Publications by authors named "Tongtong Liu"

98 Publications

EETs/sEHi alleviates nociception by blocking the crosslink between endoplasmic reticulum stress and neuroinflammation in a central poststroke pain model.

J Neuroinflammation 2021 Sep 16;18(1):211. Epub 2021 Sep 16.

Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, People's Republic of China.

Background: Central post-stroke pain (CPSP) is a chronic and intolerable neuropathic pain syndrome following a cerebral vascular insult, which negatively impacts the quality of life of stroke survivors but currently lacks efficacious treatments. Though its underlying mechanism remains unclear, clinical features of hyperalgesia and allodynia indicate central sensitization due to excessive neuroinflammation. Recently, the crosslink between neuroinflammation and endoplasmic reticulum (ER) stress has been identified in diverse types of diseases. Nevertheless, whether this interaction contributes to pain development remains unanswered. Epoxyeicosatrienoic acids (EETs)/soluble epoxy hydrolase inhibitors (sEHi) are emerging targets that play a significant role in pain and neuroinflammatory regulation. Moreover, recent studies have revealed that EETs are effective in attenuating ER stress. In this study, we hypothesized that ER stress around the stroke site may activate glial cells and lead to further inflammatory cascades, which constitute a positive feedback loop resulting in central sensitization and CPSP. Additionally, we tested whether EETs/sEHi could attenuate CPSP by suppressing ER stress and neuroinflammation, as well as their vicious cycle, in a rat model of CPSP.

Methods: Young male SD rats were used to induce CPSP using a model of thalamic hemorrhage and were then treated with TPPU (sEHi) alone or in combination with 14,15-EET or 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, the EET antagonist), tunicamycin (Tm, ER stress inducer), or 4-PBA (ER stress inhibitor). Nociceptive behaviors, ER stress markers, JNK and p38 (two well-recognized inflammatory kinases of mitogen-activated protein kinase (MAPK) signaling) expression, and glial cell activation were assessed. In addition, some healthy rats were intrathalamically microinjected with Tm or lipopolysaccharide (LPS) to test the interaction between ER stress and neuroinflammation in central pain.

Results: Analysis of the perithalamic lesion tissue from the brain of CPSP rats demonstrated decreased soluble epoxy hydrolase (sEH) expression, which was accompanied by increased expression of ER stress markers, including BIP, p-IRE, p-PERK, and ATF6. In addition, inflammatory kinases (p-p38 and p-JNK) were upregulated and glial cells were activated. Intrathalamic injection of sEHi (TPPU) increased the paw withdrawal mechanical threshold (PWMT), reduced hallmarks of ER stress and MAPK signaling, and restrained the activation of microglia and astrocytes around the lesion site. However, the analgesic effect of TPPU was completely abolished by 14,15-EEZE. Moreover, microinjection of Tm into the thalamic ventral posterior lateral (VPL) nucleus of healthy rats induced mechanical allodynia and activated MAPK-mediated neuroinflammatory signaling; lipopolysaccharide (LPS) administration led to activation of ER stress along the injected site in healthy rats.

Conclusions: The present study provides evidence that the interaction between ER stress and neuroinflammation is involved in the mechanism of CPSP. Combined with the previously reported EET/sEHi effects on antinociception and neuroprotection, therapy with agents that target EET signaling may serve as a multi-functional approach in central neuropathic pain by attenuating ER stress, excessive neuroinflammation, and subsequent central sensitization. The use of these agents within a proper time window could not only curtail further nerve injury but also produce an analgesic effect.
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http://dx.doi.org/10.1186/s12974-021-02255-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447610PMC
September 2021

Postnatal development of BAG3 expression in mouse cerebral cortex and hippocampus.

Brain Struct Funct 2021 Nov 6;226(8):2629-2650. Epub 2021 Aug 6.

Department of Histology and Embryology, China Medical University, Shenyang, 110122, China.

The decreased efficiency of autophagic processing in the central nervous system during aging may be a contributing factor in neurodegenerative diseases. BAG3 (Bcl2 associated athanogene 3) is a major member of the BAG family of co-molecular chaperones that mediate selective macroautophagy. Therefore, we analyzed the expression and distribution of BAG3 in the brain at postnatal 0 day (P0), P15, 1-, 2-, 9-, 12-, and 18 month-old C57BL/6 mice, thus covering almost all ages. Except for a significant steep drop in mRNA and protein levels in the cortex and hippocampus soon after birth, there were minimal differences in the expression and distribution of BAG3 among P15, M1, M2, M9, and M12 mice; however, at 18 months, BAG3 expression was significantly higher. Immunohistochemical analyses showed that BAG3 is mainly located in the neuronal cytoplasm and processes in C57BL/6 the cerebral cortex and hippocampus from P0 to M18 postnatal development. These findings indicate that BAG3 might be stable in young and middle-aged mice, but unstable in aged mice.
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http://dx.doi.org/10.1007/s00429-021-02356-yDOI Listing
November 2021

5α-Epoxyalantolactone Inhibits Metastasis of Triple-Negative Breast Cancer Cells by Covalently Binding a Conserved Cysteine of Annexin A2.

J Med Chem 2021 Sep 5;64(17):12537-12547. Epub 2021 Aug 5.

The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.

Triple-negative breast cancer (TNBC) has been considered the most aggressive and mortal breast cancer. Thus far, it remains an important challenge to develop TNBC targeted therapy. As revealed from numerous recent studies, ANXA2 may be a potential target to treat TNBC. In the present study, a natural product 5α-epoxyalantolactone (5α-EAL) was discovered as an anti-breast cancer stem cells (BCSCs) lead compound. Furthermore, 5α-EAL was found to be able to notably suppress the function of ANXA2 by covalently targeting cysteine 9 (Cys9) of ANXA2. To the best of our knowledge, 5α-EAL was recognized as the first small molecule functional inhibitor of ANXA2. It could significantly inhibit the formation of the heterotetrameric complex of ANXA2 and S100A10, which is capable of transporting E-cadherin (E-Ca) to the membrane. The above findings may be used as a possible strategy to develop novel anti-TNBC therapies targeting ANXA2.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00267DOI Listing
September 2021

Intermetallic [email protected] Core-Shell Nanoparticles for Oxygen Reduction Electrocatalysis.

Angew Chem Int Ed Engl 2021 Jul 31. Epub 2021 Jul 31.

State Key Laboratory of Chemical Resource Engineering, Beijing Key Laboratory of Electrochemical Process and Technology for Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.

The development of active and stable platinum (Pt)-based oxygen reduction reaction (ORR) electrocatalysts with good resistance to poisoning is a prerequisite for widespread practical application of fuel cells. An effective strategy for enhancing the electrocatalytic performance is to tune or control the physicochemical state of the Pt surface. Herein, we show a general surface-engineering approach to prepare a range of nanostructured Pt alloys by coating with alloy PtBi shells. [email protected] core-shell nanoparticles showed the best ORR performance with a mass activity of 0.96 A mg and a specific activity of 2.06 mA cm , respectively 7 times and 11 times those of the corresponding values for benchmark Pt/C. Moreover, [email protected] shows much better tolerance to methanol and carbon monoxide than conventional Pt-based electrocatalysts. The observed comprehensive enhancement in ORR performance of [email protected] can be attributed to the increased compressive strain of the Pt surface due to in-plane shearing resulting from the presence of the large Bi atoms in the surface-structured PtBi overlayers, as well as charge displacement via Pt-Bi bonding which mitigates crossover issues.
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http://dx.doi.org/10.1002/anie.202107437DOI Listing
July 2021

The therapeutic effects of naringenin on bronchial pneumonia in children.

Pharmacol Res Perspect 2021 Aug;9(4):e00825

Department of Pediatrics, Zibo Central Hospital, Zibo, Shandong, China.

Bronchial pneumonia in children is a common infectious disease in toddlers and infants, which may cause hyperpyrexia, pulmonary moist rales, and even respiratory failure. Traditional drugs for bronchial pneumonia in children often lead to drug resistance and side effects. Recently, naringenin has been reported to be a potential treatment for several airway inflammatory diseases due to its anti-inflammatory and anti-microbial activities. The current clinical study aimed to evaluate the safety and therapeutic effect of naringenin in treating bronchial pneumonia in children. A total of 180 eligible patients were randomly assigned into naringenin (NAR) group and azithromycin (AZI) group. All participants were required to follow a 5-day oral administration, and their serum cytokine levels were measured during the clinical intervention. After the treatment, the disappearance time of clinical symptoms, and the incidences of complications and adverse reactions were compared between the two groups. Naringenin was able to inhibit inflammation, shorten the disappearance time of clinical symptoms, reduce the incidences of bronchial pneumonia complications and related adverse reactions, and improve the health conditions of the patients. Our results suggested that naringenin was safe and beneficial to children with bronchial pneumonia, providing new insights into the clinical application of naringenin.
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http://dx.doi.org/10.1002/prp2.825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312741PMC
August 2021

Discrimination of Patients with Varying Degrees of Coronary Artery Stenosis by ECG and PCG Signals Based on Entropy.

Entropy (Basel) 2021 Jun 28;23(7). Epub 2021 Jun 28.

School of Control Science and Engineering, Shandong University, Jinan 250061, China.

Coronary heart disease (CHD) is the leading cause of cardiovascular death. This study aimed to propose an effective method for mining cardiac mechano-electric coupling information and to evaluate its ability to distinguish patients with varying degrees of coronary artery stenosis (VDCAS). Five minutes of electrocardiogram and phonocardiogram signals was collected synchronously from 191 VDCAS patients to construct heartbeat interval (RRI)-systolic time interval (STI), RRI-diastolic time interval (DTI), HR-corrected QT interval (QTcI)-STI, QTcI-DTI, Tpeak-Tend interval (TpeI)-STI, TpeI-DTI, Tpe/QT interval (Tpe/QTI)-STI, and Tpe/QTI-DTI series. Then, the cross sample entropy (XSampEn), cross fuzzy entropy (XFuzzyEn), joint distribution entropy (JDistEn), magnitude-squared coherence function, cross power spectral density, and mutual information were applied to evaluate the coupling of the series. Subsequently, support vector machine recursive feature elimination and XGBoost were utilized for feature selection and classification, respectively. Results showed that the joint analysis of XSampEn, XFuzzyEn, and JDistEn had the best ability to distinguish patients with VDCAS. The classification accuracy of severe CHD-mild-to-moderate CHD group, severe CHD-chest pain and normal coronary angiography (CPNCA) group, and mild-to-moderate CHD-CPNCA group were 0.8043, 0.7659, and 0.7500, respectively. The study indicates that the joint analysis of XSampEn, XFuzzyEn, and JDistEn can effectively capture the cardiac mechano-electric coupling information of patients with VDCAS, which can provide valuable information for clinicians to diagnose CHD.
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http://dx.doi.org/10.3390/e23070823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304206PMC
June 2021

Effect of Acupuncture on Neuroplasticity of Stroke Patients with Motor Dysfunction: A Meta-Analysis of fMRI Studies.

Neural Plast 2021 2;2021:8841720. Epub 2021 Jun 2.

Department of Neurology and Stroke Center, Dongzhimen Hospital, The First Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China.

Objective: To analyze the pattern of intrinsic brain activity variability that is altered by acupuncture compared with conventional treatment in stroke patients with motor dysfunction, thus providing the mechanism of stroke treatment by acupuncture.

Methods: Chinese and English articles published up to May 2020 were searched in the PubMed, Web of Science, EMBASE, and Cochrane Library databases, China National Knowledge Infrastructure, Chongqing VIP, and Wanfang Database. We only included randomized controlled trials (RCTs) using resting-state fMRI to observe the effect of acupuncture on stroke patients with motor dysfunction. R software was used to analyze the continuous variables, and Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) was used to perform an analysis of fMRI data. . A total of 7 studies comprising 143 patients in the treatment group and 138 in the control group were included in the meta-analysis. The results suggest that acupuncture treatment helps the healing process of motor dysfunction in stroke patients and exhibits hyperactivation in the bilateral basal ganglia and insula and hypoactivation in motor-related areas (especially bilateral BA6 and left BA4).

Conclusion: Acupuncture plays a role in promoting neuroplasticity in subcortical regions that are commonly affected by stroke and cortical motor areas that may compensate for motor deficits, which may provide a possible mechanism underlying the therapeutic effect of acupuncture.
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http://dx.doi.org/10.1155/2021/8841720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192216PMC
June 2021

Service acceptance of HIV non-occupational post-exposure prophylaxis(nPEP) among college students: a cross-sectional study in China.

BMC Public Health 2021 06 24;21(1):1220. Epub 2021 Jun 24.

Beijing YouAn Hospital, Capital Medical University, Beijing, China.

Background: College students were the key group we should pay more attention for acquired immune deficiency syndrome (AIDS) prevention and control in recent years in China. Few studies of HIV non-occupational post-exposure prophylaxis (nPEP) knowledge and service acceptance had been conducted among them in China. This study conducted a cross-sectional survey to understand the service acceptance of nPEP and its influencing factors among college students in the three cities of China.

Methods: A questionnaire survey was conducted to collect information on socio-demographic, behavioral characteristic, HIV/AIDS knowledge, nPEP knowledge, acceptance of nPEP services among the college students in Beijing, Shenzhen, and Kunming of China from March to April of 2019. Each participant completed an anonymous questionnaire on line by computer-assisted or mobile phone-assisted self-interview with informed consent. Multivariable logistic regression analyses identified predictors for service acceptance of nPEP.

Results: A total of 4698 students were surveyed with the average age of 20 years old. 98.0% (4605/4698) of them were undergraduates, 21.8%(1022/4698) had sexual intercourse; 48.6% (2282/4698) heard of nPEP, among which 4.95%(113/2282) received nPEP services. The awareness rate of HIV/AIDS knowledge was 85.6% (5495/4698) with the differences statistically significant between the three cities. The awareness rate of nPEP knowledge was 16.5% (774/4698). There were significant differences in receiving nPEP services among students of different ages, genders, sexual behaviors, and knowledge of HIV/AIDS by univariate analysis. Multivariable analyses indicated that age group of 18 and under (OR = 2.551, 95% CI = 1.153-5.646), male (OR = 3.131, 95% CI = 1.866-5.253), homosexual behavior (OR = 4.661,95%CI = 2.658-8.172), heterosexual behavior (OR = 1.676, 95% CI = 1.040-2.947), no awareness of AIDS knowledge (OR = 3.882, 95% CI = 2.371-6.356) and nPEP (OR = 4.788, 95% CI = 2.50-9.169) knowledge, were associated with the service acceptance of nPEP among the college students.

Conclusion: The low acceptance of nPEP services was mainly affected by low level of nPEP knowledge among the college students. Further publicity and education of nPEP knowledge were necessary, as well as promotion of knowledge of HIV/AIDS prevention and treatment. More attention should be paid to the factors associated with acceptance of nPEP services.
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http://dx.doi.org/10.1186/s12889-021-11286-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228990PMC
June 2021

Synthesis and evaluation of the anti-inflammatory activity of novel 8-quinolinesulfonamide derivatives as TLR4/MD-2 inhibitors with efficacy in adjuvant-induced arthritis.

Bioorg Chem 2021 Sep 31;114:105037. Epub 2021 May 31.

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address:

In this study, a series of 8-quinolinesulfonamidederivatives was synthesized, and their anti-inflammatory activity was evaluated. Among them, compound 3l was found to be the best anti-inflammatory agent, with IC values of 2.61 ± 0.39, 9.74 ± 0.85, and 12.71 ± 1.34 μM against NO, TNF-α and IL-1β production respectively. And 3l could significantly prevent lipopolysaccharide (LPS)-induced expression of inflammatory mediators (iNOS and COX-2). Molecule docking results showed that 3l could bind to the LPS binding site of toll-like receptor 4 (TLR4)/MD-2, and 3l was then identified as TLR4/MD-2 inhibitor by co-immunoprecipitation (co-IP) and cellular thermal shift assay (CTESA). Preliminary mechanism studies indicated that 3l could prevent TLR4 from being activated by disrupting TLR4/MD-2 heterodimerization and TLR4 homodimerization, thereby blocking the activation of the NF-κB/MAPK signaling pathway. Furthermore, observation of rat foot swelling, joint pathology and serum inflammatory cytokine levels proved that compound 3l had a significant therapeutic effect on adjuvant-induced arthritis (AIA) in rats in vivo. These results indicated that compound 3l is a potential anti-inflammatory agent, from which more effective anti-inflammatory drugs could be developed.
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http://dx.doi.org/10.1016/j.bioorg.2021.105037DOI Listing
September 2021

Detection of Coronary Artery Disease Using Multi-Domain Feature Fusion of Multi-Channel Heart Sound Signals.

Entropy (Basel) 2021 May 21;23(6). Epub 2021 May 21.

School of Control Science and Engineering, Shandong University, Jinan 250061, China.

Heart sound signals reflect valuable information about heart condition. Previous studies have suggested that the information contained in single-channel heart sound signals can be used to detect coronary artery disease (CAD). But accuracy based on single-channel heart sound signal is not satisfactory. This paper proposed a method based on multi-domain feature fusion of multi-channel heart sound signals, in which entropy features and cross entropy features are also included. A total of 36 subjects enrolled in the data collection, including 21 CAD patients and 15 non-CAD subjects. For each subject, five-channel heart sound signals were recorded synchronously for 5 min. After data segmentation and quality evaluation, 553 samples were left in the CAD group and 438 samples in the non-CAD group. The time-domain, frequency-domain, entropy, and cross entropy features were extracted. After feature selection, the optimal feature set was fed into the support vector machine for classification. The results showed that from single-channel to multi-channel, the classification accuracy has increased from 78.75% to 86.70%. After adding entropy features and cross entropy features, the classification accuracy continued to increase to 90.92%. The study indicated that the method based on multi-domain feature fusion of multi-channel heart sound signals could provide more information for CAD detection, and entropy features and cross entropy features played an important role in it.
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http://dx.doi.org/10.3390/e23060642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224099PMC
May 2021

Discovery of 7-O-1, 2, 3-triazole hesperetin derivatives as multi-target-directed ligands against Alzheimer's disease.

Chem Biol Interact 2021 Jun 24;342:109489. Epub 2021 Apr 24.

The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China. Electronic address:

The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC = 3.08 ± 0.29 μM) and exhibited good anti-neuroinflammatory activity (IC = 2.91 ± 0.47 μM) against NO production through remarkably blocking the NF-κB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 μM concentration. Furthermore, possessing significant self-mediated Aβ aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood-brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.
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http://dx.doi.org/10.1016/j.cbi.2021.109489DOI Listing
June 2021

Interactions between magnetic particles and polyaluminum chloride on the coagulation behavior in humic acid-kaolin synthetic water treatment.

Environ Res 2021 06 1;197:111093. Epub 2021 Apr 1.

State Key Laboratory of Urban Water Resource and Environment, School of Environment, Harbin Institute of Technology, Harbin, 150090, China. Electronic address:

Understanding the interactions between magnetic particles (MPs) and polyaluminum chloride (PACl) is essential to elucidate the magnetic seeding coagulation (MSC) process. However, little is known about how MPs interact with the different Al species coexisting in the PACl. Here, the relationships among pollutants removal, residual Al distribution, and floc properties were comparatively studied in the MSC and traditional coagulation (TC) processes to address this issue. The response surface analysis indicated that the interaction between PACl and MPs dosages exhibited significant effects on turbidity and DOC removal. Negligible changes of dissolved Al after MPs addition indicated the weak connection between Al and MPs. The formation of MPs-Al-HA complexes resulted in the increase of turbidity removal from 90.2% to 96.0% and the reduction of colloidal Al from 0.67 to 0.30 mg L. Humic-like components could be adsorbed on MPs forming MPs-HA complexes, which enhanced the DOC removal from 55% to 58.5%. MPs addition produced loose flocs with a small floc fractal dimension value (1.74), so the average size and strength of flocs in the MSC process (425 μm and 49.7%) were lower than that in the TC process (464 μm and 58.3%). The cumulative volume percentage of large flocs (>700 μm) was decreased from 29.7% to 20.7% with MPs addition, indicating the disruption of large flocs and the reproduction of more fragments. The effective separation of these fragments by magnetic attraction maintained the efficient coagulation performance. This study provides new insights into the interaction mechanism of MPs and PACl in the MSC process.
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http://dx.doi.org/10.1016/j.envres.2021.111093DOI Listing
June 2021

Clinical characteristics and risk factors for mortality in cancer patients with COVID-19.

Front Med 2021 Apr 23;15(2):264-274. Epub 2021 Mar 23.

Hepatic Surgery Center, Liver Cancer Institute, and Hubei Key Laboratory of HPB Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Patients with cancer are at increased risk of severe infections. From a cohort including 3060 patients with confirmed COVID-19, 109 (3.4%) cancer patients were included in this study. Among them, 23 (21.1%) patients died in the hospital. Cancer patients, especially those with hematological malignancies (41.6%), urinary carcinoma (35.7%), malignancies of the digestive system (33.3%), gynecological malignancies (20%), and lung cancer (14.3%), had a much higher mortality than patients without cancer. A total of 19 (17.4%) cancer patients were infected in the hospital. The clinical characteristics of deceased cancer patients were compared with those of recovered cancer patients. Multivariate Cox regression analysis indicated that a Nutritional Risk Screening (NRS2002) score ⩾ 3 (adjusted hazard ratio (HR) 11.00; 95% confidence interval (CI) 4.60-26.32; P < 0.001), high-risk type (adjusted HR 18.81; 95% CI 4.21-83.93; P < 0.001), tumor stage IV (adjusted HR 4.26; 95% CI 2.34-7.75; P < 0.001), and recent adjuvant therapy (< 1 month) (adjusted HR 3.16; 95% CI 1.75-5.70; P < 0.01) were independent risk factors for in-hospital death after adjusting for age, comorbidities, D-dimer, and lymphocyte count. In conclusion, cancer patients showed a higher risk of COVID-19 infection with a poorer prognosis than patients without cancer. Cancer patients with high-risk tumor, NRS2002 score ⩾ 3, advanced tumor stage, and recent adjuvant therapy (< 1 month) may have high risk of mortality.
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http://dx.doi.org/10.1007/s11684-021-0845-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985225PMC
April 2021

A network-based analysis and experimental validation of traditional Chinese medicine Yuanhu Zhitong Formula in treating neuropathic pain.

J Ethnopharmacol 2021 Jun 19;274:114037. Epub 2021 Mar 19.

Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, PR China. Electronic address:

Ethnopharmacological Relevance: The Yuanhu Zhitong Formula (YZF) consists of traditional Chinese herbs Corydalis Rhizoma (Corydalis yanhusuo (Y.H.Chou & Chun C.Hsu) W.T.Wang ex Z.Y.Su & C.Y.Wu; Chinese name, Yanhusuo) and Angelicae Dahuricae Radix (Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav.; Chinese name, Baizhi), which is usually administrated for painful conditions. It is well acknowledged that YZF has pharmacological effects on pain relief; nevertheless, limited data are available on its mechanism.

Aim Of The Study: This study aimed to explore the potential mechanism underlying YZF on nociception of rats. Also, the comprehensive mechanism of YZF was preliminarily determined based on network pharmacology on neuropathic pain.

Materials And Methods: A spared nerve injury (SNI) model was established to reveal the effects of YZF administration on nociceptive behavior in rats. Von-Frey tests were used to evaluate the paw withdrawal mechanical thresholds in rats administrated with YZF or vehicle. The "drug-ingredients" and "disease-drug-target" networks were established with a network pharmacology approach. The analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) profiles were performed based on the common targets between the herbs and neuropathic pain. Hub genes, identified with CytoHubba, were validated by Western blotting analysis.

Results: SNI rats developed significant nociceptive behavior as soon as 3 days after nerve injury, which was reversed by consecutive treatment with 300 mg/kg YZF for 7 days. Besides, 50 potential bioactive components in YZF with 1074 targets were identified. Then, 217 putative common genes related to YZF and neuropathic pain were identified for further study. After established a protein-protein interaction network, 12 subnetworks with CytoHubba and 10 predictive hub genes were obtained based on the maximal clique centrality model. Western blotting analysis indicated that SNI rats exhibited increased APP (Amyloid-beta precursor protein), SRC (Proto-oncogene tyrosine-protein kinase Src), and phosphorylation of JNK1 (Mitogen-activated protein kinase 8, JNK) and ERK1/2 (Mitogen-activated protein kinase 3/1). Obviously, continuous administration of YZF robustly reversed such changes.

Conclusions: This study revealed that YZF modulates the nociceptive behavior in SNI rats. Moreover, the drug may be useful in the treatment of neuropathic pain through multi-components, multi-targets, and multi-pathways. Nevertheless, more attention should be paid to discriminating the potential ingredients in YZF contributing to its analgesic effects in the treatment of neuropathic pain.
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http://dx.doi.org/10.1016/j.jep.2021.114037DOI Listing
June 2021

Comparative Study on Different Skin Pruritus Mouse Models.

Front Med (Lausanne) 2021 23;8:630237. Epub 2021 Feb 23.

School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.

The animal model is an important tool to study the mechanism of disease formation. Different animal models of pruritus have been adopted based on the purpose of researchers in the study of the itching mechanism. Although the symptoms of various models are quite different, scratching behavior is a key indicator. Therefore, it is necessary to find an animal model that can quickly induce animal scratching and maintain the stability of scratching behavior. In this study, we compared animal models of pruritus induced by four substances and found that the scratching behavior of mice induced by urushiol not only reached the plateau stage quickly but also showed more stability in the plateau phase than that induced by 2,4-dinitrofluorobenzene, oxazolone, and imiquimod. Meanwhile, in the animal model induced by urushiol, the changes of epidermal thickening and inflammatory cell aggregation were also more obvious. In addition, pruritus induced by urushiol is prevalent all over the world, especially in the United States and Europe, involving outdoor groups such as firefighters, forest loggers, and farmers. Therefore, we believe that the urushiol-induced animal model is an ideal choice for the study of the itch formation mechanism and the development of antipruritic drugs.
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http://dx.doi.org/10.3389/fmed.2021.630237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940346PMC
February 2021

ETCO waveforms-assisted awake nasal fibreoptic intubation.

J Clin Monit Comput 2021 Mar 10. Epub 2021 Mar 10.

Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, People's Republic of China.

Awake fibreoptic intubation has always been considered the gold standard for expected difficult airway management. However, the use of fibreoptic intubation was limited because it is time-consuming, requires skillful operators and easily affected by blood or secretions in the oral or nasopharynx. We reported a modified technique of awake fibreoptic nasal intubation with the aid of End-tidal carbon dioxide (ETCO) monitoring, aiming to improve the efficiency and safety of awake fibreoptic intubation.
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http://dx.doi.org/10.1007/s10877-021-00683-3DOI Listing
March 2021

Actinokineospora xionganensis sp. nov., a filamentous actinomycete isolated from the lakeside soil of Baiyangdian.

Antonie Van Leeuwenhoek 2021 May 6;114(5):487-496. Epub 2021 Mar 6.

College of Life Science, Institute of Life Science and Green Development, Hebei University; Engineering Laboratory of Microbial Breeding and Preservation of Hebei Province; Key Laboratory of Microbial Diversity Research and Application of Hebei Province; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Baoding, 071002, PR China.

A novel actinomycete, strain HBU206404, belonging to the genus Actinokineospora, was isolated from the lakeside soil of Baiyangdian, in China. Cells grew at 9-37 °C (optimum temperature, 28 °C) and pH 6-9 (optimum, pH 7). Meso-diaminopimelic acid was the diagnostic diamino acid of the cell-wall peptidoglycan, and sugars present in whole-cell hydrolysates were arabinose, mannose, glucose and galactose. The predominant menaquinone was MK-9(H). The predominant cellular fatty acids (> 5%) of the strain HBU206404 were iso-C (21.5%), iso-C (20.3%), Cω7c/Cω6c and/or Cω6c/Cω7c (15.0%), iso-C (8.6%), C (7.0%) and Cω8c (6.9%). The major polar lipids of the strain HBU206404 were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, six unknown aminolipids, two unknown aminolipids and an unidentified lipid. The 16S rRNA gene sequence analysis indicated that the strain HBU206404 was most closely related to Actinokineospora alba KCTC 19294 (99.58%), but whole-genome comparisons, using average nucleotide identity (ANI) value (91.77%) and digital DNA-DNA hybridization (dDDH) value (60%), confirmed low genome relatedness. Nitrogen metabolism pathway was found in the genome of strain HBU206404 which haboured nitrate reductase and nitrite reductase. Other phenotypic characteristics, such as ability to hydrolyze substances, enzyme activity, acid production from carbon source, etc., could also distinguish strain HBU206404 from Actinokineospora alba KCTC 19294. On the basis of genetic and phenotypic evidence, strain HBU206404 represents a novel species of the genus Actinokineospora, for which the name Actinokineospora xionganensis sp. nov. is proposed. The type strain is HBU206404 (= MCCC 1K04412 = KCTC 49404).
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http://dx.doi.org/10.1007/s10482-021-01532-8DOI Listing
May 2021

Suppression of ELF4 in ulcerative colitis predisposes host to colorectal cancer.

iScience 2021 Mar 9;24(3):102169. Epub 2021 Feb 9.

Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100000, China.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by relapsing and remitting colon mucosal inflammation. For patients suffering from UC, a higher risk of colon cancer has been widely recognized. Here, we found that mice developed colon tumors with 3 cycles of dextran sulfate sodium salt (DSS) treatment alone. We further showed that ELF4 suppression was prevalent in both patients with UC and DSS-induced mice models, and this suppression was caused by promoter region methylation. ELF4, upon PARylation by PARP1, transcriptionally regulated multiple DNA damage repair machinery components. Consistently, ELF4 deficiency leads to more severe DNA damage both and Oral administration of montmorillonite powder can prevent the reduction of ELF4 in DSS-induced colitis models and lower the risk of colon tumor development during azoxymethane (AOM) and DSS induced colitis-associated cancer (CAC). These data provided additional mechanism of CAC initiation and supported the "epigenetic priming model of tumor initiation".
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http://dx.doi.org/10.1016/j.isci.2021.102169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907480PMC
March 2021

Efficacy and safety of immunosuppressive therapies in the treatment of high-risk IgA nephropathy: A network meta-analysis.

Medicine (Baltimore) 2021 Feb;100(8):e24541

China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China.

Background: IgA nephropathy (IgAN) is one of the significant contributing factors of end-stage renal disease (ESRD). It is reported that over half of patients with IgAN accompany multiple high-risk factors, which increase the risk of ESRD progression. Studies have shown that immunosuppressive agents were beneficial in high-risk IgAN, but the efficacy and safety have not been fully demonstrated yet. The present study aims to elucidate the efficacy of commonly used immunosuppressants in high-risk IgAN and their relative safety profiles via a network meta-analysis strategy.

Methods: Randomized controlled trials (RCTs) eligible for this network meta-analysis were included to evaluate the efficacy and safety of different immunosuppressants for high-risk IgAN. Main outcomes and measures include incidence of renal composite end point, the rate of total remission, adverse events, and proteinuria. Besides, subgroup analysis and cluster analysis were carried out.

Results: This network meta-analysis of 37 RCTs involving 3012 participants found that Mycophenolate mofetil (MMF) combined with corticosteroids (CS) was superior to other interventions in end point events and proteinuria. Cyclosporine A (CsA) plus CS was the best option for clinical remission rate, and supportive care (SC) was the safest treatment. Cluster analysis showed that MMF+CS and Leflunomide (LEF)+CS were best protocols in efficacy and safety. Subgroup analysis indicated the best benefits of MMF were presented among the Asian population, and the benefits increased with the increase of follow-up duration. The effect of Cyclophosphamide (CTX) +CS on crescent IgAN was better than that of other risk factors. Moreover, the increasing follow-up duration was negatively associated with the effect.

Conclusions: MMF+CS and LEF+CS appear to serve as the best choice for treating high-risk IgAN than other immunosuppressive therapies.
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http://dx.doi.org/10.1097/MD.0000000000024541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909110PMC
February 2021

The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity.

EMBO Rep 2021 02 4;22(2):e51162. Epub 2021 Jan 4.

Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

Although iron is required for cell proliferation, iron-dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron-mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron-responsive element-binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)-mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage-associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor-reactive T-cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1-IREB2-TFRC signaling axis in host antitumor immunity.
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http://dx.doi.org/10.15252/embr.202051162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857436PMC
February 2021

Ultrashort Wave Combined with Human Umbilical Cord Mesenchymal Stem Cell (HUC-MSC) Transplantation Inhibits NLRP3 Inflammasome and Improves Spinal Cord Injury via MK2/TTP Signalling Pathway.

Biomed Res Int 2020 5;2020:3021750. Epub 2020 Dec 5.

Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110134, China.

Objective: To investigate the curative effects of HUC-MSCs combined with USW on spinal cord injury (SCI) and the effects on inflammatory microenvironment and to explore the regulatory mechanisms of MK2/TTP signalling pathway and NLRP3 inflammasome.

Methods: The SCI rat model was established using the modified Allen method; rats were administered with USW, HUC-MSCs, and combination therapy of USW and HUC-MSCs; the therapeutic efficacies in each group of rats were monitored and represented in BBB score. SCI levels were observed using HE staining and IF. The microglia polarisation state and released contents of inflammatory factors were detected. IF and Western Blotting were performed on to detect the expression levels of MK2/TTP signalling pathway and NLRP3 inflammasome-related proteins. Furthermore, the regulatory mechanisms of MK2/TTP pathway and NLRP3 were explored by performing on the study.

Results: Combination therapy of USW and HUC-MSCs was found of significant efficacy on improving motor functions of SCI rats, and it was further proved that this combination therapy can reduce spinal cord injury in SCI rats, of which USW plays a more important role. While transplantation of HUC-MSCs can promote microglial cells developing to SCI repair, and M2 microglial cells were taking advantages gradually. The combination therapy can inhibit the expression of MK2; downregulate NLRP3 inflammasome; suppress the expression levels of pro-caspase-1, pro-IL-1, and pro-IL-18; and simultaneously suppress the release of IL-1 and IL-18, thereby reducing spinal cord neurons apoptosis. It was found that the steady state of microglial polarisation maintained by combined treatment of USW and HUC-MSCs was destroyed with the upregulation of MK2 expression in cells, of which, M1 type microglial cell was dominant and the increased contents of inflammatory factors were detected. However, overexpressed MK2 relieved the inhibition of NLRP3 expression by TTP.

Conclusions: Combination therapy of USW and HUC-MSCs can downregulate NLRP3 expression, relieve inflammatory responses, improve immune microenvironment, and rescue spinal cord injury via suppressing phosphorylation level of MK2.
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http://dx.doi.org/10.1155/2020/3021750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738785PMC
June 2021

N-Heterocyclic Carbene/Magnesium Cocatalyzed Radical Relay Assembly of Aliphatic Keto Nitriles.

Org Lett 2021 Jan 29;23(2):394-399. Epub 2020 Dec 29.

School of Science, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.

An unprecedented N-heterocyclic carbene and magnesium cocatalyzed three-component acylcyanoalkylation of alkenes with cycloketone oxime esters and aldehydes is presented. This method displayed good scope generality, providing a transition-metal- and photoredox-free pathway to access various multifunctionalized aliphatic keto nitrile structures under mild reaction conditions. Moreover, this strategy is supposed to follow a radical relay mechanism via a single electron transfer event of a Mg/matched Breslow intermediate/oxime ester electron-donating acceptor (EDA) complex.
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http://dx.doi.org/10.1021/acs.orglett.0c03883DOI Listing
January 2021

Biological evaluation of 7-O-amide hesperetin derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease.

Chem Biol Interact 2021 Jan 8;334:109350. Epub 2020 Dec 8.

The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China. Electronic address:

A series of 7-O-amide hesperetin derivatives were subjected to multi-target biological evaluation of anti-Alzheimer's disease. Most of the compounds showed good in vitro inhibitory activity against cholinesterase, of which compound 7c (7-O-(4-(morpholinoethyl)-acetamide) hesperetin) was the most effective anti-eqBuChE derivative (IC = 0.28 ± 0.05 μM) and exerted neuroprotective effects. Further biological evaluation found that compounds 4d, 4e and 7c showed strong antioxidant, anti-Aβ self-aggregation and anti-neuroinflammatory activities. Compound 7c could inhibit the expression of iNOS and COX-2 proteins and prevent LPS-induced inflammatory response in BV2 cells. In addition, compound 7c could chelate biometal ions such as Cu and Zn. In the vivo study, the MWM test confirmed that compound 7c could improve the cognitive impairment caused by scopolamine. In summary, the above studies have shown that the optimized compound 7c has great development potential as MTDL for the treatment of AD.
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http://dx.doi.org/10.1016/j.cbi.2020.109350DOI Listing
January 2021

A Network Pharmacology-Based Strategy for Unveiling the Mechanisms of Tripterygium Wilfordii Hook F against Diabetic Kidney Disease.

J Diabetes Res 2020 20;2020:2421631. Epub 2020 Nov 20.

Department of Nephrology, Guang'anmen Hospital of China Academy of Traditional Chinese Medical Sciences, Beijing 100053, China.

Background: Diabetic kidney disease (DKD) poses a major public-health burden globally. Tripterygium wilfordii Hook F (TwHF) is a widely employed herbal medicine in decreasing albuminuria among diabetic patients. However, a holistic network pharmacology strategy to investigate the active components and therapeutic mechanism underlying DKD is still unavailable.

Methods: We collected TwHF ingredients and their targets by traditional Chinese Medicine databases (TCMSP). Then, we obtained DKD targets from GeneCards and OMIM and collected and analyzed TwHF-DKD common targets using the STRING database. Protein-protein interaction (PPI) network was established by Cytoscape and analyzed by MCODE plugin to get clusters. In addition, the cytoHubba software was used to identify hub genes. Finally, all the targets of clusters were subjected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses via DAVID.

Results: A total of 51 active ingredients in TwHF were identified and hit by 88 potential targets related to DKD. Compounds correspond to more targets include kaempferol, beta-sitosterol, stigmasterol, and Triptoditerpenic acid B, which appeared to be high-potential compounds. Genes with higher degree including VEGFA, PTGS2, JUN, MAPK8, and HSP90AA1 are hub genes of TwHF against DKD, which are involved in inflammation, insulin resistance, and lipid homeostasis. Kaempferol and VEGFA were represented as the uppermost active ingredient and core gene of TwHF in treating DKD, respectively. DAVID results indicated that TwHF may play a role in treating DKD through AGE-RAGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, insulin resistance, and calcium signaling pathway ( < 0.05).

Conclusion: Kaempferol and VEGFA were represented as the uppermost active ingredient and core gene of TwHF in treating DKD, respectively. The key mechanisms of TwHF against DKD might be involved in the reduction of renal inflammation by downregulating VEGFA.
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http://dx.doi.org/10.1155/2020/2421631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695487PMC
November 2020

Thyroid dysfunction and cardiovascular events in patients with chronic kidney disease: A protocol of systematic review and meta-analysis.

Medicine (Baltimore) 2020 Nov;99(47):e23218

Guang'anmen Hospital, China Academy of Chinese Medical Sciences.

Background: Cardiovascular disease is the main cause of death in patients with chronic kidney disease (CKD). Studies have found that hypothyroidism can significantly increase cardiovascular risk. Meanwhile, hypothyroidism is a common complication of CKD, but the correlation between hypothyroidism and cardiovascular risk in CKD patients has not been verified and paid enough attention. We therefore plan to conduct a systematic review and meta-analysis to explore whether hypothyroidism was independently predictive for the cardiovascular risk in patients with CKD.

Methods: We will search in PubMed, Embase Database, Web of Science, China National Knowledge Infrastructure (CNKI), China Biology Medicine Database (CBM), and Wanfang Database, and include the cross-sectional studies, case--control studies, and cohort studies that explore the association between hypothyroidism and cardiovascular risk in CKD patients. According to the eligibility criteria, two researchers will independently screen the retrieved literature, evaluate the methodological quality, and extract data. We will combine the extracted data based on STATA and TSA software.

Results: This systematic review will assess the association between hypothyroidism and cardiovascular risk in CKD patients based on the incidence of cardiovascular events in CKD people with hypothyroidism.

Conclusions: This study will provide more evidence for the correlation between hypothyroidism and cardiovascular risk in CKD patients, which will contribute to the management and clinical practice of CKD population.

Ethics And Dissemination: This protocol is based on available literatures so that the ethical approval and informed consent are not applicable. The results of this study will be published in a peer-reviewed journals or relevant conferences.

Protocol Registration Number: INPLASY2020100022.
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http://dx.doi.org/10.1097/MD.0000000000023218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676516PMC
November 2020

Peroxidase-mimicking Activity of PCN-222(Fe) for Colorimetric Sensing of Acetylcholinesterase Activity and Inhibition.

Anal Sci 2021 Jul 16;37(7):1023-1027. Epub 2020 Oct 16.

Key Laboratory of Analytical Chemistry for Life Science of Shaanxi Province, Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering, Shaanxi Normal University.

A colorimetric method for detection of acetylcholinesterase (AChE) activity and inhibition was developed using metal organic frameworks (i.e., PCN-222(Fe)) with peroxidase-like activity. The blue tetramethylbenzidine oxidized by PCN-222(Fe) fades due to the reduction by acetylthiocholine chloride produced from AChE catalysis. The detection method shows a linear range of 0.05 - 10 mU mL and a detection limit of 0.03 mU mL AChE. Average recoveries in serum samples varied from 93 to 115% and relative standard deviation (RSD) was lower than 4.9%.
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http://dx.doi.org/10.2116/analsci.20N023DOI Listing
July 2021

Multiple polypoid colonic metastases from rectal adenocarcinoma with signet ring cells features: a case report.

BMC Gastroenterol 2020 Oct 14;20(1):337. Epub 2020 Oct 14.

Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuai Fu Yuan, Dong Cheng District, Beijing, 100730, China.

Background: Multiple polypoid colonic metastases are very rare which mainly originated from gastric carcinoma or melanoma. For rectal cancers, liver, lung and peritoneum are the most common metastatic sites. Here we present an unusual case with rectal adenocarcinoma and metachronous multiple colonic polypoid metastases.

Case Presentation: A 53-year-old man who underwent radical resection for rectal cancer 2 years ago was admitted to our department for an elevation of CEA level of 18.4 ng/ml. Colonoscopy revealed ten ivory rubbery colonic polypoid lesions (about 5 mm in diameters) in the large bowel which were confirmed as signet ring cell carcinomas (SRCC) by biopsy, but full-body contrast enhanced CT and PET-CT showed no other suspicious lesion. Seven weeks later, a laparoscopic total colectomy was performed and more than 50 polypoid lesions were observed throughout the mucosal surface of the large intestine which were confirmed as metastatic SRCC by postoperative pathological examination. All the 34 paracolic lymph nodes retrieved were involved. After 4 months, diffuse abdominopelvic and multiple bone metastases were identified by CT and the patient died of the disease 1 month later.

Conclusion: Here we present an unusual case of multiple colonic polypoid metastases of rectal adenocarcinoma. For SRCC that is prone to have disseminated micrometastases, colonic 'polyps' may be the early noticeable sign of undetectable and extensive tumor spread. Instead of surgical resection of 'the confined disease in colon', systemic treatment maybe a more appropriate choice.
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http://dx.doi.org/10.1186/s12876-020-01493-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559435PMC
October 2020

Design and synthesis of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives as novel GSK-3β inhibitors and evaluation of their potential as multifunctional anti-Alzheimer agents.

Eur J Med Chem 2021 Jan 28;209:112874. Epub 2020 Sep 28.

The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; The Key Llaboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China. Electronic address:

Pleiotropic intervention has prominent advantages for complex pathomechanisms, such as Alzheimer's disease (AD). In this study, a series of novel 3-(4-pyridyl)-5-(4- sulfamido-phenyl)-1,2,4-oxadiazole derivatives were designed and synthesized following the multitarget-directed ligand-based strategy. All compounds were evaluated for glycogen synthase kinase 3β (GSK-3β) inhibition and antineuroinflammatory and neuroprotective activities. Given that abnormal glucose metabolism plays an important role in AD occurrence and development, the effects of all compounds on glucose consumption in HepG2 cells was evaluated. Compounds 5e and 10b showed good dual potency in GSK-3β inhibition (IC: 5e = 1.52 μM, 10b = 0.19 μM) and antineuroinflammatory potency (IC: 5e = 0.47 ± 0.64 μM, 10b = 6.94 ± 2.33 μM). The effect of compound 10b on glucose consumption was higher than that of positive drug metformin. These compounds exerted a certain neuroprotective effect. Compound 10b dramatically reduced Aβ-induced Tau hyperphosphorylation, thus inhibiting GSK-3β at the cellular level. Notably, compounds 5e and 10b exhibited good inhibitory effects on the formation of intracellular reactive oxygen species (ROS). Moreover, these compounds displayed proper blood-brain barrier permeability and lacked neurotoxicity up to 50 μM concentration. Finally, in vivo experiments revealed that compound 10b improved cognitive impairment in scopolamine-induced mouse models. Results indicated that compound 10b deserves further study as a multifunctional lead compound.
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http://dx.doi.org/10.1016/j.ejmech.2020.112874DOI Listing
January 2021

Comprehensive analysis of TGF-β-induced mRNAs and ncRNAs in hepatocellular carcinoma.

Aging (Albany NY) 2020 Oct 4;12(19):19399-19420. Epub 2020 Oct 4.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Transforming growth factor β (TGF-β) is a potent inducer of epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), and plays a critical role in its tumorigenesis and progression. Accumulating evidence indicates that protein-coding mRNAs, as well as non-coding RNAs (ncRNAs), may play key roles in the tumorigenesis and progression of HCC. In this study, we first report on the differential expression of lncRNAs, mRNAs, miRNAs, and circRNAs in Huh7 cells treated with TGF-β or DMSO for 7 days. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for significantly differentially expressed RNAs (DE RNAs). Then the competing endogenous RNA (ceRNA) network based on these DE RNAs was predicted and constructed. Among them, we identified that lncRNA SLC7A11-AS1 and hsa_circ_0006123 are involved in the EMT process induced by TGF-β and may promotes the metastasis of HCC. This knowledge may pave the way to develop novel clinical diagnostics and therapeutic approaches. Our study might open a new avenue for future investigations of the molecular mechanisms driving the EMT process induced by TGF-β in HCC.
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http://dx.doi.org/10.18632/aging.103826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732333PMC
October 2020

Development and validation of a CpG island methylator phenotype-related prognostic signature for cholangiocarcinoma.

J Cell Physiol 2021 04 29;236(4):3143-3156. Epub 2020 Sep 29.

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Cholangiocarcinoma (CCA) still has a very unfavorable prognosis with a very high mortality, which is complicated by a lack of prognostic biomarkers. In this study, CCA patients in the Gene Expression Omnibus (GEO) cohort were categorized into two subtypes. Differentially expressed and methylated genes were identified, and the impact of DNA methylation in the trans-regulation of gene expression was investigated. Finally, a CIMP-related methylation signature specific for CCA (CMSC) was trained in GEO and validated in the Tongji cohort. A subset of patients with CIMP-H was identified, which was correlated with an unfavorable prognosis. Gene enrichment analysis implied the potential mechanism of CIMP as a promoter of carcinogenesis by regulating proliferation. The trans-regulation among differentially methylated CpG sites and genes with the same change trends was positively correlated, while the converse situation showed a negative correlation. Notably, CMSC based on four genes could significantly classify CCA patients into low- and high-risk groups in the GEO cohort, and the robustness of CMSC was validated in the Tongji cohort. The results of receiver operating characteristic analysis further indicated that CMSC was capable of highly sensitive and specific prediction of the patient outcomes in CCA. In conclusion, our work highlights the clinical significance of CMSC in the prognosis of CCA.
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http://dx.doi.org/10.1002/jcp.30082DOI Listing
April 2021
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