Publications by authors named "Di Li"

708 Publications

An Anisotropic Equivalent Thermal Model for Shield Differential Through-Silicon Vias.

Micromachines (Basel) 2021 Oct 7;12(10). Epub 2021 Oct 7.

School of Microelectronics, Xidian University, Xi'an 710071, China.

An accurate equivalent thermal model is proposed to calculate the equivalent thermal conductivity (ETC) of shield differential through-silicon via (SDTSV). The mathematical expressions of ETC in both horizontal and vertical directions are deduced by considering the anisotropy of SDTSV. The accuracy of the proposed model is verified by the finite element method (FEM), and the average errors of temperature along the X-axis, Y-axis, diagonal line, and vertical directions are 1.37%, 3.42%, 1.76%, and 0.40%, respectively. Compared with COMSOL, the proposed model greatly improves the computational efficiency. Moreover, the effects of different parameters on the thermal distribution of SDTSV are also investigated. The thermal conductivity is decreased with the increase in thickness of SiO. With the increase in pitch, the maximum temperature of SDTSV increases very slowly when β = 0° , and decreases very slowly when β = 90°. The proposed model can be used to accurately and quickly describe the thermal distribution of SDTSV, which has a great prospect in the design of 3D IC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/mi12101223DOI Listing
October 2021

Endovascular Recanalization and Standard Medical Management for Symptomatic Non-acute Intracranial Artery Occlusion: Study Protocol for a Non-randomized, 24-Month, Multicenter Study.

Front Neurol 2021 28;12:729534. Epub 2021 Sep 28.

Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Beijing, China.

The management of patients with symptomatic non-acute intracranial artery occlusion (sNA-ICAO), which is a special subset with high morbidity and a high probability of recurrent serious ischemic events despite standard medical therapy (SMT), has been clinically challenging. A number of small-sample clinical studies have also discussed endovascular recanalization (ER) for sNA-ICAO; however, there is currently a lack of evidence from multicenter, prospective, large-sample cohort trials. The purpose of our present study was to evaluate the technical feasibility and safety of ER for sNA-ICAO. Our group is currently undertaking a multisite, non-randomized cohort, prospective registry study enrolling consecutive patients presenting with sNA-ICAO at 15 centers in China between January 1, 2020 and December 31, 2022. A cohort of patients who received SMT and a cohort of similar patients who received ER plus SMT were constructed and followed up for 2 years. The primary outcome is any stroke from enrollment to 2 years of follow-up. The secondary outcomes are all-cause mortality, mRS score, NIHSS score and cognitive function from enrollment to 30 days, 3 months, 8 months, 12 months, 18 months, and 2 years of follow-up. Descriptive statistics and linear/logistic multiple regression models will be generated. Clinical relevance will be measured as relative risk reduction, absolute risk reduction and the number needed to treat. The management of patients with sNA-ICAO has been clinically challenging. The current protocol aims to evaluate the technical feasibility and safety of ER for sNA-ICAO. www.ClinicalTrials.gov, identifier: NCT04864691.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2021.729534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506001PMC
September 2021

Multienzyme nanoassemblies: from rational design to biomedical applications.

Biomater Sci 2021 Oct 14. Epub 2021 Oct 14.

School of Chemical and Biomedical Engineering, Nanyang Technological University, 70 Nanyang Drive, Singapore 637457, Singapore.

Multienzyme nanoassemblies (MENAs) that combine the functions of several enzymes into one entity have attracted widespread research interest due to their improved enzymatic performance and great potential for multiple applications. Considerable progress has been made to design and fabricate MENAs in recent years. This review begins with an introduction of the up-to-date strategies in designing MENAs, mainly including substrate channeling, compartmentalization and control of enzyme stoichiometry. The desirable properties that endow MENAs with important applications are also discussed in detail. Then, the recent advances in utilizing MENAs in the biomedical field are reviewed, with a particular focus on biosensing, tumor therapy, antioxidant and drug delivery. Finally, the challenges and perspectives for development of versatile MENAs are summarized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1bm01106eDOI Listing
October 2021

Discovery of 2-(Ortho-Substituted Benzyl)-Indole Derivatives as Potent and Orally Bioavailable RORγ Agonists with Antitumor Activity.

J Med Chem 2021 Oct 13. Epub 2021 Oct 13.

Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States.

RORγ is a dual-functional drug target, which involves not only induction of inflammation but also promotion of cancer immunity. The development of agonists of RORγ promoting Th17 cell differentiation could provide a novel mechanism of action (MOA) as an immune-activating anticancer agent. Herein, we describe new 2-(ortho-substituted benzyl)-indole derivatives as RORγ agonists by scaffold hopping based on clinical RORγ antagonist VTP-43742. Interestingly, subtle structural differences of the compounds led to the opposite biological MOA. After rational optimization for structure-activity relationship and pharmacokinetic profile, we identified a potent RORγ agonist compound that was able to induce the production of IL-17 and IFNγ in tumor tissues and elicit antitumor efficacy in MC38 syngeneic mouse colorectal tumor model. This is the first comprehensive work to demonstrate the antitumor efficacy of an RORγ agonist.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.1c00828DOI Listing
October 2021

Miro1 provides neuroprotection via the mitochondrial trafficking pathway in a rat model of traumatic brain injury.

Brain Res 2021 Oct 9;1773:147685. Epub 2021 Oct 9.

Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China.

The outer mitochondrial membrane protein mitochondrial Rho-GTPase 1 (Miro1) is known to be involved in the regulation of mitochondrial transport required for neuronal protection. Previous reports established that disruption of Miro1-dependent mitochondrial movement could result in nervous system diseases such as Parkinson's disease and Alzheimer's disease. This study was designed to explore the expression and mechanisms of Miro1 in secondary brain injury after traumatic brain injury (TBI). A total of 115 male Sprague Dawley rats were used in the weight-drop TBI rat model, and Miro1 in vivo knockdown was performed 24 h before TBI modeling by treatment with Miro1 short-interfering RNA. Real-time polymerase chain reaction, western blot, immunofluorescence, adenosine triphosphate (ATP) level assay, neuronal apoptosis, brain water content measurement, and neurological score analyses were carried out. Our results showed that the mRNA and protein levels of Miro1 were increased after TBI and co-localized with neurons and astrocytes in the peri-injury cortex. Moreover, Miro1 knockdown further exacerbated neuronal apoptosis, brain edema, and neurological deficits at 48 h after TBI, accompanied by impaired mitochondrial transport, reduction of mitochondria number and energy deficiency. Additionally, the apoptosis-related factors Bax upregulation and Bcl-2 downregulation as Miro1 knockdown after TBI implied that antiapoptotic effects on neuroprotection of Miro1, which were verified by the Fluoro-Jade C (FJC) staining and TUNEL staining. In conclusion, these findings suggest that Miro1 probably plays a neuroprotective role against secondary brain injury through the mitochondria trafficking pathway, suggesting that enhancing Miro1 might be a new strategy for the treatment of TBI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2021.147685DOI Listing
October 2021

Impact of Adjuvant Therapy on Survival in Surgically Resected Limited-Stage Small Cell Lung Cancer.

Front Oncol 2021 23;11:704517. Epub 2021 Sep 23.

Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Data on efficacy of adjuvant therapy for surgically resected small cell lung cancer are scant. This study was determined to reveal the survival benefits of different adjuvant treatment modalities for limited-stage small cell lung cancer patients following surgical resection.

Methods: Data of patients with histologically confirmed small cell lung cancer after surgical resection were collected from November 2006 to June 2019. Survival analyses were calculated by Kaplan-Meier method, with log-rank test to evaluate statistical significance. Prognostic factors were identified by multivariate analysis using cox proportional hazards model. Further survival analysis and cox regression analysis stratified by clinicopathologic features were conducted to evaluate the survival benefits of different adjuvant treatment modalities.

Results: In total, 153 out of 157 patients were analyzed. Multivariate analysis showed male sex, lymph node metastasis, residual tumor, VPI and non-adjuvant therapy were independently associated with poor prognosis. Subgroup analyses revealed both adjuvant chemotherapy and adjuvant chemoradiotherapy were significantly associated with superior survival for stage pT2-4 (HR=0.176, 95%CI:0.053-0.578, p=0.004; and HR=0.115, 95%CI:0.033-0.405, p=0.001) and pure SCLC patients (HR=0.182, 95%CI:0.067-0.494, p=0.001; and HR=0.181, 95%CI:0.071-0.465, p<0.001). For pN0 patients, adjuvant chemotherapy was associated with better survival (HR=0.219, 95%CI:0.054-0.891, p=0.034), while adjuvant chemoradiotherapy was associated with improved survival for pN+ patients (HR=0.324, 95%CI:0.138-0.760, p=0.010).

Conclusions: For patients without pathologic lymph node metastasis, there is a survival benefit with adjuvant chemotherapy. However, for patients with pathologic lymph node metastasis, adjuvant chemoradiotherapy might achieve a significant survival benefit. Further prospective studies are needed to validate the results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.704517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495161PMC
September 2021

LRRC4 mediates the formation of circular RNA CD44 to inhibitGBM cell proliferation.

Mol Ther Nucleic Acids 2021 Dec 26;26:473-487. Epub 2021 Aug 26.

Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China.

Mounting evidence reveals that dysregulation of circular RNAs (circRNAs) is involved in the development of glioblastoma. Leucine-rich repeat-containing 4 (LRRC4) has been shown to suppress tumors in glioblastoma. However, whether LRRC4 can regulate the formation of circRNA is not yet understood. In this study, LRRC4 was found to interact with SAM68. LRRC4 promoted the generation of circCD44 by inhibiting the binding between SAM68 and CD44 pre-mRNA. Moreover, downregulated expression of circCD44 was found in glioblastoma multiforme (GBM) tissues and GBM primary cells. Re-expression of circCD44 significantly suppressed the proliferation, colony formation, and invasion of GBM cells and inhibited tumor growth . Mechanistically, circCD44 could regulate the expression of SMAD6 via sponging miR-326 and miR-330-5p involved in the progression of GBM. Thus, the LRRC4/SAM68/circCD44/miR-326/miR-330-5p/SMAD6 signaling axis could be a potential target for GBM treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omtn.2021.08.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479294PMC
December 2021

WNK3 Promotes Neuronal Survival after Traumatic Brain Injury in Rats.

Neuroscience 2021 Oct 6. Epub 2021 Oct 6.

Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, China.

With-no-lysine kinase 3 (WNK3) is a key regulator of chloride ion transport and neuronal survival in diverse cell types. WNK3 was previously found to regulate the activity of Na-K-2Cl cotransporter-1 (NKCC1) in ischemia-associated brain damage. However, the role of WNK3 in traumatic brain injury (TBI) has not yet been studied. A weight-drop TBI model was established in Sprague-Dawley rats. Overexpression and specific inhibition were used to investigate the role of WNK3 in TBI via Western blot, immunofluorescence, neuronal apoptosis, brain water content, and neurological score analyses. We found pronounced TBI-induced downregulation of WNK3 expression and upregulation of NKCC1 expression in neurons, especially at 48 h. Overexpression of WNK3 significantly ameliorated neuronal apoptosis, blood-brain barrier (BBB) disruption, brain edema and neurological deficits at 48 h after TBI. These effects were concomitant with reductions in p-NKCC1 and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) expression. Furthermore, bumetanide administration enhanced the neuroprotective effects of WNK3 overexpression against brain injury. Thus, WNK3 plays a neuroprotective role in TBI, and overexpression of WNK3 may increase cell resistance to apoptotic insults and brain edema, thereby alleviating secondary brain injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroscience.2021.09.021DOI Listing
October 2021

An in vivo and in vitro model on the protective effect of corilagin on doxorubicin-induced cardiotoxicity via regulation of apoptosis and PI3-K/AKT signaling pathways.

J Biochem Mol Toxicol 2021 Oct 4:e22926. Epub 2021 Oct 4.

Department of General Medicine, Chongqing University Three Gorges Hospital, Chongqing, China.

Globally, doxorubicin (DOX)-induced cardio dysfunction is a serious cause of morbidity and mortality in cancerous patients. An adverse event of cardiotoxicity is the main deem to restrict in the clinical application by oncologists. Corilagin (CN) is well known for its antioxidative, anti-fibrosis, and anticancer effects. Herein, we aimed to evaluate the action of CN on DOX-induced experimental animals and H9c2 cells. The myocardium-specific marker, CK-MB, and the influx of mitochondrial calcium levels were measured by using commercial kits. Biochemical indices reflecting oxidative stress and antioxidant attributes such as malondialdehyde, glutathione peroxidase, reduced glutathione, superoxide dismutase, and catalase were also analyzed in DOX-induced cardiotoxic animals. In addition, mitochondrial ROS were measured by DCFH-DA in H9c2 cells under fluorescence microscopy. DOX induction significantly increased oxidative stress levels and also modulated apoptosis/survival protein expressions in myocardial tissues. Western blots were used to measure the expressional levels of Bax/Bcl-2, caspase-3, PI3-K/AKT, and PPARγ signaling pathways. Histological studies were executed to observe morphological changes in myocardial tissues. All of these DOX-induced effects were attenuated by CN (100 mg/kg bw). These in vitro and in vivo results point towards the fact that CN might be a novel cardioprotective agent against DOX-induced cardiotoxicity through modulating cardio apoptosis and oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbt.22926DOI Listing
October 2021

Synergistic Integration of AuCu Co-Catalyst with Oxygen Vacancies on TiO for Efficient Photocatalytic Conversion of CO to CH.

ACS Appl Mater Interfaces 2021 Oct 24;13(39):46772-46782. Epub 2021 Sep 24.

Institute for Energy Research, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China.

Photocatalytic reduction of CO toward eight-electron CH product with simultaneously high conversion efficiency and selectivity remains great challenging owing to the sluggish charge separation and transfer kinetics and lack of active sites for the adsorption and activation of reactants. Herein, a defective TiO nanosheet photocatalyst simultaneously equipped with AuCu alloy co-catalyst and oxygen vacancies (AuCu-TiO NSs) was rationally designed and fabricated for the selective conversion of CO into CH. The experimental results demonstrated that the AuCu alloy co-catalyst not only effectively promotes the separation of photogenerated electron-hole pairs but also acts as synergistic active sites for the reduction of CO. The oxygen vacancies in TiO contribute to the separation of charge carriers and, more importantly, promote the oxidation of HO, thus providing rich protons to promote the deep reduction of CO to CH. Consequently, the optimal AuCu-TiO nanosheets (NSs) photocatalyst achieves a CO reduction selectivity toward CH up to 90.55%, significantly higher than those of TiO NSs (31.82%), Au-TiO NSs (38.74%), and Cu-TiO NSs (66.11%). Furthermore, the CH evolution rate over the AuCu-TiO NSs reaches 22.47 μmol·g·h, which is nearly twice that of AuCu-TiO NSs (12.10 μmol·g·h). This research presents a unique insight into the design and synthesis of photocatalyst with oxygen vacancies and alloy metals as the co-catalyst for the highly selective deep reduction of CO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.1c14371DOI Listing
October 2021

Prefrontal-limbic-striatum dysconnectivity associated with negative emotional endophenotypes in bipolar disorder during depressive episodes.

J Affect Disord 2021 Aug 27;295:422-430. Epub 2021 Aug 27.

The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu 610054, PR China; MOE Key Lab for Neuroinformation, High-Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu 610054, PR China. Electronic address:

Background: The prefrontal-limbic-subcortical network has been suggested as an important circuitry in the pathophysiology underlying bipolar disorder during depressive episodes (BDD). However, the relationships between disrupted prefrontal-limbic-subcortical connection and the emotional endophenotypes in BDD patients remain largely unclear.

Methods: Forty-three BDD patients and 63 matched healthy controls (HCs) underwent the resting-state functional magnetic resonance imaging scan. The altered clusters were first identified by using a spatial pairwise clustering method and then were extracted as regions of interest to calculate the functional connectivity (FC). Group comparisons were conducted to identify the abnormal FCs. Classification analysis was employed to examine whether the altered FCs could distinguish BDD from HCs. The relationships between FC alterations and the emotional endophenotypes as measured by the Affective Neuroscience Personality Scales (ANPS) were further detected in BDD.

Results: Compared with HCs, BDD patients showed abnormal FCs in the prefrontal-limbic-striatum circuit. Importantly, the altered FCs yielded 84.91% accuracy (p< 1/5000) with 93.65% sensitivity and 72.09% specificity in differentiating between BDD and HCs. Moreover, the decreased FCs in the prefrontal-striatum and prefrontal-limbic systems were positively correlated with negative emotional endophenotypes of Sadness and Fear scores.

Conclusions: The findings demonstrated that prefrontal-limbic-striatum disconnection may be identified as a potential effective biomarker for BDD, which could help further explain the neurobiological mechanisms underlying BDD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2021.08.055DOI Listing
August 2021

Histone code reader SPIN1 is a promising target of cancer therapy.

Biochimie 2021 Sep 4;191:78-86. Epub 2021 Sep 4.

The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China. Electronic address:

SPIN1 is a histone methylation reader, which can epigenetically control multiple tumorigenesis-associated signaling pathways, including the Wnt, PI3K/AKT, and RET pathways. Considerable evidence has shown that SPIN1 is overexpressed in many cancers, which can promote cell proliferation, transformation, metastasis, and chemical or radiation resistance. With the growing understanding of the SPIN1 protein structure, some inhibitors have been developed to interfere with the recognition between SPIN1 and histone H3K4me3 and H3R8me2a methylation and block the oncogenic functions of SPIN1. Therefore, SPIN1 is a potential target of cancer therapy. However, the mechanism by which SPIN1-transformed cells overcome the significant mitotic spindle defects and the factors promoting SPIN1 overexpression in cancers remain unclear. In this review, we described the current understanding of the SPIN1 protein structure and its expression, functions, and regulatory mechanisms in carcinogenesis, and discussed the challenges faced in the mechanisms of SPIN1 overexpression and oncogenic functions, and the potential application of anti-SPIN1 treatment in human cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2021.09.002DOI Listing
September 2021

Multiple strategies for metabolic engineering of Escherichia coli for efficient production of glycolate.

Biotechnol Bioeng 2021 Sep 7. Epub 2021 Sep 7.

Tianjin Institute of Industrial Biotechnology, Chinese of Academy of Sciences, Tianjin, China.

Glycolate is a bulk chemical with wide applications in the textile, food processing, and pharmaceutical industries. Glycolate can be produced from glucose via the glycolysis and glyoxylate shunt pathways, followed by reduction to glycolate. However, two problems limit the productivity and yield of glycolate when using glucose as the sole carbon source. The first is a cofactor imbalance in the production of glycolate from glucose via the glycolysis pathway, since NADPH is required for glycolate production, while glycolysis generates NADH. To rectify this imbalance, the NADP -dependent glyceraldehyde 3-phosphate dehydrogenase GapC from Clostridium acetobutylicum was introduced to generate NADPH instead of NADH in the oxidation of glyceraldehyde 3-phosphate during glycolysis. The soluble transhydrogenase SthA was further eliminated to conserve NADPH by blocking its conversion into NADH. The second problem is an unfavorable carbon flux distribution between the tricarboxylic acid cycle and the glyoxylate shunt. To solve this problem, isocitrate dehydrogenase (ICDH) was eliminated to increase the carbon flux of glyoxylate and thereby improve the glycolate titer. After engineering through the integration of gapC, combined with the inactivation of ICDH, SthA, and by-product pathways, as well as the upregulation of the two key enzymes isocitrate lyase (encoding by aceA), and glyoxylate reductase (encoding by ycdW), the glycolate titer increased to 5.3 g/L with a yield of 1.89 mol/mol glucose. Moreover, an optimized fed-batch fermentation reached a titer of 41 g/L with a yield of 1.87 mol/mol glucose after 60 h.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bit.27934DOI Listing
September 2021

Transcriptome analysis provides the first insight into the molecular basis of temperature plasticity in Banggai cardinalfish, Pterapogon kauderni.

Comp Biochem Physiol Part D Genomics Proteomics 2021 Aug 28;40:100909. Epub 2021 Aug 28.

The Key Laboratory of Mariculture (Ocean University of China), Ministry of Education, Qingdao, Shandong 266003, China. Electronic address:

Banggai cardinalfish, Pterapogon kauderni, is a tropical fish listed as an endangered species by IUCN. Its distribution and survival condition are extremely limited, and the changes of living environment caused by global warming may seriously threaten its geographical distribution. In order to understand the survival temperature range and the potential mechanism of temperature plasticity of P. kauderni, transcriptome analysis was performed under five temperature conditions (18 °C, 22 °C, 26 °C, 30 °C and 34 °C). A total of 432,444,497 clean reads were obtained from the mix tissues of whole head, viscera (except intestine), and muscle. All clean data were spliced into 194,832 unigenes. Compared with 26 °C, 57, 107, 187 and 174 differentially expressed genes (DEGs) were obtained at 18 °C, 22 °C, 30 °C and 34 °C, respectively. Gene Ontology (GO) analysis showed the most highly enriched in the DEGs were cellular processes, binding, metabolic processes and biological regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated circadian rhythm, protein processing in endoplasmic reticulum, influenza A and prion disease were significantly enriched. 47 genes that may be related to temperature stress were identified, such as Per1, MLP, IGFBP1, HSP70, HSP90α, HSPA4, DNAJB1, CALR. This is the first RNA-Seq study of P. kauderni. This information should be valuable for further targeted studies on temperature tolerance, thereby assisting the protection and development of P. kauderni.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cbd.2021.100909DOI Listing
August 2021

Potent Inhibition of HIF1α and p300 Interaction by a Constrained Peptide Derived from CITED2.

J Med Chem 2021 Sep 2;64(18):13693-13703. Epub 2021 Sep 2.

State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.

Disrupting the interaction between HIF1α and p300 is a promising strategy to modulate the hypoxia response of tumor cells. Herein, we designed a constrained peptide inhibitor derived from the CITED2/p300 complex to disturb the HIF1α/p300 interaction. Through truncation/mutation screening and a terminal aspartic acid-stabilized strategy, a constrained peptide was constructed with outstanding biochemical/biophysical properties, especially in binding affinity, cell penetration, and serum stability. To date, our study was the first one to showcase that stabilized peptides derived from CITED2 using helix-stabilizing methods acted as a promising candidate for modulating hypoxia-inducible signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.1c01043DOI Listing
September 2021

A Novel CD73 Inhibitor SHR170008 Suppresses Adenosine in Tumor and Enhances Anti-Tumor Activity with PD-1 Blockade in a Mouse Model of Breast Cancer.

Onco Targets Ther 2021 24;14:4561-4574. Epub 2021 Aug 24.

R&D Center, Shanghai Hengrui Pharmaceutical Co. Ltd., Shanghai, 200245, People's Republic of China.

Introduction: CD73 and adenosine support growth-promoting neovascularization, metastasis, and survival in cells, and promote anti-PD-1 mAb therapy-induced immune escape. Consequently, developing a CD73 inhibitor as monotherapy and a potential beneficial combination partner with immune-checkpoint inhibitors needs investigation.

Methods: CD73 inhibitors were evaluated in vitro with soluble and membrane-bound CD73 enzymes, as well as its PD biomarker responses in human peripheral blood mononuclear cells (PBMC) by flow cytometry and ELISA. The binding modes of the molecules were analyzed via molecular modeling. The anti-tumor activity and synergistic effect of SHR170008 in combination with anti-PD-1 mAb were evaluated in a syngeneic mouse breast cancer model.

Results: SHR170008 was discovered during the initial structural modifications on the link between the ribose and the α-phosphate of AMPCP, which significantly improved the stability of the compound confirmed by the metabolite identification study. Further modifications on the adenine base of AMPCP improved the potency due to forming stronger interactions with CD73 protein. It exhibited potent inhibitory activities on soluble and endogenous membrane-bound CD73 enzymes, and induced IFNγ production, reversed AMP-suppressed CD25 and CD8/CD25 expression, and enhanced granzyme B production on CD8 T cells in human PBMC. SHR170008 showed dose-dependent anti-tumor efficacy with suppression of adenosine in the tumors in EMT6 mouse breast tumor model. The increase of adenosine in tumor tissue by anti-PD-1 mAb alone was suppressed by SHR170008 in the combination groups. Simultaneous inhibition of CD73 and PD-1 neutralization synergistically enhanced antitumor immunity and biomarkers in response, and exposures of SHR170008 were correlated with the efficacy readouts.

Conclusion: Our findings suggest that CD73 may serve as an immune checkpoint by generating adenosine, which suppresses the antitumor activity of anti-PD-1 mAb, and inhibition of CD73 may be a potential beneficial combination partner with immune-checkpoint inhibitors to improve their therapeutic outcomes in general.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S326178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403083PMC
August 2021

Ag-In-Zn-S Quantum Dot-Dominated Interface Kinetics in Ag-In-Zn-S/NiFe LDH Composites toward Efficient Photoassisted Electrocatalytic Water Splitting.

ACS Appl Mater Interfaces 2021 Sep 25;13(35):42125-42137. Epub 2021 Aug 25.

School of Chemistry and Chemical Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China.

Photoassisted electrocatalysis (P-EC) emerges as a rising star for hydrogen production by embedding photoactive species in electrocatalysts, for which the interfacial structure design and charge transfer kinetics of the multifunctional catalysts remain a great challenge. Herein, Zn-AgInS quantum dots (ZAIS QDs) were embedded into 2D NiFe layered double hydroxide nanosheets through a simple hydrothermal treatment to form 0D/2D composite catalysts for P-EC. With evidence from transient photovoltage spectroscopy, we acquired a clear and fundamental understanding on the kinetics of charge extraction time and extraction amount in the 0D/2D heterojunctions that was proved to play a key role in P-EC. Upon light illumination, for HER, the optimized NiFe-ZAIS exhibits obviously reduced overpotentials of 129 and 242 mV at current densities of 10 and 50 mA cm, which are 22 and 33 mV lower than those of dark electrocatalysis, respectively. For OER, the NiFe-ZAIS electrode also shows low overpotentials of 220 and 268 mV at current densities of 10 and 50 mA cm, respectively, under light illumination, which were able to almost double the intrinsic activity. Finally, with [email protected] as both the cathode and the anode, the assembled electrolyzer only requires 1.62 V to reach the overall water splitting current density of 10 mA cm under P-EC. This work provides a useful example for the profound understanding of the design and the kinetics study of multifunctional P-EC catalysts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.1c09948DOI Listing
September 2021

An update on the importance of plasma protein binding in drug discovery and development.

Authors:
Li Di

Expert Opin Drug Discov 2021 Aug 17:1-13. Epub 2021 Aug 17.

Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT, US.

Plasma protein binding (PPB) remains a controversial topic in drug discovery and development. Fraction unbound (f) is a critical parameter that needs to be measured accurately, because it has significant impacts on the predictions of drug-drug interactions (DDI), estimations of therapeutic indices (TI), and developments of PK/PD relationships.  However, it is generally not advisable to change PPB through structural modifications, because PPB on its own has little relevance for in vivo efficacy. PPB fundamentals are discussed including the three main classes of drug binding proteins (i.e., albumin, alpha1-acid glycoprotein, and lipoproteins) and their physicochemical properties, in vivo half-life, and synthesis rate.  State-of-the-art methodologies for PPB are highlighted. Applications of PPB in drug discovery and development are presented. PPB is an old topic in pharmacokinetics, but there are still many misconceptions. Improving the accuracy of PPB for highly bound compounds is an ongoing effort in the field with high priority. As the field continues to generate high quality data, the regulatory agencies will increase their confidence in our ability to accurately measure PPB of highly bound compounds, and experimental fu values below 0.01 will more likely be used for DDI predictions in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17460441.2021.1961741DOI Listing
August 2021

Optimization of C-to-G base editors with sequence context preference predictable by machine learning methods.

Nat Commun 2021 08 12;12(1):4902. Epub 2021 Aug 12.

Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.

Efficient and precise base editors (BEs) for C-to-G transversion are highly desirable. However, the sequence context affecting editing outcome largely remains unclear. Here we report engineered C-to-G BEs of high efficiency and fidelity, with the sequence context predictable via machine-learning methods. By changing the species origin and relative position of uracil-DNA glycosylase and deaminase, together with codon optimization, we obtain optimized C-to-G BEs (OPTI-CGBEs) for efficient C-to-G transversion. The motif preference of OPTI-CGBEs for editing 100 endogenous sites is determined in HEK293T cells. Using a sgRNA library comprising 41,388 sequences, we develop a deep-learning model that accurately predicts the OPTI-CGBE editing outcome for targeted sites with specific sequence context. These OPTI-CGBEs are further shown to be capable of efficient base editing in mouse embryos for generating Tyr-edited offspring. Thus, these engineered CGBEs are useful for efficient and precise base editing, with outcome predictable based on sequence context of targeted sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-25217-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361092PMC
August 2021

Increased Level of Thrombomodulin is Associated with Endothelial Injury in Patients with Sepsis-Induced Disseminated Intravascular Coagulation.

Clin Lab 2021 Aug;67(8)

Background: The coagulation cascade and inflammatory processes target damage in endothelial cells in sepsis-induced disseminated intravascular coagulation (DIC). This study aimed to measure levels of the molecular marker of endothelial injury, thrombomodulin, in patients with sepsis-induced DIC and to investigate potential relationships with poor clinical outcomes.

Methods: From October 2017 to October 2018, 45 patients with sepsis-induced DIC were recruited at Renmin Hospital of Wuhan University, in China. Concentrations of thrombomodulin and other routine coagulation and inflammatory factors were quantified.

Results: Thrombomodulin was present in the plasma of non-survivors at significantly higher levels than in the plasma of survivors (9.30 ± 1.56 vs. 5.54 ± 0.29 TU/mL, p < 0.05). Thrombomodulin showed an area under the curve of 0.87 for predicting mortality. The hazard function curve showed significantly higher mortality risk in patients with high thrombomodulin. Multiple linear regression demonstrated a positive correlation of plasma thrombomodulin with the Sequential Organ Failure Assessment (SOFA) score (β-coefficient = 0.610, p = 0.042). Logistic regression showed that thrombomodulin level was an independent risk factor for poor prognosis (OR 1.963, 95% CI 1.006 - 3.829). The nomogram based on thrombomodulin level and SOFA score revealed that an initial death risk probability can be established for patients with sepsis-induced DIC without further testing.

Conclusions: Elevated plasma thrombomodulin is associated with poor clinical outcomes in sepsis-induced DIC; therefore, a high plasma thrombomodulin level may be a useful prognostic factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7754/Clin.Lab.2020.201204DOI Listing
August 2021

Optical Properties of Carbon Dots in the Deep-Red to Near-Infrared Region Are Attractive for Biomedical Applications.

Small 2021 Aug 8:e2102325. Epub 2021 Aug 8.

Joint Key Laboratory of the Ministry of Education, Institute of Applied Physics and Materials Engineering, University of Macau, Avenida da Universidade, Taipa, Macau SAR, 999078, P. R. China.

Carbon dots (CDs) represent a recently emerged class of luminescent materials with a great potential for biomedical theranostics, and there are a lot of efforts to shift their absorption and emission toward deep-red (DR) to near-infrared (NIR) region falling in the biological transparency window. This review offers comprehensive insights into the synthesis strategies aimed to achieve this goal, and the current approaches of modulating the optical properties of CDs over the DR to NIR region. The underlying mechanisms of their absorption, photoluminescence, and chemiluminescence, as well as the related photophysical processes of photothermal conversion and formation of reactive oxygen species are considered. The already available biomedical applications of CDs, such as in the photoacoustic imaging and photothermal therapy, photodynamic therapy, and their use as bioimaging agents and drug carriers are then shortly summarized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.202102325DOI Listing
August 2021

RAN and YBX1 are required for cell proliferation and IL-4 expression and linked to poor prognosis in oral squamous cell carcinoma.

Exp Cell Res 2021 Sep 5;406(2):112767. Epub 2021 Aug 5.

The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China. Electronic address:

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies in the world, with a high mortality rate. RAN is a member of the Ras GTPase family and is overexpressed in a range of cancers, however, the relationship between RAN and OSCC is rarely reported. In this study, we found that RAN is overexpressed in OSCC tissues. RAN inhibition retarded OSCC cell proliferation and led to apoptosis and cell cycle arrest. Knockdown of RAN inhibited tumor growth in vivo. Strikingly, we found that RAN and oncogene Y-box binding protein-1 (YBX1) are positively associated with the immune infiltrates of CD4 Th2 cells in multiple types of cancer, and can promote IL-4 expression. IL-4 treatment can partially rescue RAN knockdown-induced cell apoptosis in OSCC cells. Moreover, overexpression of RAN could rescue cell growth inhibition caused by knockdown of YBX1. Furthermore, patients with low expression of both RAN and YBX1 had better overall survival than others. Collectively, these findings indicate that RAN is a target of YBX1. RAN and YBX1 are required for cell proliferation and IL-4 expression. RAN and YBX1 are co-expressed and can serve as potential co-biomarkers for poor prognosis in OSCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yexcr.2021.112767DOI Listing
September 2021

Oxygen-doped hollow, porous NiCoP nanocages derived from Ni-Co prussian blue analogs for oxygen evolution.

Chem Commun (Camb) 2021 Aug 27;57(66):8158-8161. Epub 2021 Jul 27.

Institute for Energy Research, Jiangsu University, Zhenjiang 212013, China.

An oxygen-doped, hollow, porous NiCoP nanocage (O-NiCoP Cages) electrocatalyst was synthesized derived from Ni-Co Prussian blue analogs. O-NiCoP Cages exhibited an overpotential of 310 mV at 10 mA cm and a Tafel slope of 84 mV dec, significantly higher than that of undoped NiCoP nanocages, and also better than that of RuO and several reported phosphide electrocatalysts. This work provides a new strategy for the design of highly efficient oxygen evolution reaction (OER) electrocatalysts based on hollow, nanostructured and heteroatom-doped metal phosphides.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1cc00535aDOI Listing
August 2021

Optimized Backing Layers Design for High Frequency Broad Bandwidth Ultrasonic Transducer.

IEEE Trans Biomed Eng 2021 Jul 21;PP. Epub 2021 Jul 21.

Ultrasonic transducers with broad bandwidth are considered to have high axial resolution and good ultrasound scanning flexibility for the clinical applications. The limitations of spatial resolution due to bandwidth are of great concern in ultrasound medical imaging. The method of acoustic impedance matching between the piezoelectric element and medium is commonly used to obtain broad bandwidth and high resolution. In this study, an optimized backing layer design was proposed to broaden the bandwidth by adding a tunable acoustic impedance matching layer of backing (AIMLB) between the backing layer and the piezoelectric ceramic element. The Mason equivalent circuit method was used to analyze the effect of the backing material composition and its structure on the bandwidth of the transducer. The optimized transducer was simulated using the finite-element method with the PZFlex software. Based on the PZFlex simulations, a 20-MHz ultrasonic transducer using the AIMLB with a bandwidth of approximately 92.29% was fabricated. The experimental results were in good agreement with the simulations. The ultrasonic imaging indicated that the designed ultrasonic transducer with an additional AIMLB had high performance with good imaging capability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TBME.2021.3098567DOI Listing
July 2021

A Low-Cost Na-Ion and K-Ion Batteries Using a Common Organic Cathode and Bismuth Anode.

ChemSusChem 2021 Sep 3;14(18):3815-3820. Epub 2021 Aug 3.

School of Materials and Energy, University of Electronic Science and Technology of China (UESTC), Chengdu, 611731, P. R. China.

Molecule-aggregation organic electrodes in principle have the capability for "single-molecule-energy-storage" in metal-ion rechargeable batteries, which indicates that the same organic electrode can be simultaneously applied to multiple metal-ion rechargeable batteries. In this study, the polyanionic organic compound 9,10-anthraquinone-2,6-disulfonate (Na AQ26DS, 130 mAh g ) is used as a common cathode and metal bismuth (Bi) as a common anode to simultaneously assemble low-cost Na-ion and K-ion full cells. The Na-ion full cells can deliver the peak discharge capacity of 139 mAh g at 0.5-3.0 V, and the K-ion full cells can show the peak discharge capacity of 130 mAh g at 0.5-3.0 V. These results are comparable to the best organic-based Na-ion and K-ion full cells reported to date.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cssc.202101386DOI Listing
September 2021

Synergistically integrated [email protected] double hydroxide core-branch hierarchical architectures as efficient bifunctional electrocatalyst for water splitting.

J Colloid Interface Sci 2021 Dec 6;604:680-690. Epub 2021 Jul 6.

School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, China.

Efficient, low-cost, and robust electrocatalysts development for overall water splitting is highly desirable for renewable energy production yet still remains challenging. In this work, CoS nanoneedles arrays are synergistically integrated with NiFe-layered double hydroxide (NiFe-LDH) nanosheets to form [email protected] core-branch hierarchical architectures supported on nickel foam ([email protected] HAs/NF). The [email protected] HAs/NF exhibits high catalytic performances for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) with overpotential of 190 and 145 mV at 10 mA cm, respectively. The density functional theory calculations predict that the synergy between CoS and NiFe-LDH contributes to the high catalytic performance by lowering the energy barrier of HER. When used as both anode and cathode electrocatalyst, it can deliver 10 mA cm at a low cell voltage of 1.585 V with excellent long-term durability. This work opens a new avenue toward the exploration of highly efficient and stable electrocatalyst for overall water splitting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcis.2021.07.008DOI Listing
December 2021

Liquid-Phase Manipulation Securing Enhanced Thermoelectric Performance of AgSe.

ACS Appl Mater Interfaces 2021 Jul 19;13(29):34543-34549. Epub 2021 Jul 19.

Key Lab of Photovoltaic and Energy conservation Materials, Institute of Solid State Physics, HFIPS, Chinese Academy of Sciences, Hefei 230031, China.

Developing n-type materials with high peak and/or average ZT (ZT is the figure of merit) is an urgent need for the lower ZT of the existing n-type BiTeSe materials compared with the p-type BiSbTe materials. Here, we demonstrate that liquid-phase sintering can lead to lowered thermal conductivity and an improved power factor in n-type AgSe, which originates from the greatly lowered electronic thermal conductivity attributed to the decreased mobility and improved Seebeck coefficients because of increased effective mass. Benefiting from this, the maximum ZT (ZT) of ∼1.21 and the average ZT (ZT) of 1.06 are successfully achieved in polycrystalline AgSe. In this work, ZT is the highest reported value, being 26% larger than that of AgSe reported. Our work shows that liquid-phase sintering to achieve improved thermoelectric (TE) performance opens a great opportunity for designing prospective thermoelectrics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.1c08410DOI Listing
July 2021

Aloe vera gel extract: Safety evaluation for acute and chronic oral administration in Sprague-Dawley rats and anticancer activity in breast and lung cancer cells.

J Ethnopharmacol 2021 Nov 16;280:114434. Epub 2021 Jul 16.

Department of R&D, Biotech&Science Company of UP, Ltd., Guangzhou, 510000, China. Electronic address:

Ethnopharmacological Relevance: Aloe vera (L.) Burm. f. is a typical traditional Chinese medicine (TCM) collected in the Pharmacopoeia of the People's Republic of China (version 2015). It has been traditionally used for the treatment of constipation, and its potential therapeutic activities have been widely evaluated, including anti-tumor, anti-inflammatory and immune regulatory effects. The wide application of Aloe vera in food and therapy has raised safety issues and there are multiple safety assessments with a diverse toxicity and adverse effects from clinics and animals.

Aim Of The Study: This study aimed to investigate the safety of Aloe vera barbadensis extract C (AVBEC) in rats and analyze its anticancer activity in cell lines.

Materials And Methods: We administrated AVBEC orally in an acute toxicity study and a 6-month chronic toxicity study to observe and confirm its safety in Sprague-Dawley (SD) rats. Additionally, we explored the cytotoxicity of AVBEC in cancer cells and non-cancer cells. We further investigated the anti-tumor activity of AVBEC, and in the meantime, probed the function of component from AVBEC.

Results: No deaths or substance-relative toxicity were observed in the acute toxicity study or the 6-month chronic toxicity study with doses of 44.8 g·kg and 4.48 g·kg, respectively. In the chronic toxicity study, AVBEC did not cause organ toxicity, including crucial organ structure and chemical function, and peripheral and central immune system damage. Additionally, we found that AVBEC could induce cancer cell apoptosis with a relatively higher apoptotic ratio than in non-cancer cells by decreasing adenosine triphosphate (ATP) concentration and enhancing reactive oxygen species (ROS) production. We also identified components in AVBEC using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) and probed the function of malic acid. This demonstrated that under the same circumstances, malic acid induced cell necrosis in cancer cells and non-cancer cells, while AVBEC did not.

Conclusions: These results reveal a novel mechanism of aloe gel extract in regulating cancer cell apoptosis via modulating the mitochondrial metabolism and imply a possible application of AVBEC for the treatment of malignant cancer with the safety evaluation from rats and anticancer investigation from cancer cells and non-cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2021.114434DOI Listing
November 2021

Consideration of the Unbound Drug Concentration in Enzyme Kinetics.

Methods Mol Biol 2021 ;2342:113-145

Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, CT, USA.

The study of enzyme kinetics in drug metabolism involves assessment of rates of metabolism and inhibitory potencies over a suitable concentration range. In all but the very simplest in vitro system, these drug concentrations can be influenced by a variety of nonspecific binding reservoirs that can reduce the available concentration to the enzyme system(s) under investigation. As a consequence, the apparent kinetic parameters, such as K or K, that are derived can deviate from the true values. There are a number of sources of these nonspecific binding depots or barriers, including membrane permeation and partitioning, plasma or serum protein binding, and incubational binding. In the latter case, this includes binding to the assay apparatus as well as biological depots, depending on the characteristics of the in vitro matrix being used. Given the wide array of subcellular, cellular, and recombinant enzyme systems utilized in drug metabolism, each of these has different components which can influence the free drug concentration. The physicochemical properties of the test compound are also paramount in determining the influential factors in any deviation between true and apparent kinetic behavior. This chapter describes the underlying mechanisms determining the free drug concentration in vitro and how these factors can be accounted for in drug metabolism studies, illustrated with case studies from the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-0716-1554-6_5DOI Listing
August 2021
-->