Publications by authors named "Zhen Zou"

180 Publications

Stabilization of Nrf2 leading to HO-1 activation protects against zinc oxide nanoparticles-induced endothelial cell death.

Nanotoxicology 2021 May 10:1-19. Epub 2021 May 10.

Institute of Life Sciences, Chongqing Medical University, Chongqing, People's Republic of China.

With the abundant production and wide application of zinc oxide nanoparticles (ZnONPs), the potential health risks of ZnONPs have raised serious concerns. Oxidative stress is recognized as the most important outcome of the toxicity induced by ZnONPs. The Nrf2-Keap1 system and its downstream antioxidative genes are the fundamental protective mechanisms for redox hemeostasis. However, the detailed mechanisms of Nrf2 activation in ZnONPs-treated endothelial cells and murine blood vessels have yet to be elucidated. Herein, we show that Nrf2 was activated and played a negative role in cell death induced by ZnONPs. Moreover, we demonstrate that HO-1 was the most extensively upregulated antioxidative gene-activated by Nrf2. Forced overexpression of HO-1, pharmacological activation of HO-1 with the agonists RTA-408 (omaveloxolone, an FDA-approved drug) and RTA-402 repressed cell death, and treatment with HO-1 antagonist SnPP exacerbated the cell death. Importantly, loss of HO-1 diminished the cytoprotective role induced by Nrf2 in ZnONPs-treated HUVEC cells, indicating that the Nrf2-HO-1 axis was the crucial regulatory mechanism for the antioxidative response in the context of ZnONPs-induced endothelial damage. Mechanistically, we demonstrate that the p62-Keap1 axis was not involved in the activation of Nrf2. Intriguingly, the degradation half-life of Nrf2 in HUVEC cells was increased from less than 1 h under quiescent conditions to approximately 6 h under ZnONPs treatment condition; moreover, ZnONPs treatment induced activation of Nrf2/HO-1 and accumulation of ubiquitin in the aorta ventralis of mouse, suggesting that the ubiquitin-proteasome system had been perturbed, which subsequently led to the stabilization of Nrf2 and activation of HO-1. This study might contribute to a better understanding of ZnONPs-associated toxicity.
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http://dx.doi.org/10.1080/17435390.2021.1919330DOI Listing
May 2021

E93 confers steroid hormone responsiveness of digestive enzymes to promote blood meal digestion in the midgut of the mosquito Aedes aegypti.

Insect Biochem Mol Biol 2021 Apr 24;134:103580. Epub 2021 Apr 24.

Department of Entomology, University of California, Riverside, CA, 92521, USA; Institute of Integrative Genome Biology, University of California, Riverside, CA, 92521, USA. Electronic address:

Anautogenous female mosquitoes obtain the nutrients needed for egg development from vertebrate blood, and consequently they transmit numerous pathogens of devastating human diseases. Digestion of blood proteins into amino acids that are used for energy production, egg maturation and replenishment of maternal reserves is an essential part of the female mosquito reproductive cycle. However, the regulatory mechanisms underlying this process remain largely unknown. Here, we report that the transcription factor E93 is a critical factor promoting blood meal digestion in adult females of the major arboviral vector Aedes aegypti in response to the steroid hormone 20-hydroxyecdysone (20E). E93 was upregulated in the female mosquito midgut after a blood meal, and RNA interference (RNAi)-mediated knockdown of E93 inhibited midgut blood digestion. E93 RNAi depletion repressed late trypsin (LT), serine protease I (SPI), SPVI and SPVII, and activated early trypsin (ET) expression in the female mosquito midgut after a blood meal. Injection of 20E activated E93, LT, SPI, SPVI and SPVII, and repressed ET expression, whereas RNAi knockdown of the ecdysone receptor (EcR) repressed E93, LT, SPI, SPVI and SPVII, and activated ET expression in the midgut. Furthermore, E93 depletion resulted in a complete loss of 20E responsiveness of LT, SPVI and SPVII. Our findings reveal important mechanisms regulating blood meal digestion in disease-transmitting mosquitoes.
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http://dx.doi.org/10.1016/j.ibmb.2021.103580DOI Listing
April 2021

Knock-down of transcription factor skinhead-1 exacerbates arsenite-induced oxidative damage in Caenorhabditis elegans.

Biometals 2021 Jun 21;34(3):675-686. Epub 2021 Apr 21.

Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, People's Republic of China.

Transcription factor, skinhead-1 (skn-1) has been demonstrated to play central roles in regulation of oxidative damage. Arsenite is an oxidative damage inducer in the environment. However, the role of skn-1 in arsenite-induced oxidative damage remains unclear. Thus, in this study, by using RNAi feeding, different toxic responses of wild-type and skn-1 knockdown nematodes to arsenite were evaluated. Our results demonstrated that arsenite did not show any significant impacts on locomotory behaviors, but skn-1 knock-down worms were much more sensitive to arsenite treatment, manifested by an aggravated reduction of survival rate than that of wild-type nematodes. In arsenite-treated worms, down-regulation of skn-1 significantly exacerbated the arsenite-induced changed expressions of oxidative damage-related genes, xbp-1, apl-1 and trxr-2, but these regulated effects of skn-1 were not observed on spr-4 and sel-12 expressions under arsenite treatment. These findings together suggest that skn-1 may play a vital role in protection of C. elegans from arsenite-induced oxidative damage.
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http://dx.doi.org/10.1007/s10534-021-00303-2DOI Listing
June 2021

Ferritinophagy is involved in the zinc oxide nanoparticles-induced ferroptosis of vascular endothelial cells.

Autophagy 2021 Apr 12:1-20. Epub 2021 Apr 12.

College of Pharmacy, Chongqing Medical University, Chongqing, People's Republic of China.

Zinc oxide nanoparticles (ZnONPs) hold great promise for biomedical applications. Previous studies have revealed that ZnONPs exposure can induce toxicity in endothelial cells, but the underlying mechanisms have not been fully elucidated. In this study, we report that ZnONPs can induce ferroptosis of both HUVECs and EA.hy926 cells, as evidenced by the elevation of intracellular iron levels, lipid peroxidation and cell death in a dose- and time-dependent manner. In addition, both the lipid reactive oxygen species (ROS) scavenger ferrostatin-1 and the iron chelator deferiprone attenuated ZnONPs-induced cell death. Intriguingly, we found that ZnONPs-induced ferroptosis is macroautophagy/autophagy-dependent, because the inhibition of autophagy with a pharmacological inhibitor or by gene knockout profoundly mitigated ZnONPs-induced ferroptosis. We further demonstrated that NCOA4 (nuclear receptor coactivator 4)-mediated ferritinophagy (autophagic degradation of the major intracellular iron storage protein ferritin) was required for the ferroptosis induced by ZnONPs, by showing that knockdown can reduce the intracellular iron level and lipid peroxidation, and subsequently alleviate ZnONPs-induced cell death. Furthermore, we showed that ROS originating from mitochondria (mtROS) probably activated the AMPK-ULK1 axis to trigger ferritinophagy. Most importantly, pulmonary ZnONPs exposure caused vascular inflammation and ferritinophagy in mice, and ferrostatin-1 supplementation significantly reversed the vascular injury induced by pulmonary ZnONPs exposure. Overall, our study indicates that ferroptosis is a novel mechanism for ZnONPs-induced endothelial cytotoxicity, and that NCOA4-mediated ferritinophagy is required for ZnONPs-induced ferroptotic cell death.
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http://dx.doi.org/10.1080/15548627.2021.1911016DOI Listing
April 2021

Pulmonary Exposure to Copper Oxide Nanoparticles Leads to Neurotoxicity via Oxidative Damage and Mitochondrial Dysfunction.

Neurotox Res 2021 Apr 7. Epub 2021 Apr 7.

Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, People's Republic of China.

Copper oxide nanoparticles (CuONPs) are widely used in pharmaceutical, food, and textile industries. They have been shown to cause lung, liver, and kidney damage. However, whether an intratracheal instillation of CuONPs would affect the brain and its underlying mechanisms remain poorly studied. In this study, healthy C57BL/6J male mice were equally subdivided into control group, low-dose (30 μg/animal), medium-dose (50 μg/animal), and high-dose (100 μg/animal) CuONPs-treated groups. Mice were subjected to acute exposure of CuONPs via intratracheal instillation. Brain histopathology, inflammatory factors, oxidative stress markers, and mitochondrial function-related protein expression were determined. Our results demonstrated that CuONPs caused a dose-dependent brain damage in mice. Histopathological changes in the brain, elevation of inflammatory factors (Tnf, Il-6), and significant alterations in oxidative stress markers were also observed after treatment with CuONPs. Intriguingly, we did not observe infiltration of macrophage cell. Moreover, Tim23, TFAM, and MFN2 protein expression levels showed the decreasing trend after treatment with CuONPs. Taken together, these results indicate that pulmonary exposure to CuONPs induces pathological damage, inflammation, oxidative stress, and mitochondrial dysfunction in the cerebral cortex, suggesting that neurotoxicity caused by pulmonary exposure of CuONPs needs more attention from the public and relevant departments.
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http://dx.doi.org/10.1007/s12640-021-00358-6DOI Listing
April 2021

Arsenite induces ferroptosis in the neuronal cells via activation of ferritinophagy.

Food Chem Toxicol 2021 May 13;151:112114. Epub 2021 Mar 13.

Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, People's Republic of China; Dongsheng Lung-Brain Disease Joint Lab, Chongqing Medical University, Chongqing, 400016, People's Republic of China. Electronic address:

Ferroptosis is a novel form of cell death that involves in the pathophysiological process of diverse brain diseases. However, how arsenite induces ferroptosis in the neuronal cells remains unsolved. In this study, by using in vitro and in vivo models, we demonstrated that arsenite was able to trigger ferroptosis in the neuronal cells. Exposure of arsenite for 6 months at 0.5, 5 and 50 mg/L arsenite via drinking water significantly reduced the number of neurons and caused the pathological changes in the mitochondria of hippocampus. Treatment of arsenite elevated the contents of lipid peroxidation products, disrupted the iron homeostasis, altered the expressions of ferroptosis-related proteins in the hippocampus and PC-12 cells. The results also showed that arsenite significantly decreased the expressions of ferritin and NCOA4, but sharply enhanced the level of autophagy marker LC3B, suggesting the activation of ferritinophagy by arsenite. Co-treatment of arsenite with ferroptosis inhibitor ferrostatin-1, or autophagy inhibitors 3-MA and BafA1, all remarkably attenuated the cytotoxic effects of arsenite. These findings not only present a novel mechanism that arsenite triggers ferroptosis in the neuronal cells via activation of ferritinophagy, but also indicate that regulating ferritinophagy to control iron level may provide a clue for prevention against arsenite neurotoxicity.
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http://dx.doi.org/10.1016/j.fct.2021.112114DOI Listing
May 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Complex patterns of circulating fatty acid levels in gestational diabetes mellitus subclasses across pregnancy.

Clin Nutr 2021 Feb 6. Epub 2021 Feb 6.

College of Medicine, Biological Sciences and Psychology, University of Leicester, UK.

Background & Aims: To investigate the relationship between maternal serum fatty acid levels and gestational diabetes mellitus (GDM) subtypes across pregnancy.

Methods: A total of 680 singleton mothers enrolled in the Complex Lipids in Mothers and Babies (CLIMB) study in Chongqing, China were included. Clinical information and serum samples were collected at gestational weeks (GWs) 11-14, 22-28, and 32-34. 75 g Oral Glucose Tolerance Test (OGTT) was conducted at GW 24-28 and GDM subtypes divided into three groups using International Association of Diabetes and Pregnancy Study Group (IADPSG) guidelines criteria: elevated fasting plasma glucose (FPG group; n = 59); 1-h and/or 2-h post-load glucose (1h/2h-PG group; n = 94); combined group (FPG&1h/2h-PG group; n = 42). Non-GDM pregnancies were included (n = 485) as controls. Twenty fatty acids were quantified in serum using gas chromatography-mass spectrometry (GC-MS) analysis.

Results: Overall, most serum fatty acid concentrations increased rapidly from the first to second trimester, followed by a plateauing or reduction in the third trimester (p < 0.001). In cross sectional analysis, fatty acid concentrations were significantly higher in the FPG group at GW 11-14 and decreased in the 1h/2h-PG group at GW 32-34, relative to controls. Moreover, higher α-linolenic acid (ALA; the second tertile: adjusted odds ratio [aOR] = 2.53, 95% CI: 1.17 to 5.47; the third tertile: aOR = 2.60, 95% CI: 1.20 to 5.65) and docosahexaenoic acid (DHA; the second tertile: aOR = 2.34, 95% CI: 1.10 to 4.97; the third tertile: aOR = 2.16, 95% CI: 1.00 to 4.63) were significantly associated with a higher risk of GDM in women with elevated fasting plasma glucose at GW 11-14 (first tertile as reference).

Conclusions: Our findings highlight the importance of considering GDM subtypes for the individualised management of GDM in pregnancy. ALA and DHA in early pregnancy are associated with a higher risk of FPG-GDM subtype. This has widespread implications when recommending n-3 PUFAs supplementation for women with GDM.
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http://dx.doi.org/10.1016/j.clnu.2021.01.046DOI Listing
February 2021

The ecdysone-induced protein 93 is a key factor regulating gonadotrophic cycles in the adult female mosquito .

Proc Natl Acad Sci U S A 2021 Feb;118(8)

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, People's Republic of China;

Repeated blood feedings are required for adult female mosquitoes to maintain their gonadotrophic cycles, enabling them to be important pathogen carriers of human diseases. Elucidating the molecular mechanism underlying developmental switches between these mosquito gonadotrophic cycles will provide valuable insight into mosquito reproduction and could aid in the identification of targets to disrupt these cycles, thereby reducing disease transmission. We report here that the transcription factor ecdysone-induced protein 93 (E93), previously implicated in insect metamorphic transitions, plays a key role in determining the gonadotrophic cyclicity in adult females of the major arboviral vector Expression of the gene in mosquitoes is down-regulated by juvenile hormone (JH) and up-regulated by 20-hydroxyecdysone (20E). We find that E93 controls Hormone Receptor 3 (HR3), the transcription factor linked to the termination of reproductive cycles. Moreover, knockdown of expression via RNAi impaired fat body autophagy, suggesting that E93 governs autophagy-induced termination of vitellogenesis. RNAi silencing prior to the first gonadotrophic cycle affected normal progression of the second cycle. Finally, transcriptomic analysis showed a considerable E93-dependent decline in the expression of genes involved in translation and metabolism at the end of a reproductive cycle. In conclusion, our data demonstrate that E93 acts as a crucial factor in regulating reproductive cycle switches in adult female mosquitoes.
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http://dx.doi.org/10.1073/pnas.2021910118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923369PMC
February 2021

Associations of early pregnancy BMI with adverse pregnancy outcomes and infant neurocognitive development.

Sci Rep 2021 Feb 15;11(1):3793. Epub 2021 Feb 15.

College of Life Sciences, University of Leicester, Leicester, UK.

The prevalence of overweight and obesity amongst reproductive women has been increasing worldwide. Our aim was to compare pregnancy outcomes and infant neurocognitive development by different BMI classifications and investigate whether early pregnancy BMI was associated with risks of adverse outcomes in a Southwest Chinese population. We analysed data from 1273 women enrolled in the Complex Lipids in Mothers and Babies (CLIMB) randomized controlled trial in Chongqing, China. Maternal BMI was classified as underweight, normal weight and overweight/obese according to the Chinese, WHO Asian, and WHO European standards. For the adverse pregnancy outcomes, after adjustment for potential confounders, an underweight BMI was associated with increased risk of small for gestational age (SGA) babies, and an overweight/obese BMI was associated with increased risk of maternal gestational diabetes mellitus (GDM), caesarean section (C-section), macrosomia and large for gestational age (LGA) babies. For infant neurocognitive development, 1017 mothers and their children participated; no significant differences were seen in the Mental Development Index (MDI) or the Psychomotor Development Index (PDI) between the three BMI groups. Our findings demonstrate that abnormal early pregnancy BMI were associated with increased risks of adverse pregnancy outcomes in Chinese women, while early pregnancy BMI had no significant influence on the infant neurocognitive development at 12 months of age.
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http://dx.doi.org/10.1038/s41598-021-83430-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884778PMC
February 2021

Scavenger receptor B1 mediates phagocytosis and the antimicrobial peptide pathway in the endoparasitic wasp Micropilits mediator.

Dev Comp Immunol 2021 Jun 4;119:104039. Epub 2021 Feb 4.

Department of Entomology, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China; State Key Laboratory of Crop Stress Biology for Arid Areas, Northwest A&F University, Yangling, Shaanxi, China. Electronic address:

Scavenger receptors (SRs) are a family of pattern recognition receptors (PRRs) in the immune system. They are required for phagocytosis and act as co-receptors of Toll-like receptors to regulate immune signaling pathways in the fight against pathogens. Little is known about the function of SRs in insects. Here, we reported on a member of the SR family from the parasitic wasp Micropilits mediator (designated MmSR-B1) that is responsive to bacterial infection. The recombinant extracellular CD36 domain of MmSR-B1 produced in Escherichia coli cells is capable of binding to peptidoglycans and bacterial cells, causing agglutination of bacteria. Furthermore, we demonstrated that double-stranded RNA-mediated knockdown of MmSR-B1 impedes hemocyte phagocytosis and downregulates the expression of antimicrobial peptide (AMP) genes defensins and hymenoptaecins. Knockdown of MmSR-B1 led to increased death of the wasps when challenged by bacteria. Our study suggests that MmSR-B1 mediates phagocytosis and the production of AMPs in M. mediator wasps.
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http://dx.doi.org/10.1016/j.dci.2021.104039DOI Listing
June 2021

Microbiota modulates gut immunity and promotes baculovirus infection in Helicoverpa armigera.

Insect Sci 2021 Jan 18. Epub 2021 Jan 18.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.

Baculoviruses are natural enemies of agricultural and forest insect pests and play an important role in biological pest control. Oral infection by baculovirus in the insect midgut is necessary for establishing systemic infection and eventually killing the insect. Since the insect midgut continuously encounters microbiota, the gut microbiota could affect baculovirus infection. Here, we demonstrated that gut microbiota modulates immune responses and promotes baculovirus infection in the cotton bollworm, Helicoverpa armigera. After oral infection, numerous host immunity-related genes including genes encoding Toll and immune deficiency (IMD) pathway components were upregulated in the midgut. Elimination of the gut microbiota significantly increased the resistance to viral infection in H. armigera. Quantitative real-time reverse transcription polymerase chain reaction and proteomic analysis showed that downregulation of the antiviral factor prophenoloxidase (PPO) could be mediated by microbiota during infection. It implied that midgut microbiota diminishes the expression of PPO to facilitate viral infection in H. armigera. Our findings revealed that the microbiota plays an important role in modulating the resistance of H. armigera to baculovirus infection, providing new insights in applying biopesticide.
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http://dx.doi.org/10.1111/1744-7917.12894DOI Listing
January 2021

Defining disease progression in Chinese mainland people: Association between bone mineral density and knee osteoarthritis.

J Orthop Translat 2021 Jan 6;26:39-44. Epub 2020 Nov 6.

The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China.

Objective: To evaluate change in bone mineral density (BMD) during development of knee osteoarthritis (OA) in elderly Chinese community residents. Further, to monitor disease progression by recording speed of sound (SOS), one parameter of BMD provided by quantitative ultrasound measurement.

Methods: A total of 4173 community residents of the Chinese mainland were organized to complete questionnaires and relevant measurements, including anthropometry, radiology and quantitative ultrasound (QUS). SOS measurements of the distal radius were acquired using QUS measurements. The Kellgren-Lawrence (KL) grade of knee OA was evaluated by two experienced radiographers using X-rays. Finally, a general linear models analysis was performed to determine potential relationships. Further, the area under the receiver operating characteristic curve (ROC AUC) was applied to assess the distinction model.

Results: The SOS score in the OA group was significantly lower than that in the control group ( ​ ​0.001). However, after adjustment for age and body mass index (BMI), no significant difference was observed in the male population ( ​= ​0.841), while a significantly lower SOS score presented in knee OA participants in the female population ( ​= ​0.033). A turning point in SOS scores, from increasing to decreasing trends, occurred around KL grade 2; the SOS score gradually increased with progression in participants from KL grades 0 to 2, whereas the SOS score presented a significant decrease in participants with KL grades 3 and 4. The AUC for the model to distinguish OA progression was 0.891.

Conclusion: There was a non-linear and stage-specific association between SOS score and knee OA, which presented a positive relationship in early stages, but a negative relationship in advanced stages. A decline of SOS score in knee OA patients in early stages should alert clinicians to the possibility of disease progression.

The Translational Potential Of This Article: In the present study, the relationship between OA and BMD had established by SOS. The results suggested that close monitoring of SOS in elderly Chinese communities residents with knee OA could alert disease progression involvement by an easily accessible method, and help early referral to orthopedist consultation for further examination and treatment.
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http://dx.doi.org/10.1016/j.jot.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773972PMC
January 2021

Comparative Analysis of the Gut Microbiota of Adult Mosquitoes From Eight Locations in Hainan, China.

Front Cell Infect Microbiol 2020 15;10:596750. Epub 2020 Dec 15.

Key Laboratory of Tropical Translational Medicine of Ministry of Education and School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou, China.

The midgut microbial community composition, structure, and function of field-collected mosquitoes may provide a way to exploit microbial function for mosquito-borne disease control. However, it is unclear how adult mosquitoes acquire their microbiome, how the microbiome affects life history traits and how the microbiome influences community structure. We analyzed the composition of 501 midgut bacterial communities from field-collected adult female mosquitoes, including , , , , and , across eight habitats using the HiSeq 4000 system and the V3-V4 hyper-variable region of 16S rRNA gene. After quality filtering and rarefaction, a total of 1421 operational taxonomic units, belonging to 29 phyla, 44 families, and 43 genera were identified. (75.67%) were the most common phylum, followed by (10.38%), (6.87%), (4.60%), and (1.58%). The genera (33.00%), (20.27%), (7.49%), (7.00%), (4.52%), and (4.31%) were dominant in the samples analyzed and accounted for 76.59% of the total genera. We characterized the midgut bacterial communities of six mosquito species in Hainan province, China. The gut bacterial communities were different in composition and abundance, among locations, for all mosquito species. There were significant differences in the gut microbial composition between some species and substantial variation in the gut microbiota between individuals of the same mosquito species. There was a marked variation in different mosquito gut microbiota within the same location. These results might be useful in the identification of microbial communities that could be exploited for disease control.
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http://dx.doi.org/10.3389/fcimb.2020.596750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769952PMC
December 2020

Defending the homeland: microbiome molecules provide protection to their vertebrate hosts.

Future Microbiol 2020 12 22;15:1697-1712. Epub 2020 Dec 22.

Laboratory of Biomembrane & Membrane Protein, West China Hospital, Sichuan University, Chengdu, 610041, China.

The resident bacterial microbiome may shape and protect the health of vertebrate host. An array of molecules secreted by microbiome may contribute to the ecological stability of the microbiome itself. ELISA, radioactivity, immunofluorescence and cytokines measurements were used to observe the bioactivity and stability of colicin Ia level in oviparous and viviparous animal circulation. Colicin Ia, a protein antimicrobial produced by , is not present in animals at birth, but increases in concentration with the establishment of a stable gut microbiome and drops when the microbiome is experimentally disrupted. Colicin introduced is transported to tissues at concentrations able to prevent or eliminate bacterial infection. Our findings suggest an unexpected benefit provided by the presence of a resident microbiome in the form of active, circulating, bacterially-synthesized antimicrobial molecules.
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http://dx.doi.org/10.2217/fmb-2020-0008DOI Listing
December 2020

High-throughput profiling of diapause regulated genes from Trichogramma dendrolimi (Hymenoptera: Trichogrammatidae).

BMC Genomics 2020 Dec 4;21(1):864. Epub 2020 Dec 4.

Engineering Research Center of Natural Enemies, Institute of Biological Control, Jilin Agricultural University, Changchun, 130118, China.

Background: The parasitoid wasp, Trichogramma dendrolimi, can enter diapause at the prepupal stage. Thus, diapause is an efficient preservation method during the mass production of T. dendrolimi. Previous studies on diapause have mainly focused on ecological characteristics, so the molecular basis of diapause in T. dendrolimi is unknown. We compared transcriptomes of diapause and non-diapause T. dendrolimi to identify key genes and pathways involved in diapause development.

Results: Transcriptome sequencing was performed on diapause prepupae, pupae after diapause, non-diapause prepupae, and pupae. Analysis yielded a total of 87,022 transcripts with an average length of 1604 bp. By removing redundant sequences and those without significant BLAST hits, a non-redundant dataset was generated, containing 7593 sequences with an average length of 3351 bp. Among them, 5702 genes were differentially expressed. The result of Gene Ontology (GO) enrichment analysis revealed that regulation of transcription, DNA-templated, oxidation-reduction process, and signal transduction were significantly affected. Ten genes were selected for validation using quantitative real-time PCR (qPCR). The changes showed the same trend as between the qPCR and RNA-Seq results. Several genes were identified as involved in diapause, including ribosomal proteins, zinc finger proteins, homeobox proteins, forkhead box proteins, UDP-glucuronosyltransferase, Glutathione-S-transferase, p53, and DNA damage-regulated gene 1 (pdrg1). Genes related to lipid metabolism were also included.

Conclusions: We generated a large amount of transcriptome data from T. dendrolimi, providing a resource for future gene function research. The diapause-related genes identified help reveal the molecular mechanisms of diapause, in T. dendrolimi, and other insect species.
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http://dx.doi.org/10.1186/s12864-020-07285-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718664PMC
December 2020

Regulation of antimicrobial peptides by juvenile hormone and its receptor, Methoprene-tolerant, in the mosquito Aedes aegypti.

Insect Biochem Mol Biol 2021 Jan 29;128:103509. Epub 2020 Nov 29.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, 100049, China; Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou, 311300, China. Electronic address:

The trade-off between reproduction and immunity has been established for a number of insect species. However, the regulatory mechanisms governing this event is not well understood. In the mosquito Aedes aegypti, the vector of dangerous human arboviral diseases, juvenile hormone (JH) is required for the female post-eclosion development and reproductive maturation. In this study, we have revealed the JH negative effect on the expression of immunity-related genes, such as antimicrobial peptides (AMPs), during the post-eclosion phase of the female mosquito gonadotrophic reproductive cycle. Mosquitoes treated with JH became more sensitive to microbial infection. Mosquitoes subjected to the RNA interference knockdown (RNAi) of the JH receptor, Methoprene-tolerant (Met), showed increased expression of several AMP genes. Met binds to the E-box-like recognition motifs in the regulatory region of the diptericin (Dpt) gene, indicating that JH can suppress the Dpt gene expression through its receptor Met. Hence, JH is involved in the modulation of immune responses during the post-eclosion phase of reproduction. The RNAi knockdown of the peptidoglycan recognition protein (PGRP-LC) led to a significant reduction of the Dpt transcript level, indicating the PGRP-LC activating role on this AMP gene. Thus, Dpt appeared to be under the dual regulation of both the JH and the immune deficiency (IMD) signaling pathways. Our study provides a better understanding of how JH regulates insect immunity in adult mosquitoes.
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http://dx.doi.org/10.1016/j.ibmb.2020.103509DOI Listing
January 2021

Mosquito Diversity and Population Genetic Structure of Six Mosquito Species From Hainan Island.

Front Genet 2020 29;11:602863. Epub 2020 Oct 29.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

Hainan is a tropical island in southern China with abundant mosquito species, putting Hainan at risk of mosquito-borne virus disease outbreaks. The population genetic diversity of most mosquito species on Hainan Island remains elusive. In this study, we report the diversity of mosquito species and the genetic diversity of the predominant species on Hainan. Field populations of adults or larvae were collected from 12 regions of Hainan Island in 2018 and 2019. A fragment of the mitochondrial cytochrome c oxidase subunit I () gene was sequenced from 1,228 mosquito samples and used for species identification and genetic diversity analysis. Twenty-three known mosquito species from the genera , , , , and and nine unconfirmed mosquito species were identified. , , and were the most prevalent mosquito species on Hainan. The regions north of Danzhou, Tunchang, and Qionghai exhibited high mosquito diversity (26 species). The order of the total haplotype diversity and nucleotide diversity of the populations from high to low was as follows: , , , , , and . Tajima's and Fu's tests showed that , , , and had experienced population expansion, while the and populations were in genetic equilibrium. Significant genetic differentiation existed in the overall populations of , , , and . The populations on Hainan were characterized by frequent gene exchange with populations from Guangdong and four other tropical countries, raising the risk of viral disease outbreaks in these regions. Two subgroups were reported in the populations for the first time. Our findings may have important implications for vector control on Hainan Island.
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http://dx.doi.org/10.3389/fgene.2020.602863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658394PMC
October 2020

Crosstalk of gut microbiota and serum/hippocampus metabolites in neurobehavioral impairments induced by zinc oxide nanoparticles.

Nanoscale 2020 Oct;12(41):21429-21439

Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, People's Republic of China. and Dongsheng Lung-Brain Disease Joint Lab, Chongqing Medical University, Chongqing, 400016, People's Republic of China.

The gut microbiome can be readily influenced by external factors, such as nanomaterials. However, the role of the microbiota-gut-brain axis in nanomaterials-induced neurotoxicity remains largely unknown. In this study, young mice aged 4 weeks were treated with either a vehicle solution or 26 mg kg-1 zinc oxide nanoparticles (ZnONPs) by intragastric administration for 30 days. The neurobehavioral alterations were assessed by the Morris water maze and open field test. Gut microbiota and the metabolites in both blood and hippocampus were detected using 16S rRNA sequencing and liquid chromatography-mass spectrometry metabolomics, respectively. The results demonstrated that oral exposure to ZnONPs resulted in neurobehavioral impairments in young mice, mainly manifested by spatial learning and memory deficits, and the inhibition of locomotor activity. Intriguingly, ZnONPs caused a marked disturbance of the gut microbial composition, but did not alter the α-diversity of the microbiota. The correlation analysis further revealed that neurobehavioral impairments induced by ZnONPs were closely associated with a perturbation in the gut microbiota composition that were specific to changes of neurobehavior-related genes (such as Bdnf and Dlg4), and correlated with serum and hippocampal metabolites. We also identified a unique metabolite [DG(15:0/0:0/22:4n6)] that linked relationships among the gut microbiota, metabolites and neurobehavior-related genes. Taken together, our results illustrated that oral exposure to ZnONPs not only altered the gut microbiome community, but also substantially disturbed the metabolic profiles leading to neurobehavioral impairments via the microbiota-gut-brain axis. These findings will provide a novel view for understanding the neurotoxicity of ZnONPs, and are helpful for identifying potential prevention and treatment strategies.
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http://dx.doi.org/10.1039/d0nr04563bDOI Listing
October 2020

Transcriptome analysis of the innate immune system of Hyalomma asiaticum.

J Invertebr Pathol 2020 11 6;177:107481. Epub 2020 Oct 6.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou 571199, China. Electronic address:

Ticks are considered to be the second most important vectors of human infectious diseases. The innate immune system is the key factor that affects its vector competence. Hyalomma asiaticum is the primary vector of Crimean-Congo hemorrhagic fever virus (CCHFV). However, the immune system of H. asiaticum remains virtually unknown. Here, a high throughput full-length mRNA sequencing method was adopted to define the immunotranscriptome of H. asiaticum infected with the fungal pathogen Beauveria bassiana and gram-negative bacterium Enterobacter cloacae. The analysis yielded 22,300 isoforms with an average length of 3233 bps. In total, 68 potential immunity-related genes were identified based on similarity to the homologs known to be involved in immunity. These included most members of the Toll and JAK/STAT signaling pathways, but not the IMD signaling pathway. Moreover, two copies of Dicer-2 and five copies of Argonaute-2 were detected. These genes are postulated to be involved in the RNA interference (RNAi) pathway, which is an important defense against RNA viruses. Overall, this study provides the foundation for understanding the immune response of H. asiaticum to CCHFV.
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http://dx.doi.org/10.1016/j.jip.2020.107481DOI Listing
November 2020

TGF-β/Smad2 signalling regulates enchondral bone formation of Gli1 periosteal cells during fracture healing.

Cell Prolif 2020 Nov 30;53(11):e12904. Epub 2020 Sep 30.

Institute of Orthopadics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.

Objectives: Most bone fracture heals through enchondral bone formation that relies on the involvement of periosteal progenitor cells. However, the identity of periosteal progenitor cells and the regulatory mechanism of their proliferation and differentiation remain unclear. The aim of this study was to investigate whether Gli1-Cre can identify a population of murine periosteal progenitor cells and the role of TGF-β signalling in periosteal progenitor cells on fracture healing.

Materials And Methods: Double heterozygous Gli1-CreER ;Rosa26-tdTomato mice were sacrificed at different time points for tracing the fate of Gli1 cells in both intact and fracture bone. Gli1-CreER -mediated Tgfbr2 knockout (Gli1-CreER ;Tgfbr2 ) mice were subjected to fracture surgery. At 4, 7, 10, 14 and 21 days post-surgery, tibia samples were harvested for tissue analyses including μCT, histology, real-time PCR and immunofluorescence staining.

Results: Through cell lineage-tracing experiments, we have revealed that Gli1-Cre can be used to identify a subpopulation of periosteal progenitor cells in vivo that persistently reside in periosteum and contribute to osteochondral elements during fracture repair. During the healing process, TGF-β signalling is continually activated in the reparative Gli1 periosteal cells. Conditional knockout of Tgfbr2 in these cells leads to a delayed and impaired enchondral bone formation, at least partially due to the reduced proliferation and chondrogenic and osteogenic differentiation of Gli1 periosteal cells.

Conclusions: TGF-β signalling plays an essential role on fracture repair via regulating enchondral bone formation process of Gli1 periosteal cells.
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http://dx.doi.org/10.1111/cpr.12904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653269PMC
November 2020

Runx2 plays a central role in Osteoarthritis development.

J Orthop Translat 2020 Jul 23;23:132-139. Epub 2019 Dec 23.

Department of Orthopedic Surgery, Washington University at St. Louis, MO, USA.

Osteoarthritis (OA) is the most common form of arthritis, is the leading cause of impaired mobility in the elderly, and accounts for more than a third of chronic moderate to severe pain. As a degenerative joint disorder, OA affects the whole joint and results in synovial hyperplasia, degradation of articular cartilage, subchondral sclerosis, osteophyte formation, and chronic pain. Currently, there is no effective drug to decelerate OA progression and molecular targets for drug development have been insufficiently investigated. Anti-OA drug development can benefit from more and precise knowledge of molecular targets for drug development. Runt-related transcription factor 2 (Runx2) is a key transcription factor controlling osteoblast and chondrocyte differentiation and is among the most promising potential therapeutic targets. Notably, Runx2 expression is upregulated in several murine OA models, suggesting a role in disease pathogenesis. In this review article, we summarized recent findings on Runx2 related to OA development and evaluated its potential as a therapeutic target.

The Translational Potential Of This Article: A better understanding of the role of Runx2 in osteoarthritis pathogenesis will contribute to the development of novel intervention of osteoarthritis disease.
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http://dx.doi.org/10.1016/j.jot.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452174PMC
July 2020

Hemolymph protease-5 links the melanization and Toll immune pathways in the tobacco hornworm, .

Proc Natl Acad Sci U S A 2020 09 8;117(38):23581-23587. Epub 2020 Sep 8.

Department of Entomology and Plant Pathology, Oklahoma State University, Stillwater, OK 74078;

Proteolytic activation of phenoloxidase (PO) and the cytokine Spätzle during immune responses of insects is mediated by a network of hemolymph serine proteases (HPs) and noncatalytic serine protease homologs (SPHs) and inhibited by serpins. However, integration and conservation of the system and its control mechanisms are not fully understood. Here we present biochemical evidence that PO-catalyzed melanin formation, Spätzle-triggered Toll activation, and induced synthesis of antimicrobial peptides are stimulated via hemolymph (serine) protease 5 (HP5) in Previous studies have demonstrated a protease cascade pathway in which HP14 activates proHP21; HP21 activates proPAP2 and proPAP3, which then activate proPO in the presence of a complex of SPH1 and SPH2. We found that both HP21 and PAP3 activate proHP5 by cleavage at ESDR*IIGG. HP5 then cleaves proHP6 at a unique site of LDLH*ILGG. HP6, an ortholog of Persephone, activates both proHP8 and proPAP1. HP8 activates proSpätzle-1, whereas PAP1 cleaves and activates proPO. HP5 is inhibited by serpin-4, serpin-1A, and serpin-1J to regulate its activity. In summary, we have elucidated the physiological roles of HP5, a CLIPB with unique cleavage specificity (cutting after His) that coordinates immune responses in the caterpillar.
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http://dx.doi.org/10.1073/pnas.2004761117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519321PMC
September 2020

Zinc Oxide Nanoparticles Induce Ferroptotic Neuronal Cell Death in vitro and in vivo.

Int J Nanomedicine 2020 27;15:5299-5315. Epub 2020 Jul 27.

Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, People's Republic of China.

Purpose: Zinc oxide nanoparticles (ZnONPs) are one of the most important nanomaterials that are widely used in the food, cosmetic and medical industries. Humans are often exposed to ZnONPs via inhalation, and they may reach the brain where neurotoxic effects could occur via systemic distribution. However, the mechanisms underlying how ZnONPs produce neurotoxic effects in the brain remain unclear. In this study, we aimed to investigate the novel mechanism involved in ZnONPs-induced neurotoxicity.

Methods And Results: We demonstrated for the first time that pulmonary exposure to ZnONPs by intratracheal instillation could trigger ferroptosis, a new form of cell death, in the neuronal cells of mouse cerebral cortex. A similar phenomenon was also observed in cultured neuron-like PC-12 cell line. By using a specific inhibitor of ferroptosis ferrostatin-1 (Fer-1), our results showed that inhibition of ferroptosis by Fer-1 could significantly alleviate the ZnONPs-induced neuronal cell death both in vivo and in vitro. Mechanistic investigation revealed that ZnONPs selectively activated the JNK pathway and thus resulted in the ferroptotic phenotypes, JNK inhibitor SP600125 could reverse lipid peroxidation upregulation and ferroptotic cell death induced by ZnONPs in PC-12 cells.

Conclusion: Taken together, this study not only demonstrates that pulmonary exposure of ZnONPs can induce JNK-involved ferroptotic cell death in mouse cortex and PC-12 cells, but also provides a clue that inhibition of ferroptosis by specific agents or drugs may serve as a feasible approach for reducing the untreatable neurotoxicity induced by ZnONPs.
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http://dx.doi.org/10.2147/IJN.S250367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436556PMC
November 2020

Platelet-rich plasma promotes bone formation, restrains adipogenesis and accelerates vascularization to relieve steroids-induced osteonecrosis of the femoral head.

Platelets 2020 Aug 24:1-10. Epub 2020 Aug 24.

Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.

Steroid-associated necrosis of the femoral head (SANFH) is one of the most common and refractory chronic diseases with increasing incidence. The typical pathological changes of SANFH include decreased osteogenic differentiation, enhanced intramedullary adipocytes deposition and impaired osseous circulation. In this study, we investigated the effects and potential mechanisms of Platelet-rich plasma (PRP) on SANFH. Sixty Sprague-Dawley rats were randomly divided into the control, PRP donor, model, and PRP groups. Compared to the model group, PRP treatment significantly increased the hemorheological indexes and serum levels of bone gla-protein (BGP) and vascular endothelial growth factor (VEGF), while decreased the levels of triglyceride (TG) and total cholesterol (TC). Meanwhile, Micro-CT and histopathological stain (Hematoxylin-eosin and Alcian blue-hematoxylin/orange G staining) were performed on the femoral head for morphological and histopathological evaluation, indicating that bone trabecular microstructure and bone mineral density (BMD) were significantly improved after PRP treatment. Immunohistochemical analysis revealed that PRP remarkably up-regulated the expression of osteogenic markers including β-catenin and alkaline phosphatase (ALP), angiogenic markers containing VEGF and platelet endothelial cell adhesion molecule-1 (CD31), while down-regulated adipogenic markers involving fatty acid-binding protein (FABP-4), and peroxisome proliferator-activated receptor gamma (PPAR-γ) in SANFH rat models. In summary, for the first time, PRP was demonstrated to prevent the development of SANFH through stimulating bone formation and vascularization as well as retarding adipogenesis.
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http://dx.doi.org/10.1080/09537104.2020.1810221DOI Listing
August 2020

Thiol-suppressed I-etching of AuNRs: acetylcholinesterase-mediated colorimetric detection of organophosphorus pesticides.

Mikrochim Acta 2020 08 15;187(9):497. Epub 2020 Aug 15.

Hunan Provincial Key Laboratory of Cytochemistry, Hunan Provincial Engineering Research Center for Food Processing of Aquatic Biotic Resources, School of Chemistry and Food Engineering, Changsha University of Science and Technology, Changsha, 410114, People's Republic of China.

For the first time it is demonstrated that sulfhydryl compounds can suppress longitudinal etching of gold nanorods via consuming oxidizers, which provides a new signaling mechanism for colorimetric sensing. As a proof of concept, a colorimetric assay is developed for detecting organophosphorus pesticides, which are most widely used in modern agriculture to improve food production but with high toxicity to animals and the ecological environment. Triazophos was selected as a model organophosphorus pesticide. In the absence of triazophos, the active acetylcholinesterase can catalyze the conversion of acetylthiocholine iodide to thiocholine whose thiol group can suppress the I-induced etching of gold nanorods. When triazophos is present, the activity of AchE is inhibited, and I-induced etching of gold nanorods results in triazophos concentration-dependent color change from brown to blue, pink, and red. The aspect ratio of gold nanorods reduced with gradually blue-shifted longitudinal absorption. There was a linear detection range from 0 to 117 nM (R = 0.9908), the detection limit was 4.69 nM, and a good application potential was demonstrated by the assay of real water samples. This method will not only contribute to public monitoring of organophosphorus pesticides but also has verified a new signaling mechanism which will open up a new path to develop colorimetric detection methods. It has been first found that sulfhydryl compounds can suppress longitudinal etching of gold nanorods (AuNRs) via consuming oxidizers, which provides a new signaling mechanism for colorimetric sensing. As a proof of concept, a colorimetric assay is developed for sensitively detecting organophosphorus pesticides (OPs). It will not only contribute to public monitoring of OPs but also has verified a new signaling mechanism which will open up a new path to develop multicolor colorimetric methods.
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http://dx.doi.org/10.1007/s00604-020-04486-2DOI Listing
August 2020

MiTF is Associated with Chemoresistance to Cisplatin in A549 Lung Cancer Cells via Modulating Lysosomal Biogenesis and Autophagy.

Cancer Manag Res 2020 29;12:6563-6573. Epub 2020 Jul 29.

Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, People's Republic of China.

Background: Non-small cell lung carcinoma (NSCLC) is often fatal; advanced NSCLC has a 5-year survival rate less than 20%. Platinum-based chemotherapy, in particular, -diamminedichloroplatinum (II) (cisplatin or DDP), is employed for the treatment of NSCLC; however, the drug resistance occurs frequently. Autophagy is defined as the process of intracellular degradation of cytoplasmic materials in the lysosome; however, the correlation between autophagy and drug resistance remains controversial. Herein, we investigated the correlation between autophagy and cisplatin resistance and also explored the underlying mechanisms.

Methods And Results: We demonstrated that DDP-resistant NSCLC A549 (A549/DDP) cells had higher autophagy activity in comparison with its parental A549 cells; DDP treatment induced a time- and dose-dependent decrease of autophagy. Intriguingly, inhibition of autophagy with pharmacological drugs or knockdown of ATG5 or Beclin-1 aggravated cell death induced by DDP treatment, indicating that autophagy played protective roles during DDP treatment. Further mechanistic investigation revealed that DDP treatment could decrease the mRNA expression level of key autophagy-related genes, such as ATG5, Beclin-1, and ATG7, suggesting DDP repressed autophagy at the transcriptional level. The MiTF/TFE family (including TFEB, TFE3, TFEC, and MiTF) were involved in nutrient sensing and organelle biogenesis, and specifically, the lysosomal biogenesis. We found that only MiTF was dramatically decreased upon DDP treatment, and also a profound decrease of lysosomal markers, LAMP-1 or LAMP-2, suggesting that MiTF was involved in the modulation of lysosomal biogenesis and, consequently, the autophagy. Moreover, the knockdown of MiTF resulted in more severe cell death in A549/DDP cells, indicting the substantial correlation between MiTF and cisplatin chemoresistance.

Conclusion: Our study provides novel insights into the association between MiTF and DDP chemoresistance in NSCLC cells, and suggests targeting MiTF and/or autophagy might be a potential strategy for the reversal of DDP chemoresistance for NSCLC treatment.
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http://dx.doi.org/10.2147/CMAR.S255939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398682PMC
July 2020

Pregnancy exposure to carbon black nanoparticles induced neurobehavioral deficits that are associated with altered mA modification in offspring.

Neurotoxicology 2020 12 9;81:40-50. Epub 2020 Aug 9.

Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, PR China; Dongsheng Lung-Brain Diseases Joint Lab, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address:

Increasing occupational and accidental exposure to carbon black nanoparticles (CBNPs) raise concerns over their possible effects on the nervous system. However, the influences of CBNPs on the neurodevelopment remain unclear. Thus, in this study, pregnant mice were exposed to different doses of CBNPs by intranasal instillation on gestation days 9-18. Our results demonstrated that maternal exposure to CBNPs caused significant changes on maternal behaviors. Pregnancy exposure to CBNPs also delayed the onset of incisor eruption, testes descent and vaginal opening in offspring, and caused the reduced body weight until adulthood. In the neurobehavioral tests, CBNPs-exposed offspring exhibited the elevated latency of negative geotaxis and surface right reflex, reduced grasping time and increased cliff avoidance. Histopathological changes were present in F1 generation but not in F2 generation. Intriguingly, our data revealed that the levels of total mA modification were significantly decreased by CBNPs. Similar trends were observed on the mRNA expressions of mA methyltransferases and demethylases. In summary, these findings provide the novel evidence that pregnancy exposure to CBNPs affects the maternal behaviors and partially induces the neurobehavioral, muscular and histopathological changes in offspring. Of note, these adverse effects may be associated with reduced levels of total mA modification in brain.
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http://dx.doi.org/10.1016/j.neuro.2020.07.004DOI Listing
December 2020

Heterozygous disruption of beclin 1 mitigates arsenite-induced neurobehavioral deficits via reshaping gut microbiota-brain axis.

J Hazard Mater 2020 11 14;398:122748. Epub 2020 May 14.

Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, People's Republic of China; Dongsheng Lung-Brain Disease Joint Lab, Chongqing Medical University, Chongqing, 400016, People's Republic of China. Electronic address:

Gut microbiota is intimately involved in numerous aspects of human health. Arsenite expouse can perturb gut microbiota and is linked to increased susceptibility of individual to arsenite-related diseases. However, how microbiome factors influence arsenite-induced neurotoxicity remains largely unknown. In this study, after treating of healthy adult female mice with arsenite via drinking water for 6 months, our results clearly revealed that chronic arsenite exposure not only perturbed the composition of gut microbiota but also caused neurobehavioral dysfunctions, which manifested by learning and memory deficits and anxiety-like behavior. Given that the overactive autophagy directly leads to gut pathological changes, we further assessed whether inhibiton of autophagy by genetic mean could reverse arsenite-induced neurobehavioral dysfunctions. Our results illustrated for the first time that heterozygous disruption of beclin 1, which played a central role in autophagy, alleviated the perturbation of gut microbiome phenotypes induced by arsenite, and ultimately leading to the improvement of neurobehavioral deficits through gut-brain communication. These findings provide a new clue that regulation of autophagy is a potential approach for probing the functional impacts of arsenite on the gut microbiome, and it also may be severed as a way for protection strategies against arsenite neurotoxicity.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122748DOI Listing
November 2020

Bushenhuoxue formula accelerates fracture healing via upregulation of TGF-β/Smad2 signaling in mesenchymal progenitor cells.

Phytomedicine 2020 Jun 1;76:153256. Epub 2020 Jun 1.

Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China. Electronic address:

Background: Although Bushenhuoxue formula (BSHXF) is successfully used as a non-traumatic therapy in treating bone fracture in China, the molecular mechanism underlying its effects remains poorly understood.

Purpose: The present study aims to explore the therapeutic effects of BSHXF on fracture healing in mice and the underlying mechanism.

Methods: We performed unilateral open transverse tibial fracture procedure in C57BL/6 mice which were treated with or without BSHXF. Fracture callus tissues were collected and analyzed by X-ray, micro-CT, biomechanical testing, histopathology and quantitative gene expression analysis. Tibial fracture procedure was also performed in Cre-negative and Gli1-CreER; Tgfbr2flox/flox conditional knockout (KO) mice (Tgfbr2) to determine if BSHXF enhances fracture healing in a TGF-β-dependent manner. In addition, scratch-wound assay and cell counting kit-8 (CCK-8) assay were used to evaluate the effect of BSHXF on cell migration and cell proliferation in C3H10T1/2 mesenchymal stem cells, respectively.

Results: BSHXF promoted endochondral ossification and enhanced bone strength in wild-type (WT) or Cre- control mice. In contrast, BSHXF failed to promote bone fracture healing in Tgfbr2 conditional KO mice. In the mice receiving BSHXF treatment, TGF-β/Smad2 signaling was significantly activated. Moreover, BSHXF enhanced cell migration and cell proliferation in C3H10T1/2 cells, which was strongly attenuated by the small molecule inhibitor SB525334 against TGF-β type I receptor.

Conclusion: These data demonstrated that BSHXF promotes fracture healing by activating TGF-β/Smad2 signaling. BSHXF may be used as a type of alternative medicine for the treatment of bone fracture healing.
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http://dx.doi.org/10.1016/j.phymed.2020.153256DOI Listing
June 2020