Publications by authors named "Xuejun Jiang"

319 Publications

Exposure to carbon black nanoparticles during pregnancy aggravates lipopolysaccharide-induced lung injury in offspring: an intergenerational effect.

Am J Physiol Lung Cell Mol Physiol 2021 Sep 29. Epub 2021 Sep 29.

Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, China.

Carbon black nanoparticles (CBNPs) are one of the most frequently used nanoparticles. Exposure to CBNPs during pregnancy (PrE to CBNPs) can directly induce inflammation, lung injury and genotoxicity in dams, and results in abnormalities in offspring. However, whether exposure to CBNPs during pregnancy enhances the susceptibility of offspring to environmental stimuli remains unknown. To address this issue, in this study, we intranasally treated pregnant mice with mock or CBNPs from gestational day (GD) 9 to GD18, and F1 and F2 offspring were normally obtained. By intratracheal instillation of mice with lipopolysaccharide (LPS) to trigger a classic animal model for acute lung injury, we intriguingly found that after LPS treatment, F1 and F2 offspring after exposure during pregnancy to CBNPs both exhibited more pronounced lung injury symptoms, including more degenerative histopathological changes, vascular leakage, elevated MPO activity and activation of inflammation-related signaling transduction, compared to F1 and F2 offspring in the mock treatment group, suggesting PrE to CBNPs would aggravate LPS-induced lung injury in offspring, and this effect is intergenerational. We also observed that PrE to CBNPs upregulated the mRNA expression of DNA methyltransferases (Dnmt) 1/3a/3b and DNA hypermethylation in both F1 and F2 offspring, which might partially account for the intergenerational effect. Together, our study demonstrates for the first time that PrE to CBNPs can enhance sensitivity to LPS in both F1 and F2 offspring, and this intergenerational effect may be related to DNA hypermethylation caused by CBNPs.
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http://dx.doi.org/10.1152/ajplung.00545.2020DOI Listing
September 2021

Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11.

Cancer Res 2021 Oct 12;81(20):5217-5229. Epub 2021 Aug 12.

Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.

Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment. SIGNIFICANCE: This study uncovers a SOX2-SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530936PMC
October 2021

The Expression Patterns and Roles of Lysyl Oxidases in Aortic Dissection.

Front Cardiovasc Med 2021 7;8:692856. Epub 2021 Jul 7.

Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Lysyl oxidases (LOXs), including LOX, LOXL1, LOXL2, LOXL3, and LOXL4, catalyze the formation of a cross-link between elastin (ELN) and collagen. Multiple LOX mutations have been shown to be associated with the occurrence of aortic dissection (AD) in humans, and LOX-knockout mice died during the perinatal period due to aortic aneurysm and rupture. However, the expression levels and roles of other LOX members in AD remain unknown. A total of 33 aorta samples of AD and 15 normal aorta were collected for LOXs mRNA and protein levels detection. We also analyzed the datasets of AD in GEO database through bioinformatics methods. LOXL2 and LOXL3 were knocked down in primary cultured human aortic smooth muscle cells (HASMCs) via lentivirus. Here, we show that the protein levels of LOXL2 and LOXL3 are upregulated, while LOXL4 is downregulated in AD subjects compared with non-AD subjects, but comparable protein levels of LOX and LOXL1 are detected. Knockdown of LOXL2 suppressed MMP2 expression, the phosphorylation of AKT (p-AKT) and S6 (p-S6), but increased the mono-, di-, tri-methylation of H3K4 (H3K4me1/2/3), H3K9me3, and p-P38 levels in HASMCs. These results indicate that LOXL2 is involved in regulation of the extracellular matrix (ECM) in HASMCs. In contrast, LOXL3 knockdown inhibited PCNA and cyclin D1, suppressing HASMC proliferation. Our results suggest that in addition to LOX, LOXL2 and LOXL3 are involved in the pathological process of AD by regulating ECM and the proliferation of HASMCs, respectively. Furthermore, we found that LOXL2 and LOXL4 was inhibited by metformin and losartan in HASMCs, which indicated that LOXL2 and LOXL4 are the potential targets that involved in the therapeutic effects of metformin and losartan on aortic or aneurysm expansion. Thus, differential regulation of LOXs might be a novel strategy to prevent or treat AD.
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http://dx.doi.org/10.3389/fcvm.2021.692856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292648PMC
July 2021

New Diterpenoids and Isocoumarin Derivatives from the Mangrove-Derived Fungus sp.

Mar Drugs 2021 Jun 24;19(7). Epub 2021 Jun 24.

State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.

Two new diterpenoids, hypoxyterpoids A () and B (), and four new isocoumarin derivatives, hypoxymarins A-D (-), together, with seven known metabolites ( and -) were obtained from the crude extract of the mangrove-derived fungus sp. The structures of the new compounds were elucidated on the basis of 1- and 2-dimensional (1D/2D) nuclear magnetic resonance (NMR) spectroscopic and mass spectrometric analysis. The absolute configurations of compounds , , , and were determined by comparison of experimental and calculated electronic circular dichroism (ECD) spectra, and the absolute configurations of C-4' in and C-9 in were determined by [Rh(OCOCF)]-induced ECD spectra. Compound showed moderate -glucosidase inhibitory activities with IC values of 741.5 ± 2.83 μM. Compounds and exhibited DPPH scavenging activities with IC values of 15.36 ± 0.24 and 3.69 ± 0.07 μM, respectively.
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http://dx.doi.org/10.3390/md19070362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305793PMC
June 2021

iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4.

Nat Commun 2021 06 15;12(1):3644. Epub 2021 Jun 15.

Institute for Cancer Genetics, and Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center,Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, 10032, USA.

Here, we identify iPLA2β as a critical regulator for p53-driven ferroptosis upon reactive oxygen species (ROS)-induced stress. The calcium-independent phospholipase iPLA2β is known to cleave acyl tails from the glycerol backbone of lipids and release oxidized fatty acids from phospholipids. We found that iPLA2β-mediated detoxification of peroxidized lipids is sufficient to suppress p53-driven ferroptosis upon ROS-induced stress, even in GPX4-null cells. Moreover, iPLA2β is overexpressed in human cancers; inhibition of endogenous iPLA2β sensitizes tumor cells to p53-driven ferroptosis and promotes p53-dependent tumor suppression in xenograft mouse models. These results demonstrate that iPLA2β acts as a major ferroptosis repressor in a GPX4-independent manner. Notably, unlike GPX4, loss of iPLA2β has no obvious effect on normal development or cell viability in normal tissues but iPLA2β plays an essential role in regulating ferroptosis upon ROS-induced stress. Thus, our study suggests that iPLA2β is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns.
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http://dx.doi.org/10.1038/s41467-021-23902-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206155PMC
June 2021

Silicon dioxide nanoparticles induced neurobehavioral impairments by disrupting microbiota-gut-brain axis.

J Nanobiotechnology 2021 Jun 10;19(1):174. Epub 2021 Jun 10.

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

Background: Silicon dioxide nanoparticles (SiONPs) are widely used as additive in the food industry with controversial health risk. Gut microbiota is a new and hot topic in the field of nanotoxicity. It also contributes a novel and insightful view to understand the potential health risk of food-grade SiONPs in children, who are susceptible to the toxic effects of nanoparticles.

Methods: In current study, the young mice were orally administrated with vehicle or SiONPs solution for 28 days. The effects of SiONPs on the gut microbiota were detected by 16S ribosomal RNA (rRNA) gene sequencing, and the neurobehavioral functions were evaluated by open field test and Morris water maze. The level of inflammation, tissue integrity of gut and the classical indicators involved in gut-brain, gut-liver and gut-lung axis were all assessed.

Results: Our results demonstrated that SiONPs significantly caused the spatial learning and memory impairments and locomotor inhibition. Although SiONPs did not trigger evident intestinal or neuronal inflammation, they remarkably damaged the tissue integrity. The microbial diversity within the gut was unexpectedly enhanced in SiONPs-treated mice, mainly manifested by the increased abundances of Firmicutes and Patescibacteria. Intriguingly, we demonstrated for the first time that the neurobehavioral impairments and brain damages induced by SiONPs might be distinctively associated with the disruption of gut-brain axis by specific chemical substances originated from gut, such as Vipr1 and Sstr2. Unapparent changes in liver or lung tissues further suggested the absence of gut-liver axis or gut-lung axis regulation upon oral SiONPs exposure.

Conclusion: This study provides a novel idea that the SiONPs induced neurotoxic effects may occur through distinctive gut-brain axis, showing no significant impact on either gut-lung axis or gut-liver axis. These findings raise the exciting prospect that maintenance and coordination of gastrointestinal functions may be critical for protection against the neurotoxicity of infant foodborne SiONPs.
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http://dx.doi.org/10.1186/s12951-021-00916-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194163PMC
June 2021

Autophagy deficiency exacerbates acute lung injury induced by copper oxide nanoparticles.

J Nanobiotechnology 2021 May 31;19(1):162. Epub 2021 May 31.

Molecular Biology Laboratory of Respiratory Diseases, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.

Copper oxide nanoparticles (CuONPs) are one of the widely used metal nanoparticles in the industrial and commercial fields. Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome and has been linked to nanoparticles-induced toxicity. In particular, the roles of autophagy in response to CuONPs have been explored in vitro, although the conclusions are controversial. To clarify the role of autophagy in CuONPs-induced acute lung injury, microtubule-associated protein 1 light chain 3 beta (Map1lc3b or lc3b) knockout mice and their corresponding wild type mice are applied. Our results showed that single-dose intratracheal instillation of CuONPs with dosages of 1.25, 2.5 or 5 mg/kg caused acute lung injury 3 days after treatment in a dose-dependent manner, as evidenced by deteriorative lung histopathology, more infiltration of macrophage cells, increased oxidative stress and copper ions. Loss of lc3b resulted in aggravated lung injury induced by CuONPs, which was probably due to the blockade of mitophagy and consequently the accumulation of aberrant mitochondria with overloaded copper ions. Our study provides the first in vivo evidence that autophagy deficiency exacerbates CuONPs-induced acute lung injury, and highlights that targeting autophagy is a meaningful strategy against CuONPs-associated respiratory toxicity.
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http://dx.doi.org/10.1186/s12951-021-00909-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166141PMC
May 2021

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

Nanotoxicology 2021 08 10;15(6):779-797. 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
August 2021

Daphnetin Preconditioning Decreases Cardiac Injury and Susceptibility to Ventricular Arrhythmia following Ischaemia-Reperfusion through the TLR4/MyD88/NF-Κb Signalling Pathway.

Pharmacology 2021 26;106(7-8):369-383. Epub 2021 Apr 26.

Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, China.

Background/aims: Daphnetin (7,8-dihydroxycoumarin, DAP) exhibits various bioactivities, such as anti-inflammatory and antioxidant activities. However, the role of DAP in myocardial ischaemia/reperfusion (I/R) injury and I/R-related arrhythmia is still uncertain. This study aimed to investigate the mechanisms underlying the effects of DAP on myocardial I/R injury and electrophysiological properties in vivo and in vitro.

Methods: Myocardial infarct size was measured by triphenyltetrazolium chloride staining. Cardiac function was assessed by echocardiographic and haemodynamic analyses. The levels of creatine kinase-MB, lactate dehydrogenase, malondialdehyde, superoxide dismutase, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) were detected using commercial kits. Apoptosis was measured by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labelling staining and flow cytometry. The viability of H9c2 cells was determined by the Cell Counting Kit-8 assay. In vitro, the levels of IL-6 and TNF-α were measured by quantitative PCR. The expression levels of proteins associated with apoptosis, inflammation, and the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signalling pathway were detected by Western blot analysis. The RR, PR, QRS, and QTc intervals were assessed by surface ECG. The 90% action potential duration (APD90), threshold of APD alternans, and ventricular tachycardia inducibility were measured by the Langendorff perfusion technique.

Results: DAP preconditioning decreased myocardial I/R injury and hypoxia/reoxygenation (H/R) injury in cells. DAP preconditioning improved cardiac function after myocardial I/R injury. DAP preconditioning also suppressed apoptosis, attenuated oxidative stress, and inhibited inflammatory responses in vivo and in vitro. Furthermore, DAP preconditioning decreased the susceptibility to ventricular arrhythmia after myocardial I/R. Finally, DAP preconditioning inhibited the expression of TLR4, MyD88, and phosphorylated NF-κB (p-NF-κB)/P65 in mice subjected to I/R and cells subjected to H/R.

Conclusions: DAP preconditioning protected against myocardial I/R injury and decreased susceptibility to ventricular arrhythmia by inhibiting the TLR4/MyD88/NF-κB signalling pathway.
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http://dx.doi.org/10.1159/000513631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315677PMC
April 2021

Mitochondrial NADP(H) generation is essential for proline biosynthesis.

Science 2021 05 22;372(6545):968-972. Epub 2021 Apr 22.

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

The coenzyme nicotinamide adenine dinucleotide phosphate (NADP) and its reduced form (NADPH) regulate reductive metabolism in a subcellularly compartmentalized manner. Mitochondrial NADP(H) production depends on the phosphorylation of NAD(H) by NAD kinase 2 (NADK2). Deletion of in human cell lines did not alter mitochondrial folate pathway activity, tricarboxylic acid cycle activity, or mitochondrial oxidative stress, but rather led to impaired cell proliferation in minimal medium. This growth defect was rescued by proline supplementation. NADK2-mediated mitochondrial NADP(H) generation was required for the reduction of glutamate and hence proline biosynthesis. Furthermore, mitochondrial NADP(H) availability determined the production of collagen proteins by cells of mesenchymal lineage. Thus, a primary function of the mitochondrial NADP(H) pool is to support proline biosynthesis for use in cytosolic protein synthesis.
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http://dx.doi.org/10.1126/science.abd5491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241437PMC
May 2021

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

Biometals 2021 06 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

Early childhood traffic-related air pollution and risk of allergic rhinitis at 2-4 years of age modification by family stress and male gender: a case-control study in Shenyang, China.

Environ Health Prev Med 2021 Apr 17;26(1):48. Epub 2021 Apr 17.

Department of Otolaryngology, First Affiliated Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110001, China.

Background: Few studies have explored the modifications by family stress and male gender in the relationship between early exposure to traffic-related air pollution (TRAP) and allergic rhinitis (AR) risk in preschool children.

Methods: We conducted a case-control study of 388 children aged 2-4 years in Shenyang, China. These children AR were diagnosed by clinicians. By using measured concentrations from monitoring stations, we estimated the exposures of particulate matter less than 10 μm in diameter (PM), nitrogen dioxide (NO), ozone (O), carbon monoxide (CO), and sulfur dioxide (SO) in preschool children aged 2-4 years. After adjusted potential confounding factors, we used logistic regression model to evaluate the odds ratio (OR) and 95% confidence interval (CI) for childhood AR with exposure to different air pollutants according to the increasing of the interquartile range (IQR) in the exposure level.

Results: The prevalence of AR in children aged 2-4 years (6.4%) was related to early TRAP exposure. With an IQR (20 μg/m) increase in PM levels, an adjusted OR was significantly elevated by 1.70 (95% CI, 1.19 to 2.66). Also, with an IQR (18 μg/m) increase in NO, an elevated adjusted OR was 1.85 (95% CI, 1.52 to 3.18). Among children with family stress and boys, PM and NO were positively related to AR symptoms. No significant association was found among children without family stress and girls.

Conclusions: Family stress and male gender may increase the risk of AR in preschool children with early exposure to PM and NO.
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http://dx.doi.org/10.1186/s12199-021-00969-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053259PMC
April 2021

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

Neurotox Res 2021 Aug 7;39(4):1160-1170. 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
August 2021

BCAT1 overexpression regulates proliferation and c‑Myc/GLUT1 signaling in head and neck squamous cell carcinoma.

Oncol Rep 2021 05 24;45(5). Epub 2021 Mar 24.

Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Branched chain amino acid transaminase 1 (BCAT1) overexpression has been reported in various cancers; however, at present, its significance and biological role in head and neck squamous cell carcinoma (HNSCC) remain unknown. BCAT1 protein expression was upregulated in 56/106 (52.8%) cases of HNSCC. BCAT1 overexpression was associated with tumor‑node‑metastasis stage, tumor stage and nodal metastasis. The Cancer Genome Atlas data suggested that high BCAT1 expression was associated with poor patient survival. Oncomine data suggested that BCAT1 expression was increased in HNSCC. Functionally, BCAT1 overexpression promoted cell proliferation, colony formation, invasion and cisplatin resistance in FaDu cells. BCAT1 overexpression also upregulated the mitochondrial membrane potential, and increased ATP production, glucose consumption and glucose uptake. Western blotting demonstrated that BCAT1 overexpression upregulated c‑Myc and glucose transporter 1 (GLUT1) protein levels. Depletion of c‑Myc using small interfering RNA abolished the influence of BCAT1 on GLUT1. Chromatin immunoprecipitation assays demonstrated that c‑Myc has binding sites in the GLUT1 promoter. Collectively, the present findings suggested that BCAT1 is upregulated in human HNSCC and regulates HNSCC cell proliferation, invasion, cisplatin sensitivity and c‑Myc/GLUT1 signaling.
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http://dx.doi.org/10.3892/or.2021.8003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962101PMC
May 2021

CQMUH-011 mitigates autoimmune hepatitis via inhibiting the function of T lymphocytes.

Drug Dev Res 2021 Mar 17. Epub 2021 Mar 17.

Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China.

CQMUH-011 is a modified adamantane sulfonamide compound, that inhibits macrophage proliferation and possesses anti-inflammatory properties. Here, fresh mouse splenocytes were obtained and stimulated with concanavalin A (ConA, 5 μg/ml) in vitro; and experimental autoimmune hepatitis (AIH) was induced by ConA (20 mg/kg, iv) in vivo, to clarify the protective effects of CQMUH-011 against AIH and its possible mechanisms. Our results demonstrated that CQMUH-011 pretreatment can dose-dependently inhibit the proliferation of splenocytes in vitro. In vivo, CQMUH-011 administration reduced the hepatic histopathological score and the infiltration of lymphocytes in the liver parenchyma; additionally, it downregulated the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and pro-inflammatory cytokines interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in serum, as well as those of methane dicarboxylic aldehyde and myeloperoxidase in the liver tissues. It also down-regulated the expression of p-NF-κB and related proteins in the liver tissues. Furthermore, CQMUH-011 could maintain the balance of CD3 CD4 /CD3 CD8 and decrease the percentages of CD8 CD69 and CD4 CD25 CD69 T-cells in the splenocytes of ConA-challenged mice. Moreover, we found thatCD4 CD25 CD69 T-cells were significantly correlated with ALT levels, especially CD4 CD25 CD69 T-cells. In conclusion, CQMUH-011 exerts potential protective effects against ConA-induced hepatitis, which may be partially attributed to its inhibition of T cells, especially the suppression of the proliferation of CD4 CD25 CD69 and CD8 CD69 subsets in the spleen. CQMUH-011 also reduced the early apoptosis of lymphocytes in the thymus.
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http://dx.doi.org/10.1002/ddr.21813DOI Listing
March 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

The miR-136-5p/ROCK1 axis suppresses invasion and migration, and enhances cisplatin sensitivity in head and neck cancer cells.

Exp Ther Med 2021 Apr 3;21(4):317. Epub 2021 Feb 3.

Department of Otorhinolaryngology Head and Neck Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China.

Laryngeal squamous cell carcinoma (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC) are two types of head and neck cancers with high incidence rates and relatively poor prognoses. The aim of the present study was to determine the effects of microRNA (miR/miRNA)-136-5p and its downstream target, Rho-associated coiled-coil containing protein kinase 1 (ROCK1), on LSCC and HPSCC progression and cisplatin sensitivity. The miRNA and protein expression levels in head and neck cancer cell lines were evaluated using reverse transcription-quantitative PCR and western blotting, respectively. MTT, wound healing assays, transwell assays and flow cytometry analysis were performed to measure cell properties. The binding between miR-136-5p and ROCK1 was detected using a dual-luciferase reporter assay. Autophagy double-labeled adenoviral infection assays were used to assess cell autophagy. The results showed that miR-136-5p was expressed in LSCC and HPSCC cells. Functional experiments showed that the expression of miR-136-5p in LSCC and HPSCC cells was negatively correlated with cell viability, invasion and migration. Additionally, miR-136-5p overexpression inhibited epithelial-mesenchymal transition, whereas miR-136-5p knockdown had the opposite effect. Dual-luciferase reporter assays confirmed the targeting relationship between miR-136-5p and ROCK1. miR-136-5p overexpression increased the cisplatin sensitivity of LSCC and HPSCC cells by reducing cell viability, as well as promoting cell apoptosis and autophagy. miR-136-5p overexpression decreased the expression levels of its downstream target ROCK1 and attenuated activity of the Akt/mTOR signaling pathway in cisplatin-treated LSCC and HPSCC cells. Conversely, miR-136-5p knockdown increased ROCK1 levels and decreased cisplatin sensitivity of the LSCC and HPSCC cells by increasing cell viability and inhibiting cell apoptosis, which was reversed by ROCK1 inhibition using the ROCK1 inhibitor, Y27632. Taken together, the results showed that the miR-136-5p/ROCK1 axis inhibits cell invasion and migration, and increases the sensitivity of LSCC and HPSCC cells to cisplatin.
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http://dx.doi.org/10.3892/etm.2021.9748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885062PMC
April 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

Key factors leading to fatal outcomes in COVID-19 patients with cardiac injury.

Sci Rep 2021 02 18;11(1):4144. Epub 2021 Feb 18.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China.

Cardiac injury among patients with COVID-19 has been reported and is associated with a high risk of mortality, but cardiac injury may not be the leading factor related to death. The factors related to poor prognosis among COVID-19 patients with myocardial injury are still unclear. This study aimed to explore the potential key factors leading to in-hospital death among COVID-19 patients with cardiac injury. This retrospective single-center study was conducted at Renmin Hospital of Wuhan University, from January 20, 2020 to April 10, 2020, in Wuhan, China. All inpatients with confirmed COVID-19 (≥ 18 years old) and cardiac injury who had died or were discharged by April 10, 2020 were included. Demographic data and clinical and laboratory findings were collected and compared between survivors and nonsurvivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with mortality in COVID-19 patients with cardiac injury. A total of 173 COVID-19 patients with cardiac injury were included in this study, 86 were discharged and 87 died in the hospital. Multivariable regression showed increased odds of in-hospital death were associated with advanced age (odds ratio 1.12, 95% CI 1.05-1.18, per year increase; p < 0.001), coagulopathy (2.54, 1.26-5.12; p = 0·009), acute respiratory distress syndrome (16.56, 6.66-41.2; p < 0.001), and elevated hypersensitive troponin I (4.54, 1.79-11.48; p = 0.001). A high risk of in-hospital death was observed among COVID-19 patients with cardiac injury in this study. The factors related to death include advanced age, coagulopathy, acute respiratory distress syndrome and elevated levels of hypersensitive troponin I.
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http://dx.doi.org/10.1038/s41598-021-82396-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892550PMC
February 2021

Ferroptosis: mechanisms, biology and role in disease.

Nat Rev Mol Cell Biol 2021 04 25;22(4):266-282. Epub 2021 Jan 25.

Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany.

The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.
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http://dx.doi.org/10.1038/s41580-020-00324-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142022PMC
April 2021

An N-terminal conserved region in human Atg3 couples membrane curvature sensitivity to conjugase activity during autophagy.

Nat Commun 2021 01 14;12(1):374. Epub 2021 Jan 14.

Departments of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA.

During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation. Here, we have demonstrated that an N-terminal conserved region of human Atg3 (hAtg3) communicates information from the N-terminal membrane curvature-sensitive amphipathic helix (AH), which presumably targets the enzyme to the tip of phagophore, to the C-terminally located catalytic core for LC3-PE conjugation. Mutations in the putative communication region greatly reduce or abolish the ability of hAtg3 to catalyze this conjugation in vitro and in vivo, and alter the membrane-bound conformation of the wild-type protein, as reported by NMR. Collectively, our results demonstrate that the N-terminal conserved region of hAtg3 works in concert with its geometry-selective AH to promote LC3-PE conjugation only on the target membrane, and substantiate the concept that highly curved membranes drive spatial regulation of the autophagosome biogenesis during autophagy.
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http://dx.doi.org/10.1038/s41467-020-20607-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809043PMC
January 2021

Appearance and morphologic features of laryngeal tuberculosis using laryngoscopy: A retrospective cross-sectional study.

Medicine (Baltimore) 2020 Dec;99(51):e23770

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.

Abstract: Laryngeal tuberculosis (LTB) is highly contagious and can cause permanent laryngeal damage. Therefore, correctly identifying laryngoscopic LTB lesion locations, sizes, and morphologic features are essential for LTB diagnoses. This study aimed to explore the appearance and morphologic features of LTB and correlated these features with clinical symptoms.We retrospectively analysed 39 LTB patients in our hospital between January 2013 and December 2019. Medical records, including clinical presentation, lesion appearance (locations, sizes, and morphology), complementary examination results, and histopathologic features were summarized and analysed.In this patient cohort, dysphonia and sore throat were the two most common clinical symptoms. In LTB patients with extensive lesions, ulcerative lesions were most common, and the proportion of cases with concurrent pulmonary tuberculosis (86.4%, P = .033) infection was higher, as were the positive rates of sputum smears (72.7%, P = .011) and cultures (86.4%, P = .002) than patients without concurrent pulmonary TB and with more localized and exophytic lesions. The histopathologic features of LTB-related ulcerative lesions included fewer granulomas and more areas with caseous necrosis. These lesions were more likely to have acid-fast bacilli detected with a Ziehl-Neelsen stain than exophytic lesions that rarely showed detectable bacilli.A complete knowledge regarding the visual and morphologic features of LTB on laryngoscopy is needed for the early detection and diagnosis of LTB. Our study revealed the lesion sites, sizes, and morphologic features of LTB. These parameters were also correlated with patient clinical symptoms. Future studies are needed to support and expand the results of this retrospective study.
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http://dx.doi.org/10.1097/MD.0000000000023770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748357PMC
December 2020

Smart Responsive Nanoformulation for Targeted Delivery of Active Compounds From Traditional Chinese Medicine.

Front Chem 2020 10;8:559159. Epub 2020 Dec 10.

Key Laboratory of Molecular Target and Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

Traditional Chinese medicine (TCM) has been used to treat disorders in China for ~1,000 years. Growing evidence has shown that the active ingredients from TCM have antibacterial, antiproliferative, antioxidant, and apoptosis-inducing features. However, poor solubility and low bioavailability limit clinical application of active compounds from TCM. "Nanoformulations" (NFs) are novel and advanced drug-delivery systems. They show promise for improving the solubility and bioavailability of drugs. In particular, "smart responsive NFs" can respond to the special external and internal stimuli in targeted sites to release loaded drugs, which enables them to control the release of drug within target tissues. Recent studies have demonstrated that smart responsive NFs can achieve targeted release of active compounds from TCM at disease sites to increase their concentrations in diseased tissues and reduce the number of adverse effects. Here, we review "internal stimulus-responsive NFs" (based on pH and redox status) and "external stimulus-responsive NFs" (based on light and magnetic fields) and focus on their application for active compounds from TCM against tumors and infectious diseases, to further boost the development of TCM in modern medicine.
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http://dx.doi.org/10.3389/fchem.2020.559159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758496PMC
December 2020

Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis.

Proc Natl Acad Sci U S A 2020 12 23;117(49):31189-31197. Epub 2020 Nov 23.

Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;

Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models.
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http://dx.doi.org/10.1073/pnas.2017152117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733797PMC
December 2020

Gender differences of amplitude of low-frequency fluctuations in bipolar disorder: A resting state fMRI study.

J Affect Disord 2021 02 11;280(Pt A):189-196. Epub 2020 Nov 11.

Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Department of Gerontology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.

Background: The clinical and epidemiological features of bipolar disorder (BD) between females and males have many differences. The association between brain function and gender in BD is unknown. This research aimed to investigate the association between brain function and gender in BD by using amplitude of low-frequency fluctuations (ALFFs).

Methods: Ninety-eight patients (49 females and 49 males) with BD and 171 matched healthy controls (HCs, 89 females and 82 males) were recruited for resting-state functional magnetic resonance imaging. ALFF was used to estimate brain function.

Results: A main effect of diagnosis in ALFF was observed in the dorsal lateral prefrontal cortex (DLPFC), ventral prefrontal cortex (VPFC), caudate and occipital lobe. A main effect of gender in ALFF was found in the right VPFC, DLPFC, thalamus, and occipital lobe. A main effect of diagnosis gender interaction in ALFF was observed in the left DLPFC. Analyses of two-sample t-test indicated that male patients with BD had increased ALFF in the right hippocampus, right amygdala, left caudate, and left DLPFC, and decreased ALFF in the occipital lobe compared with male HC. Female patients with BD demonstrated increased ALFF in the right VPFC and right DLPFC compared with female HC. Male patients with BD exhibited increased ALFF in the right VPFC and left DLPFC and decreased ALFF in the occipital lobe compared with female patients with BD.

Limitations: This study did not consider the effect of medications and emotional states on brain activity.

Conclusions: Results suggested gender differences in the dysfunctions of the cortico-limbic neural system in BD.
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http://dx.doi.org/10.1016/j.jad.2020.11.087DOI Listing
February 2021

Clinical characteristics and antibiotics treatment in suspected bacterial infection patients with COVID-19.

Int Immunopharmacol 2021 Jan 3;90:107157. Epub 2020 Nov 3.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, Hubei, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, Hubei, PR China. Electronic address:

Coronavirus disease 2019 (COVID-19) pandemic has brought challenges to health and social care systems. However, the empirical use of antibiotics is still confusing. Presently, a total of 1123 patients with COVID-19 admitted to Renmin Hospital of Wuhan University was included in this retrospective cohort study. The clinical features, complications and outcomes were compared between the suspected bacterial infection and the no evidence of bacterial infection. The risk factors of mortality and the incidence of acute organ injury were analyzed. As a result, 473 patients were selected to suspected bacterial infection (SI) group based on higher white blood cell count and procalcitonin or bacterial pneumonia on chest radiography. 650 patients were selected to the no evidence of bacterial infection (NI) group. The SI group had more severely ill patients (70.2% vs. 39.8%), more death (20.5% vs. 2.2%), and more acute organ injury (40.2% vs. 11.2%). Antibiotics were found associated with improved mortality and an increased risk for acute organ injury in hospitalized patients with COVID-19. Intravenous moxifloxacin and meropenem increased the death rate in patients with suspected bacterial infection, while oral antibiotics reduced mortality in this group. Moreover, penicillin and meropenem treatments were associated with increased mortality of the patients with no evidence of bacterial infection. In conclusion, patients with suspected bacterial infection were more likely to have negative clinical outcomes than those without bacterial infection. Empirical use of antibiotics may not have the expected benefits.
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http://dx.doi.org/10.1016/j.intimp.2020.107157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608018PMC
January 2021

Preparation of Isorhamnetin Nanoparticles and Their Targeting Efficiency to Nasopharynx Cancer.

J Nanosci Nanotechnol 2021 02;21(2):1293-1299

Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.

Cancer is a serious threat to human health and longevity, and is an important cause of disease death. At present, cancer is mainly treated by surgery, radiotherapy, chemotherapy, etc. The existing various methods of treating tumors have their limitations. Although there are immune, genetic and other treatment methods, they are still immature. Therefore, tumor-targeted drug delivery systems have attracted more and more attention in cancer treatment. Targeted nano-drugs are selectively targeted to the tumor surface to achieve targeted drug delivery. New nano-drugs have created new hotspots in medical research. It could be a new strategy for treating cancer. Carboxymethyl chitosan (CMC) is formed by the carboxylation of chitosan. It has good water solubility and biodegradability, biocompatibility and antibacterial properties, so CMC is the best choice as a nanomaterial. Isorhamnetin (Iso) is an important anticancer drug. This article uses nanomedicine technology to construct CMC as a carrier, Iso as an antitumor drug, and using polydopamine (PDA) to modify the surface of the particles. Through and in vivo experiments, the Iso/CMC-PDA nanosphere Targeting and Growth Inhibition of Cervical Cancer Cells.
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http://dx.doi.org/10.1166/jnn.2021.18690DOI Listing
February 2021

Different Role of Raptor and Rictor in Regulating Rasfonin-Induced Autophagy and Apoptosis in Renal Carcinoma Cells.

Chem Biodivers 2020 Dec 26;17(12):e2000743. Epub 2020 Nov 26.

State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, P. R. China.

Both Raptor and Rictor are the key components in the complexes of mammalian target of rapamycin (mTOR), which play a vital role in mediating autophagy. Unlike mTOR, the regulatory role of either Raptor or Rictor in the regulation of autophagic process is relatively less explored. In present study, we found that rasfonin, which isolated from Talaromyces sp. 3656-A1 and was a fungal natural product, activated both caspase-dependent apoptosis and autophagy in ACHN, a renal carcinoma cell line. Knockdown of Raptor decreased both rasfonin-induced autophagic flux and PARP-1 cleavage, and in contrast, Rictor silencing increased apoptosis concomitantly enhancing rasfonin-induced autophagy. Unexpectedly, API-2, which was widely used as an inhibitor of Akt, promoted rasfonin-dependent autophagy in Raptor-depleted but not Rictor-deprived cells. Collectively, these results demonstrated that Raptor and Rictor could play a distinctly regulatory role in rasfonin-enhanced autophagy and apoptosis.
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http://dx.doi.org/10.1002/cbdv.202000743DOI Listing
December 2020

Tumor Microenvironment-Responsive Nanomaterials as Targeted Delivery Carriers for Photodynamic Anticancer Therapy.

Front Chem 2020 29;8:758. Epub 2020 Sep 29.

Key Laboratory of Molecular Target and Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Science & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

Photodynamic therapy (PDT), as an alternative approach to treat tumors through reactive oxygen species (ROS) produced by the activated photosensitizers (PS) upon light irradiation, has attracted wide attention in recent years due to its low invasive and highly efficient features. However, the low hydrophilicity and poor targeting of PS limits the clinical application of PDT. Stimuli-responsive nanomaterials represent a major class of remarkable functional nanocarriers for drug delivery. In particular, tumor microenvironment-responsive nanomaterials (TMRNs) can respond to the special pathological microenvironment in tumor tissues to release the loaded drugs, that allows them to control the release of PS within tumor tissues. Recent studies have demonstrated that TMRNs can achieve the targeted release of PS at tumor sites, increase the concentration of PS in tumor tissues, and reduce side effects of PDT. Hence, in the present paper, we review TMRNs, mainly including pH-, redox-, enzymes-, and hypoxia-responsive smart nanomaterials, and focus on the application of these smart nanomaterials as targeted delivery carriers of PS in photodynamic anticancer therapy, to further boost the development of PDT in tumor therapy.
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http://dx.doi.org/10.3389/fchem.2020.00758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550754PMC
September 2020
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