Publications by authors named "Hua Zhu"

768 Publications

Diagnostic Value of Delayed PET/MR in Liver Metastasis in Comparison With PET/CT.

Front Oncol 2021 30;11:717687. Epub 2021 Aug 30.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, China.

Objectives: The aim of this study was to evaluate the value of a delayed positron emission tomography/magnetic resonance (PET/MR) scan relative to a single positron emission tomography/computed tomography (PET/CT) scan for liver metastasis detection.

Methods: In this study, 70 patients with solid malignancies and suspicious liver lesions undergoing 2-deoxy-2-[F]fluoro--glucose [(F)FDG] PET/CT and subsequent delayed liver PET/MR scans were analyzed. The histopathological analysis and/or imaging follow-up were performed as the standard of reference. Lesion maximum standardized uptake value (SUVmax), diameter, and tumor to nontumor ratio (T/N) were measured. Lesion detection sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for both examinations.

Results: (1) The standard of reference revealed 208 liver lesions in 70 patients (metastasis in 56 patients with 196 lesions; benign in 14 patients with 12 lesions). Compared with PET/CT, PET/MR had higher accuracy (98.6% 78.6%), sensitivity (98.2% 76.8%), and specificity (100.0% 85.7%) (2). The therapeutic strategies of 29 patients (41.4%) needed reconsideration after the additional PET/MR, including new metastases detected (13/70), new affected lobes identified (14/70), and false-positive corrected (2/70) (3). PET/MR detected significantly more metastases than PET/CT did, especially with small lesions. The SUVmax of the same lesion correlated well between the two acquisitions, while the delayed PET showed a higher T/N ratio.

Conclusions: In liver metastasis detection, the diagnostic value of the delayed PET/MR is validated to be superior to that of PET/CT, which may aid the clinical decision-making.
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http://dx.doi.org/10.3389/fonc.2021.717687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435726PMC
August 2021

SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration.

Signal Transduct Target Ther 2021 09 6;6(1):337. Epub 2021 Sep 6.

NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether and how SARS-CoV-2 crosses the blood-brain barrier (BBB). Herein, SARS-CoV-2 RNA was occasionally detected in the vascular wall and perivascular space, as well as in brain microvascular endothelial cells (BMECs) in the infected K18-hACE2 transgenic mice. Moreover, the permeability of the infected vessel was increased. Furthermore, disintegrity of BBB was discovered in the infected hamsters by administration of Evans blue. Interestingly, the expression of claudin5, ZO-1, occludin and the ultrastructure of tight junctions (TJs) showed unchanged, whereas, the basement membrane was disrupted in the infected animals. Using an in vitro BBB model that comprises primary BMECs with astrocytes, SARS-CoV-2 was found to infect and cross through the BMECs. Consistent with in vivo experiments, the expression of MMP9 was increased and collagen IV was decreased while the markers for TJs were not altered in the SARS-CoV-2-infected BMECs. Besides, inflammatory responses including vasculitis, glial activation, and upregulated inflammatory factors occurred after SARS-CoV-2 infection. Overall, our results provide evidence supporting that SARS-CoV-2 can cross the BBB in a transcellular pathway accompanied with basement membrane disrupted without obvious alteration of TJs.
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http://dx.doi.org/10.1038/s41392-021-00719-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419672PMC
September 2021

Comprehensive analysis of pan-cancer reveals potential of ASF1B as a prognostic and immunological biomarker.

Cancer Med 2021 Sep 2. Epub 2021 Sep 2.

Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.

Background: Anti-silencing function 1 (ASF1) is a conserved histone H3-H4 chaperone protein. ASF1B, a paralog of ASF1, acts by promoting cell proliferation and influencing cell cycle progression. Although there is some evidence demonstrating that ASF1B plays a key role in the development, progression, and prognosis of certain cancers, there are no pan-cancer analyses of ASF1B.

Methods: We used a range of bioinformatics approaches to investigate the predictive role of ASF1B, including its correlation with prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), and immune cell infiltration, in diverse cancer types.

Results: We found that ASF1B was highly expressed in 22 cancers and was negatively correlated with the prognosis of multiple major cancer types. Furthermore, ASF1B expression was correlated with TMB in 21 cancers and with MSI in 7 cancers. We found that ASF1B was coexpressed with genes encoding immune activators, immune suppressors, major histocompatibility complexes, chemokines, and chemokine receptors. We further found that the role of ASF1B in the infiltration of different types of immune cells varied across tumor types. ASF1B may potentially affect several key immune-related pathways, such as those involved in antigen processing and presentation, natural killer cell-mediated cytotoxicity, and autoimmune thyroid disease.

Conclusions: Our findings show that ASF1B may serve as a prognostic marker and potential immunotherapeutic target for several malignancies due to its role in tumorigenesis and immune infiltration.
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http://dx.doi.org/10.1002/cam4.4203DOI Listing
September 2021

Ga-labeled ODAP-Urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent.

Eur J Nucl Med Mol Imaging 2021 Aug 28. Epub 2021 Aug 28.

Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China.

Purpose: Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here, we report the synthesis of an optimized Ga-labeled ODAP-Urea-based ligand, [Ga]Ga-P137, and first-in-human results.

Methods: Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice-bearing 22Rv1 prostate tumors by microPET. Lead compound [Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [Ga]Ga-P137 was performed in three patients head-to-head compared to [Ga]Ga-PSMA-617.

Results: Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (K of 0.13 to 5.47 nM). [Ga]Ga-P137 was stable and hydrophilic. [Ga]Ga-P137 showed higher uptake than [Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98%IA/g vs 3.41 ± 1.31%IA/g at 60-min post-injection. In human studies, the normal organ biodistribution of [Ga]Ga-P137 was grossly equivalent to that of [Ga]Ga-PSMA-617 except for within the urinary tract, in which [Ga]Ga-P137 demonstrated lower uptake.

Conclusion: The optimized ODAP-Urea-based ligand [Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [Ga]Ga-PSMA-617, in a preliminary, first-in-human study.

Trial Registration: ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725.
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http://dx.doi.org/10.1007/s00259-021-05486-xDOI Listing
August 2021

The effects of exposure to microplastics on grass carp (Ctenopharyngodon idella) at the physiological, biochemical, and transcriptomic levels.

Chemosphere 2021 Aug 11;286(Pt 3):131831. Epub 2021 Aug 11.

Key Laboratory of Freshwater Aquatic Genetic Resources Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, China; National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China; Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China. Electronic address:

Microplastics (MPs) are pollutants that are widely distributed in the aquatic environment. Fish are directly exposed to water and are at risk of ingesting a large amount of MPs. In the present study, the grass carp were exposed to two concentrations of MPs (1000 and 100 μg/L) and fluorescence signals were detected in the liver digestion solution. Grass carp exposed to MPs for 21-days showed liver cytoplasmic vacuolation and inhibited growth. At the end of the exposure period, the fish treated with MPs exhibited inhibition of the antioxidant system and enhancement oxidative stress in comparison with the control group. The transcriptome analysis of grass carp was then performed to reveal the molecular mechanism of the response to MPs. In total, 1554 differentially expressed genes (DEGs) were identified. The results of GO and KEGG pathway analysis of the DEGs identified energy metabolism-related pathways and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Taken together, the present study not only highlighted oxidative stress and metabolism disorders related to MP ingestion, but also determined the risk of MP exposure to teleost.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131831DOI Listing
August 2021

Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella).

BMC Genomics 2021 Aug 16;22(1):620. Epub 2021 Aug 16.

Key Laboratory of Freshwater Aquatic Genetic Resources Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, China.

Background: Grass carp (Ctenopharyngodon idella) is one of the most widely cultivated fishes in China. High stocking density can reportedly affect fish growth and immunity. Herein we performed PacBio long-read single-molecule real-time (SMRT) sequencing and Illumina RNA sequencing to evaluate the effects of high stocking density on grass carp transcriptome.

Results: SMRT sequencing led to the identification of 33,773 genes (14,946 known and 18,827 new genes). From the structure analysis, 8,009 genes were detected with alternative splicing events, 10,219 genes showed alternative polyadenylation sites and 15,521 long noncoding RNAs. Further, 1,235, 962, and 213 differentially expressed genes (DEGs) were identified in the intestine, muscle, and brain tissues, respectively. We performed functional enrichment analyses of DEGs, and they were identified to be significantly enriched in nutrient metabolism and immune function. The expression levels of several genes encoding apolipoproteins and activities of enzymes involved in carbohydrate enzymolysis were found to be upregulated in the high stocking density group, indicating that lipid metabolism and carbohydrate decomposition were accelerated. Besides, four isoforms of grass carp major histocompatibility complex class II antigen alpha and beta chains in the aforementioned three tissue was showed at least a 4-fold decrease.

Conclusions: The results suggesting that fish farmed at high stocking densities face issues associated with the metabolism and immune system. To conclude, our results emphasize the importance of maintaining reasonable density in grass carp aquaculture.
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http://dx.doi.org/10.1186/s12864-021-07924-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369720PMC
August 2021

[Effects of miR-335-5p targeting G6PD on proliferation and apoptosis of colon cancer cells].

Zhongguo Ying Yong Sheng Li Xue Za Zhi 2021 Jul;37(4):402-406

Department ofLaboratory, Sanya People's Hospital, Sanya 572000, China.

To investigate the effects of miR-335-5p targeting glucose-6-phosphate dehydrogenase (G6PD) on the proliferation and apoptosis of colon cancer cells. Normal colon cell group, blank control group, NC group and miRNA-335-5p mimic group were set up. Colonic epithelial cells (IEC) and human colon cancer cells SW480 were cultured in vitro, and the cells in the NC group and miRNA-335-5p mimic group cells were transfected. RT-qPCR was used to detect the expression levels of miR-335-5p and G6PD mRNA in each group of cells. The targeting effect of miR-335-5p on G6PD was verified by Double Luciferase Report experiment. MTT assay was used to detect cell proliferation. Flow cytometry was used to detect the apoptosis rate. The expressions of G6PD, Bax, Bcl-2 and caspase-3 were detected by Western blot. Compared with normal colon cells, the relative expression levels of miR-335-5p in SW480 cells of colon cancer in the blank control group and NC group were decreased, and the relative expression level of G6PD mRNA was increased (<0.05); compared with the blank control group and NC group, the expression level of miR-335-5p in miR-335-5p mimic group was increased significantly, and the expression of G6PD mRNA was decreased significantly (<0.05). Compared with the blank control group and NC group, the proliferative activity of colon cancer SW480 cells in miR-335-5p mimic group was decreased significantly, and the apoptosis rate was increased significantly (<0.05). The relative activity of luciferase in miR-335-5p mimic + WT-G6PD 3 '- UTR group was lower than that in miR-335-5p NC + WT-G6PD 3' - UTR group (<0.05). Compared with the blank control group, the relative expression levels of G6PD and bcl-2 protein in miR-335-5p mimic group were decreased significantly, and the expression levels of Bax and caspase-3 protein were increased significantly (<0.05). MiR-335-5p may inhibit the proliferation and promote apoptosis of colon cancer cells by targeting G6PD.
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http://dx.doi.org/10.12047/j.cjap.6090.2021.041DOI Listing
July 2021

The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma.

Front Oncol 2021 22;11:696705. Epub 2021 Jul 22.

Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Sorafenib is approved by the U.S. Food and Drug Administration to be a first-line chemotherapy agent for patients with advanced HCC. A portion of advanced HCC patients can benefit from the treatment with sorafenib, but many patients ultimately develop sorafenib resistance, leading to a poor prognosis. The molecular mechanisms of sorafenib resistance are sophisticated and indefinite. Notably, non-coding RNAs (ncRNAs), which include long ncRNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs), are critically participated in the occurrence and progression of tumors. Moreover, growing evidence has suggested that ncRNAs are crucial regulators in the development of resistance to sorafenib. Herein, we integrally and systematically summarized the molecular mechanisms and vital role of ncRNAs impact sorafenib resistance of HCC, and ultimately explored the potential clinical administrations of ncRNAs as new prognostic biomarkers and therapeutic targets for HCC.
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http://dx.doi.org/10.3389/fonc.2021.696705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340683PMC
July 2021

Janus Kinase Inhibition Ameliorates Ischemic Stroke Injury and Neuroinflammation Through Reducing NLRP3 Inflammasome Activation JAK2/STAT3 Pathway Inhibition.

Front Immunol 2021 22;12:714943. Epub 2021 Jul 22.

Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.

Background: Inflammatory responses play a multiphase role in the pathogenesis of cerebral ischemic stroke (IS). Ruxolitinib (Rux), a selective oral JAK 1/2 inhibitor, reduces inflammatory responses the JAK2/STAT3 pathway. Based on its anti-inflammatory and immunosuppressive effects, we hypothesized that it may have a protective effect against stroke. The aim of this study was to investigate whether inhibition of JAK2 has a neuroprotective effect on ischemic stroke and to explore the potential molecular mechanisms.

Methods: Rux, MCC950 or vehicle was applied to middle cerebral artery occlusion (MCAO) mice and an oxygen-glucose deprivation/reoxygenation (OGD/R) model . After 3 days of reperfusion, neurological deficit scores, infarct volume and brain water content were assessed. Immunofluorescence staining and western blots were used to measure the expression of NLRP3 inflammasome components. The infiltrating cells were investigated by flow cytometry. Proinflammatory cytokines were assessed by RT-qPCR. The expression of the JAK2/STAT3 pathway was measured by western blots. Local STAT3 deficiency in brain tissue was established with a lentiviral vector carrying STAT3 shRNA, and chromatin immunoprecipitation (ChIP) assays were used to investigate the interplay between NLRP3 and STAT3 signaling.

Results: Rux treatment improved neurological scores, decreased the infarct size and ameliorated cerebral edema 3 days after stroke. In addition, immunofluorescence staining and western blots showed that Rux application inhibited the expression of proteins related to the NLRP3 inflammasome and phosphorylated STAT3 (P-STAT3) in neurons and microglia/macrophages. Furthermore, Rux administration inhibited the expression of proinflammatory cytokines, including TNF-α, IFN-γ, HMGB1, IL-1β, IL-2, and IL-6, suggesting that Rux may alleviate IS injury by inhibiting proinflammatory reactions JAK2/STAT3 signaling pathway regulation. Infiltrating macrophages, B, T, cells were also reduced by Rux. Local STAT3 deficiency in brain tissue decreased histone H3 and H4 acetylation on the NLRP3 promoter and NLRP3 inflammasome component expression, indicating that the NLRP3 inflammasome may be directly regulated by STAT3 signaling. Rux application suppressed lipopolysaccharide (LPS)-induced NLRP3 inflammasome secretion and JAK2/STAT3 pathway activation in the OGD/R model .

Conclusion: JAK2 inhibition by Rux in MCAO mice decreased STAT3 phosphorylation, thus inhibiting the expression of downstream proinflammatory cytokines and the acetylation of histones H3 and H4 on the NLRP3 promoter, resulting in the downregulation of NLRP3 inflammasome expression.
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http://dx.doi.org/10.3389/fimmu.2021.714943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339584PMC
July 2021

New Insight Into Neutrophils: A Potential Therapeutic Target for Cerebral Ischemia.

Front Immunol 2021 14;12:692061. Epub 2021 Jul 14.

Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.

Ischemic stroke is one of the main issues threatening human health worldwide, and it is also the main cause of permanent disability in adults. Energy consumption and hypoxia after ischemic stroke leads to the death of nerve cells, activate resident glial cells, and promote the infiltration of peripheral immune cells into the brain, resulting in various immune-mediated effects and even contradictory effects. Immune cell infiltration can mediate neuronal apoptosis and aggravate ischemic injury, but it can also promote neuronal repair, differentiation and regeneration. The central nervous system (CNS), which is one of the most important immune privileged parts of the human body, is separated from the peripheral immune system by the blood-brain barrier (BBB). Under physiological conditions, the infiltration of peripheral immune cells into the CNS is controlled by the BBB and regulated by the interaction between immune cells and vascular endothelial cells. As the immune response plays a key role in regulating the development of ischemic injury, neutrophils have been proven to be involved in many inflammatory diseases, especially acute ischemic stroke (AIS). However, neutrophils may play a dual role in the CNS. Neutrophils are the first group of immune cells to enter the brain from the periphery after ischemic stroke, and their exact role in cerebral ischemia remains to be further explored. Elucidating the characteristics of immune cells and their role in the regulation of the inflammatory response may lead to the identification of new potential therapeutic strategies. Thus, this review will specifically discuss the role of neutrophils in ischemic stroke from production to functional differentiation, emphasizing promising targeted interventions, which may promote the development of ischemic stroke treatments in the future.
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http://dx.doi.org/10.3389/fimmu.2021.692061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317226PMC
July 2021

The regulatory role of the BDNF/TrkB pathway in organ and tissue fibrosis.

Histol Histopathol 2021 Jul 30:18368. Epub 2021 Jul 30.

Department of Pharmacy, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, China.

Fibrosis across diverse organ systems is one of the leading causes of morbidity and mortality by inducing progressive architectural remodeling and organ dysfunction. Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase receptor B (TrkB) play crucial roles in regulating neural survival, development, function and plasticity in the central and the peripheral nervous system. Previous studies demonstrated that the BDNF/TrkB pathway is widely distributed in different cell types such as neuron, epithelial cell, hepatocyte, and cardiomyocyte. Recently, there is increasing recognition that BDNF and TrkB are also expressed in fibroblasts in different organs. Moreover, growing evidence was obtained regarding the functional roles of BDNF/TrkB signaling in organ and tissue fibrosis. Thus, this review summarizes the basic molecular characteristics of the BDNF/TrkB cascade and the findings of the crucial roles and therapeutic value in organ and tissue fibrosis including pulmonary fibrosis, hepatic fibrosis, renal fibrosis, cardiac fibrosis, bladder fibrosis and skin fibrosis. Small molecule BDNF mimetic and BDNF-related non-coding RNAs are also discussed for developing new therapeutic approaches for fibrotic disorders.
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http://dx.doi.org/10.14670/HH-18-368DOI Listing
July 2021

First-in-human evaluation of a PD-L1-binding peptide radiotracer in non-small cell lung cancer patients with PET.

J Nucl Med 2021 Jul 29. Epub 2021 Jul 29.

Peking University Cancer Hospital and Institute, China.

Ga-NOTA-WL12 is a peptide-based positron emission tomography (PET) imaging agent. We conducted a first-in-human study of Ga-NOTA-WL12 for PET to study the in vivo biodistribution, metabolism, radiation dosimetry, safety, and potential for quantifying programmed death ligand-1 (PD-L1) expression levels in advanced non-small cell lung cancer (NSCLC) patients. In vitro assessment of the relationship between PD-L1 expression and cellular uptake of Ga-NOTA-WL12 was performed, followed by in vivo evaluation of Ga-NOTA-WL12 uptake in animal models. Nine NSCLC patients with positive PD-L1 expression in lesions were enrolled. Ga-NOTA-WL12 and paired F-FDG PET/CT imaging were performed. The patients were monitored for adverse events. The uptake (SUV/L and kBq/mL) values of tumors and normal organs were obtained. The biodistribution, radiation dosimetry and relationship of tumor uptake and PD-L1 expression were then evaluated. Follow-up F-FDG PET/CT was performed in patients who had undergone treatment with a combination of pembrolizumab with chemotherapy. The cellular and animal experiments demonstrated that PD-L1 expression correlated with the uptake of Ga-NOTA-WL12, and PD-L1-positive tumors exhibited high uptake of Ga-NOTA-WL12. Clinical research showed that Ga-NOTA-WL12 PET imaging is safe with acceptable radiation dosimetry. Physiological tracer uptake was mainly visible in the liver, spleen, small intestine and kidney. High contrast of tumors was observed, particularly in the lungs with a T/lung ratio of 4.45 ±1.89 at 1 h. One hour was a suitable timepoint for image acquisition because no significant differences were noted in the tumor-to-background ratios between 1 and 2 h. Additionally, a strong relationship was found between the tumor uptake (SUVpeak) and PD-L1 immunohistochemistry results (r = 0.9349; = 0.002). Ga-NOTA-WL12 uptake before therapy might indicate the therapeutic efficacy of pembrolizumab plus chemotherapy combination treatment. Our first-in-human findings demonstrate the safety and feasibility of Ga-NOTA-WL12 for noninvasive in vivo detection of the tumor PD-L1 expression levels, indicating potential benefits for clinical PD-L1 therapy.
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http://dx.doi.org/10.2967/jnumed.121.262045DOI Listing
July 2021

BMP6 increases CD68 expression by up-regulating CTGF expression in human granulosa-lutein cells.

Mol Cell Endocrinol 2021 10 24;536:111414. Epub 2021 Jul 24.

Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada. Electronic address:

Bone morphogenetic protein 6 (BMP6) and connective tissue growth factor (CTGF) are critical growth factors required for normal follicular development and luteal function. Cluster of Differentiation 68 (CD68) is an intraovarian marker of macrophages that plays an important role in modulating the physiological regression of the corpus luteum. The aim of this study was to investigate the effect of BMP6 on the expression of CTGF and the subsequent increase in CD68 expression as well as its underlying mechanisms. Primary and immortalized (SVOG) human granulosa cells obtained from infertile women undergoing in vitro fertilization treatment were used as cell models to conduct the in vitro experiments. Our results showed that BMP6 treatment significantly increased the expression levels of CTGF and CD68. Using BMP type I receptor inhibitors (dorsomorphin, DMH-1 and SB431542), we demonstrated that both activin receptor-like kinase (ALK)2 and ALK3 are involved in BMP6-induced stimulatory effects on the expression of CTGF and CD68. Additionally, SMAD4-knock down reversed the BMP6-induced up-regulation of CTGF and CD68, indicating that the canonical SMAD signaling pathway is required for these effects. Moreover, CTGF-knock down abolished the BMP6-induced up-regulation of CD68 expression. These findings indicate that intrafollicular CTGF mediates BMP6-induced increases in CD68 expression through the ALK2/ALK3-mediated SMAD-dependent signaling pathway.
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http://dx.doi.org/10.1016/j.mce.2021.111414DOI Listing
October 2021

Quantum Dot Photocatalysts for Organic Transformations.

J Phys Chem Lett 2021 Aug 26;12(30):7180-7193. Epub 2021 Jul 26.

Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States.

Quantum dots (QDs) with tunable photo-optical properties and colloidal nature are ideal for a wide range of photocatalytic reactions. In particular, QD photocatalysts for organic transformations can provide new and effective synthetic routes to high value-added molecules under mild conditions. In this Perspective, we discuss the advances of employing QDs for visible-light-driven organic transformations categorized into net reductive reactions, net oxidative reactions, and redox neutral reactions. We then provide our outlook for potential future directions in the field: nanostructure engineering to improve charge separation efficiencies, ligand shell engineering to optimize overall catalyst performance, comprehensive studies to delineate underlying reaction mechanisms, and laboratory automation with the assistance of modern computing techniques to revolutionize the reaction optimization process.
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http://dx.doi.org/10.1021/acs.jpclett.1c01717DOI Listing
August 2021

First-in-human DR5 PET reveals insufficient DR5 expression in patients with gastrointestinal cancer.

J Immunother Cancer 2021 Jul;9(7)

Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, China

Background: Death receptor 5 (DR5) is a promising therapeutic target for cancer therapy. However, many clinical trials of DR5 agonists failed to show significant therapeutic efficacy in patients with cancer. The study aimed to investigate the feasibility of using Zr-CTB006 positron emission tomography (PET) for noninvasive imaging of DR5 expression in preclinical models and patients with gastrointestinal (GI) cancers.

Methods: Balb/c, Sp2/0 xenograft and patient-derived tumor xenograft were employed for micro-PET/CT imaging in vivo. In the clinical study, patients with GI cancers planning to undergo surgical operation were enrolled and underwent F-FDG and Zr-CTB006 PET/CT. The tumor tissues were obtained through surgical operation and DR5 expression levels were confirmed by RNAscope.

Results: Preclinical studies showed that Zr-CTB006 PET could specifically detect DR5 expression levels in vivo. Twenty-one patients, including nine gastric cancers and 12 colorectal cancers, were enrolled. The biodistribution showed high uptake in the liver and spleen and low uptake in the brain, lung and muscle with an acceptable whole-body dosimetry of 0.349 mSv/MBq. Strikingly, the adrenal glands maintained stable high uptake over the entire examination in all patients. The tumor lesions showed different levels of uptake of Zr-CTB006 with a mean maximum standardized uptake value (SUV) of 6.63±3.29 (range 1.8-13.8). Tumor tissue was obtained from 18 patients, and Zr-CTB006 uptake in patients with RNAscope scores of 3-4 was significantly higher than that in patients with scores of 0-2. An SUV of 9.3 at 48 hours and 6.3 at 72 hours could be used to discriminate the DR5 expression status of tumors both with a sensitivity and specificity of 100% and 92.9%, respectively.

Conclusions: Zr-CTB006 PET/CT is capable of detecting DR5 expression in cancer patients and is a promising approach to screen patients with DR5 overexpression.
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http://dx.doi.org/10.1136/jitc-2021-002926DOI Listing
July 2021

Characteristics and antifatigue activity of graded polysaccharides from Ganoderma lucidum separated by cascade membrane technology.

Carbohydr Polym 2021 Oct 10;269:118329. Epub 2021 Jun 10.

Department of Food Science and Technology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, People's Republic of China; Key Laboratory of Food Macromolecular Resources Processing Technology Research (Zhejiang University of Technology), China National Light Industry, People's Republic of China. Electronic address:

In this paper, cascade membrane technology was utilized to classify polysaccharides from Ganoderma lucidum (GLPs). The properties and antifatigue activity of graded polysaccharides were identified and compared. GLPs were separated using cascade ultrafiltration membranes of 100 kDa, 10 kDa and 1 kDa in sequence. The molecular weights of polysaccharides in these GLP fractions were approximately 322.0 kDa, 18.8 kDa and 6.4 kDa, and all polysaccharides were in active β-configurations. This showed that all graded GLPs could elongate swimming time, improve endurance and promote fatigue recovery, especially polysaccharides with molecular weights above 10 kDa. This demonstrated that GLPs could decrease the activities of SUN and CK and the levels of MDA and BLA. They also increased the level of Gly, accelerated fat transformation, and improved the activities of GPx, SOD and LDH in all treated mice. Accordingly, GLPs above 10 kDa might be potential agents with antifatigue activity.
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http://dx.doi.org/10.1016/j.carbpol.2021.118329DOI Listing
October 2021

MG53 suppresses NF-κB activation to mitigate age-related heart failure.

JCI Insight 2021 Sep 8;6(17). Epub 2021 Sep 8.

Department of Surgery, Division of Cardiac Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.

Aging is associated with chronic oxidative stress and inflammation that affect tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here, we demonstrate that the expression of MG53 was reduced in failing human hearts and aged mouse hearts, concomitant with elevated NF-κB activation. We evaluated the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements revealed beneficial effects of rhMG53 treatment in improving heart function of aged mice. Biochemical and histological studies demonstrated that the cardioprotective effects of rhMG53 are linked to suppression of NF-κB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administration of rhMG53 in aged mice did not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.
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http://dx.doi.org/10.1172/jci.insight.148375DOI Listing
September 2021

Correction to: Transmission of H7N9 influenza virus in mice by different infective routes.

Virol J 2021 Jul 6;18(1):140. Epub 2021 Jul 6.

Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical Collage (PUMC); Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, No. 5 Pan Jia Yuan Nan Li, Chaoyang District, Beijing, 100021, China.

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http://dx.doi.org/10.1186/s12985-021-01603-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261966PMC
July 2021

Molecular PET/CT Profiling of ACE2 Expression In Vivo: Implications for Infection and Outcome from SARS-CoV-2.

Adv Sci (Weinh) 2021 08 26;8(16):e2100965. Epub 2021 Jun 26.

Key Laboratory of Carcinogenesis and Translational Research, NMPA Key Laboratory for Research Evaluation of Radiopharmaceuticals (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, 100142, China.

Rapid progress has been made to identify and study the causative agent leading to coronavirus disease 2019 (COVID-19) but many questions including who is most susceptible and what determines severity remain unanswered. Angiotensin-converting enzyme 2 (ACE2) is a key factor in the infection process of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In this study, molecularly specific positron emission tomography imaging agents for targeting ACE2 are first developed, and these novel agents are evaluated in vitro, in preclinical model systems, and in a first-in-human translational ACE2 imaging of healthy volunteers and a SARS-CoV-2 recovered patient (NCT04422457). ACE2 expression levels in different organs in live subjects are quantitatively delineated and observable differences are measured in the patient recovered from COVID-19. Surprising sites of uptake in the breast, reproductive system and very low uptake in pulmonary tissues are reported. This novel method can add a unique tool to facilitate SARS-CoV-2 related research and improve understanding of this enigmatic disease. Molecular imaging provides quantitative annotation of ACE2, the SARS-CoV-2 entry receptor, to noninvasively monitor organs impacted by the COVID-19.
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http://dx.doi.org/10.1002/advs.202100965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373167PMC
August 2021

Cu-PSMA-BCH: a new radiotracer for delayed PET imaging of prostate cancer.

Eur J Nucl Med Mol Imaging 2021 Jun 25. Epub 2021 Jun 25.

Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Rd, Beijing, 100142, China.

Purpose: Develop a Cu labeled radiopharmaceutical targeting prostate specific membrane antigen (PSMA) and investigate its application for prostate cancer imaging.

Methods: Cu-PSMA-BCH was prepared and investigated for stability, PSMA specificity, and micro-PET imaging. With the approval of Ethics Committee of Beijing Cancer Hospital (No. 2017KT97), PET/CT imaging in 4 patients with suspected prostate cancer was performed and the radiation dosimetry was estimated. Then, PSMA PET-ultrasound image-guided biopsies were performed on 3 patients and the fine needle aspirates were further performed for autoradiography and immunohistochemistry analysis.

Results: Cu-PSMA-BCH was prepared with high radiochemical yield and stability. In vivo study showed higher uptake in PSMA ( +) 22Rv1 cells than PSMA ( -) PC-3 cells (5.59 ± 0.36 and 1.97 ± 0.22 IA%/10 cells at 1 h). It accumulated in 22Rv1 tumor with increasing radioactivity uptake and T/N ratios from 1 to 24 h post-injection. In patients with suspected prostate cancer, SUVmax and T/N ratios increased within 24 h post-injection. Compared with image at 1 h post-injection, more tumor lesions were detected at 6 h and 24 h post-injection. The human organ radiation dosimetry showed gallbladder wall was most critical, liver and kidneys were followed, and the whole-body effective dose was 0.0292 mSv/MBq. Two fine needle aspirates obtained by PET-ultrasound-guided targeted biopsy showed high radioactive signal by autoradiography, with 100% PSMA expression in cytoplasm and 30% expression in nucleus.

Conclusion: Cu-PSMA-BCH was PSMA specific and showed high stability in vivo with lower uptake in liver than Cu-PSMA-617. Biodistribution in mice and PCa patients showed similar profile compared with other PSMA ligands and it was safe with moderate effective dosimetry. The increased tumor uptake and T/N ratios by delayed imaging may facilitate the detection of small lesions and guiding targeted biopsies.
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http://dx.doi.org/10.1007/s00259-021-05426-9DOI Listing
June 2021

Clinical translational evaluation of AlF-NOTA-FAPI for fibroblast activation protein-targeted tumour imaging.

Eur J Nucl Med Mol Imaging 2021 Jun 24. Epub 2021 Jun 24.

Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China.

Purpose: In this study, a novel aluminium-[F]fluoride (AlF)-labelled 1,4,7‑triazacyclononane-N,N',N″-triacetic acid (NOTA)-conjugated fibroblast activation protein inhibitor (FAPI) probe, named AlF-NOTA-FAPI, was developed for fibroblast activation protein (FAP)-targeted tumour imaging; it could deliver hundreds of millicuries of radioactivity using automated synthesis. The tumour detection efficacy of AlF-NOTA-FAPI was further validated in both preclinical and clinical translational studies.

Methods: The radiolabelling procedure of AlF-NOTA-FAPI was optimized. Cell uptake and competitive binding assays were completed with the U87MG and A549 cell lines to evaluate the affinity and specificity of the AlF-NOTA-FAPI probe. The biodistribution, pharmacokinetics, radiation dosimetry and tumour imaging efficacy of the AlF-NOTA-FAPI probe were researched in healthy Kunming (KM) and/or U87MG model mice. After the approval of the ethical committee, the AlF-NOTA-FAPI probe was translated into the clinic for PET/CT imaging of the first 10 cancer patients.

Results: The radiolabelling yield of AlF-NOTA-FAPI was 33.8 ± 3.2% using manual synthesis (n = 10), with a radiochemical purity over 99% and the specific activity of 9.3-55.5 MBq/nmol. The whole body effective dose of AlF-NOTA-FAPI was estimated to be 1.24E - 02 mSv/MBq, which was lower than several other FAPI probes (Ga-FAPI-04, Ga-FAPI-46 and Ga-FAPI-74). In U87MG tumour-bearing mice, AlF-NOTA-FAPI showed good tumour detection efficacy based on the results of micro PET/CT imaging and biodistribution studies. In an organ biodistribution study of patients, AlF-NOTA-FAPI showed a lower SUVmean than 2-[F]-fluoro-2-deoxy-D-glucose (2-[F]FDG) in most organs, especially in the liver (1.1 ± 0.2 vs. 2.0 ± 0.9), brain (0.1 ± 0.0 vs. 5.9 ± 1.3), and bone marrow (0.9 ± 0.1 vs. 1.7 ± 0.4). Meanwhile, AlF-NOTA-FAPI did not show extensive bone uptake, and was able to detect more lesions than 2-[F]FDG in the PET/CT imaging of several patients.

Conclusion: The AlF-NOTA-FAPI probe was successfully fabricated and applied in fibroblast activation protein-targeted tumour PET/CT imaging, which showed excellent imaging quality and tumour detection efficacy in U87MG tumour-bearing mice as well as in cancer patients.

Trial Registration: Chinese Clinical Trial Registry ChiCTR2000038080. Registered 09 September 2020. http://www.chictr.org.cn/showproj.aspx?proj=61192.
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http://dx.doi.org/10.1007/s00259-021-05470-5DOI Listing
June 2021

Serp-1 Promotes Corneal Wound Healing by Facilitating Re-epithelialization and Inhibiting Fibrosis and Angiogenesis.

Front Cardiovasc Med 2021 4;8:649124. Epub 2021 Jun 4.

Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Chemical corneal injuries carry a high morbidity and commonly lead to visual impairment. Here, we investigate the role of Serp-1, a serine protease inhibitor, in corneal wound healing. An alkaline-induced corneal injury was induced in 14 mice. Following injury, five mice received daily topical saline application while nine mice received Serp-1 100 μL topically combined with a daily subcutaneous injection of 100 ng/gram body weight of Serp-1. Corneal damage was monitored daily through fluorescein staining and imaging. Cross sectional corneal H&E staining were obtained. CD31 was used as marker for neovascularization. Serp-1 facilitates corneal wound healing by reducing fibrosis and neovascularization while mitigating inflammatory cell infiltration with no noticeable harm related to its application. Serp-1 effectively mitigates inflammation, decreases fibrosis, and reduce neovascularization in a murine model of corneal injury without affecting other organs. Our study provides preclinical data for topical application of Serp-1 to treat corneal wounds.
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http://dx.doi.org/10.3389/fcvm.2021.649124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216079PMC
June 2021

Gut lactate-producing bacteria promote CD4 T cell recovery on Anti-retroviral therapy in HIV-infected patients.

Comput Struct Biotechnol J 2021 11;19:2928-2937. Epub 2021 May 11.

CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, & China National Center for Bioinformation, Beijing 100101, China.

Anti-retroviral therapy (ART) effectively suppresses viral replication in HIV-infected patients, however CD4 + cell restoration to normal value is not achieved by 15-20% of patients who are called immune non-responders. Gut microbiota composition has been shown to influence host immunity. Herein, to identify intestinal microbial agents that may influence the CD4 recovery in HIV-infected patients, we utilized a "Quasi-paired cohort" method to analyze intestinal metagenome data from immunological responders (IRs) and immunological non-responders (INRs). This method identified significant enrichment for sp. and related lactate-producing bacteria (LAB) in IRs. In a validation cohort, positive correlations between the abundance of these LAB and the post-ART CD4 + recovery was observed, and a prediction model based on these LAB performed well in predicting immune recovery. Finally, experiments using a germ-free mouse model of antibody-induced CD4 + cell depletion showed that supplementation with a lactate-producing commensal strongly promoted CD4 recovery. In conclusion, our study identified a group of LAB that was associated with enhanced immune recovery in post-ART HIV-infected patients and promotes CD4 + cell restoration in a mouse model. These findings favour supplementation of LAB commensal as a therapeutic strategy for CD4 + cell count improvement in HIV-infected patients.
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http://dx.doi.org/10.1016/j.csbj.2021.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191414PMC
May 2021

STAT1 epigenetically regulates LCP2 and TNFAIP2 by recruiting EP300 to contribute to the pathogenesis of inflammatory bowel disease.

Clin Epigenetics 2021 Jun 10;13(1):127. Epub 2021 Jun 10.

Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China.

Background: The aetiology of inflammatory bowel disease (IBD) is related to genetics and epigenetics. Epigenetic regulation of the pathogenesis of IBD has not been well defined. Here, we investigated the role of H3K27ac events in the pathogenesis of IBD. Based on previous ChIP-seq and RNA-seq assays, we studied signal transducer and activator of transcription 1 (STAT1) as a transcription factor (TF) and investigated whether the STAT1-EP300-H3K27ac axis contributes to the development of IBD. We performed ChIP-PCR to investigate the interaction between STAT1 and H3K27ac, and co-IP assays were performed to investigate the crosstalk between STAT1 and EP300.

Results: Lymphocyte cytosolic protein 2 (LCP2) and TNF-α-inducible protein 2 (TNFAIP2) are target genes of STAT1. p-STAT1 binds to the enhancer loci of the two genes where H3K27ac is enriched, and EP300 subsequently binds to regulate their expression. In mice with dextran sulfate sodium (DSS)-induced acute colitis, an EP300 inhibitor significantly inhibited colitis.

Conclusions: p-STAT1 and EP300 promote TNFAIP2 and LCP2 expression through an increase in H3K27ac enrichment on their enhancers and contribute to the pathogenesis of chronic inflammation.
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http://dx.doi.org/10.1186/s13148-021-01101-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194145PMC
June 2021

Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy.

J Nanobiotechnology 2021 Jun 10;19(1):175. Epub 2021 Jun 10.

Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Background: Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies.

Methods: We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (Cu-NOTA-DBCO) using bioorthogonal chemistry. Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi).

Results: CTLs can be stably radiolabeled with Cu with a minimal effect on cell viability. PET imaging of Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms.

Conclusion: These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens.
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http://dx.doi.org/10.1186/s12951-021-00924-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194184PMC
June 2021

Hierarchical Porous Graphene Bubbles as Host Materials for Advanced Lithium Sulfur Battery Cathode.

Front Chem 2021 24;9:653476. Epub 2021 May 24.

Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.

The serious shuttle effect, low conductivity, and large volume expansion have been regarded as persistent obstacles for lithium sulfur (Li-S) batteries in its practical application. Carbon materials, such as graphene, are considered as promising cathode hosts to alleviate those critical defects and be possibly coupled with other reinforcement methods to further improve the battery performance. However, the open structure of graphene and the weak interaction with sulfur species restrict its further development for hosting sulfur. Herein, a rational geometrical design of hierarchical porous graphene-like bubbles (PGBs) as a cathode host of the Li-S system was prepared by employing magnesium oxide (MgO) nanoparticles as templates for carbonization, potassium hydroxide (KOH) as activation agent, and car tal pitch as a carbon source. The synthesized PGBs owns a very thin carbon layer around 5 nm that can be comparable to graphite nanosheets. Its high content of mesoporous and interconnected curved structure can effectively entrap sulfur species and impose restrictions on their diffusion and shuttle effect, leading to a much stable electrochemical performance. The reversible capacity of [email protected] 0.3 C still can be maintained at 831 mAh g after 100 cycles and 512 mAh g after 500 cycles.
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http://dx.doi.org/10.3389/fchem.2021.653476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181144PMC
May 2021

Muscle multiorgan crosstalk with MG53 as a myokine for tissue repair and regeneration.

Curr Opin Pharmacol 2021 08 27;59:26-32. Epub 2021 May 27.

Department of Surgery Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Electronic address:

Through stress and injury to tissues, the cell membrane is damaged and can lead to cell death and a cascade of inflammatory events. Soluble factors that mitigate and repair membrane injury are important to normal homeostasis and are a potential therapeutic intervention for regenerative medicine. A myokine is a type of naturally occurring factors that come from muscle and have impact on remote organs. MG53, a tripartite motif-containing family protein, is such a myokine which has protective effects on lungs, kidneys, liver, heart, eye, and brain. Three mechanisms of action for the beneficial regenerative medicine potential of MG53 have been identified and consist of 1) repair of acute injury to the cellular membrane, 2) anti-inflammatory effects associated with chronic injuries, and 3) rejuvenation of stem cells for tissue regeneration. As such, MG53 has the potential to be a novel and effective regeneration medicine therapeutic.
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http://dx.doi.org/10.1016/j.coph.2021.04.005DOI Listing
August 2021

7,8-Dihydroxyflavone suppresses proliferation and induces apoptosis of human osteosarcoma cells.

Acta Biochim Biophys Sin (Shanghai) 2021 Jul;53(7):903-911

Department of Pharmacy, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou 225001, China.

Recent studies suggest that 7,8-dihydroxyflavone (7,8-DHF) inhibits the development of several tumors. However, its role in osteosarcoma (OS) remains unknown. This study was designed to investigate the effects and underlying mechanisms of 7,8-DHF that may influence OS development. Human OS cell lines (U2OS and 143B) were treated with 7,8-DHF; cell viability and cell migration were assessed by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and wound-healing assay, respectively; and cell death and apoptosis were evaluated by LIVE/DEAD staining and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, respectively. Reactive oxygen species production was measured using 2,7-dichlorodihydrofluorescein diacetate probe. Akt, Bcl-xL/Bcl-2 asociated death promoter (Bad), p38 mitogen-activated protein kinase (MAPK), extracellular regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK) expression and their respective phosphorylation levels were detected by western blot analysis. We found that 7,8-DHF reduced cell viability in a dose-dependent manner and also promoted apoptosis, inhibited migration, and induced oxidative stress in OS cells. Moreover, 7,8-DHF inhibited Akt, Bad, and p38MAPK, but activated ERK and JNK signals. In summary, our results suggest that 7,8-DHF inhibits OS progression, possibly by regulating Akt/Bad and MAPK signaling. These findings provide new evidence for the pharmacological effects of 7,8-DHF that may improve drug therapy for OS patients.
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http://dx.doi.org/10.1093/abbs/gmab060DOI Listing
July 2021

SETD8 involved in the progression of inflammatory bowel disease via epigenetically regulating p62 expression.

J Gastroenterol Hepatol 2021 May 14. Epub 2021 May 14.

Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China.

Background And Aim: Epigenetic modification is an important part of the pathogenesis of inflammatory bowel disease (IBD). Some studies proved that p62 was involved in inflammatory response and upregulated in IBD patients, and histone modification plays an important role in regulating p62 expression. SETD8, a histone H4K20 methyltransferase, has been reported downregulated in some inflammatory diseases. Here, we investigated the role of SETD8 in the development of IBD and its underlying mechanisms.

Methods: An inflammatory cell model was established to elucidate whether SETD8 involved in inflammatory response in macrophages. Three percent dextran sodium sulfate-induced colitis murine model injection with SETD8 inhibitor was used in our study to investigate whether SETD8 inhibition can affect the progress of IBD. The expression of SETD8 and p62 was measured by qRT-PCR and western blot. The mRNA level of inflammatory cytokines was analyzed by qRT-PCR. In addition, chromatin immunoprecipitation-PCR was performed to identify the mechanism by which SETD8 regulates p62.

Results: SETD8 expression obviously decreased in vitro, in vivo models and in IBD patients. In lipopolysaccharide-activated RAW264.7 cells, knockdown of SETD8 significantly increased the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, IL-6, IL-1β, and MCP-1. Based on the dataset, we verified that p62 was a target gene of SETD8 and chromatin immunoprecipitation-PCR assay identified that silence of SETD8 distinctly decreases the H4K20me1 enrichment in the promoter of p62. Moreover, silencing of p62 partly reverses the SETD8 inhibition-mediated pro-inflammatory effect in vitro. Finally, SETD8 pharmacological inhibitor (UNC0379) aggravated the disease progression in dextran sodium sulfate-induced murine colitis.

Conclusion: Our findings elucidate an epigenetic mechanism by which SETD8 regulates the p62 expression and restrains the inflammatory response in colitis. Our result suggests that targeting SETD8 may be a promising therapy for IBD.
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http://dx.doi.org/10.1111/jgh.15550DOI Listing
May 2021

Imaging superiority of [Ga]-FAPI-04 over [F]-FDG PET/CT in alveolar soft part sarcoma (ASPS).

Eur J Nucl Med Mol Imaging 2021 Oct 13;48(11):3741-3742. Epub 2021 May 13.

Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, No. 52 Fucheng Rd., Beijing, 100142, China.

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http://dx.doi.org/10.1007/s00259-021-05388-yDOI Listing
October 2021
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