, mitophagy, and neuroprotection. These findings suggest that SI protects against ATR-induced mitochondrial dysfunction and neurotoxicity by activating the BEX2/BNIP3/NIX pathway.


Assuntos
Atrazina , Isoflavonas , Atrazina/toxicidade , Neurônios Dopaminérgicos , Isoflavonas/farmacologia , Proteínas de Membrana , Mitofagia , Soja
20.
Ecotoxicol Environ Saf ; 225: 112791, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34555721

RESUMO

Mercury (Hg) brings adverse effects to the environment and human beings and inorganic mercury (IHg) is a typical hepatic toxin. This work studied the impacts of IHg on gut microbes and metabolome together with its damage to liver and gut in rats through gut microbiome, metabolomics and metallomics. Sprague Dawley (SD) rats were orally exposed to 0.4 µg/mL IHg and sacrificed after 24 h. It was found that IHg perturbed greatly on the gut microbiota, such as increased pathogenic bacteria like G. bacillus. In addition, IHg also changed gut-liver axis related metabolites, which was confirmed by the secretion of a large number of inflammatory factors in both the gut and the liver. The changed gut-liver axis related metabolites correlated well to the changes of gut microbiome. In all, besides the direct deposition in liver of Hg, the perturbance to gut microbiome and alteration of gut-liver axis related metabolites by IHg also contributed to its hepatoxicity, which provides new insights about the hepatoxicity of chemicals. The strategy applied in this work may also be used to understand the hepatoxicity of other chemicals.


Assuntos
Microbioma Gastrointestinal , Mercúrio , Animais , Fígado , Mercúrio/toxicidade , Metabolômica , Ratos , Ratos Sprague-Dawley
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