Publications by authors named "Kui Lu"

97 Publications

Predicting mortality in acute ischaemic stroke treated with mechanical thrombectomy: analysis of a multicentre prospective registry.

BMJ Open 2021 04 1;11(4):e043415. Epub 2021 Apr 1.

Department of Neurology, Jinan University First Affiliated Hospital, Guangzhou, China

Objectives: We aimed to determine predictors of mortality within 90 days and develop a simple score for patients with mechanical thrombectomy (MT).

Design: Analysis of a multicentre prospective registry.

Setting: In six participating centres, patients who had an acute ischaemic stroke (AIS) treated by MT between March 2017 and May 2018 were documented prospectively.

Participants: 224 patients with AIS were treated by MT.

Results: Of 224 patients, 49 (21.9%) patients died, and 87 (38.8%) were independent. Variables associated with 90-day mortality were age, previous stroke, admission National Institutes of Health Stroke Scale (NIHSS), fasting blood glucose and occlusion site. Logistic regression identified four variables independently associated with 90-day mortality: age ≥80 years (OR 3.26, 95% CI 1.45 to 7.33), previous stroke (OR 2.33, 95% CI 1.04 to 5.21), admission NIHSS ≥18 (OR 2.37, 95% CI 1.13 to 4.99) and internal carotid artery or basilar artery occlusion (OR 2.92, 95% CI 1.34 to 6.40). Using these data, we developed predicting 90-day mortality of AIS with MT (PRACTICE) score ranging from 0 to 6 points. The receiver operator curve analysis found that PRACTICE score (area under the curve (AUC)=0.744, 95% CI 0.669 to 0.820) was numerically better than iScore (AUC=0.661, 95% CI 0.577 to 0.745) and Predicting Early Mortality of Ischemic Stroke score (AUC=0.638, 95% CI 0.551 to 0.725) for predicting 90-day mortality.

Conclusions: We developed a simple score to estimate the 90-day mortality of patients who had an AIS treated with MT. But the score needs to be prospectively validated.

Trial Registration Number: Chinese Clinical Trial Registry (ChiCTR-OOC-17013052).
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http://dx.doi.org/10.1136/bmjopen-2020-043415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021751PMC
April 2021

Interaction of two peptide drugs with biomacromolecules analyzed by molecular docking and multi-spectroscopic methods.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Jul 9;255:119673. Epub 2021 Mar 9.

School of Chemical Engineering and Food Science, Zhengzhou University of Technology, Zhengzhou 450044, China. Electronic address:

Peptide drugs, which are mainly used for the treatment of AIDS, myeloma, and breast cancer, have evolved rapidly owing to their high efficacy and low side effects. The interaction mechanisms of two peptide drugs with two biological macromolecules (protein and DNA), which are of great significance in disease prevention and drug design, were investigated using molecular docking, fluorescence spectroscopy, circular dichroism (CD) spectroscopy, UV-visible spectroscopy and viscosity measurements. The interaction between a series of common drugs and ovalbumin (OVA) was simulated by molecular docking, and two peptide drugs with the highest energy values, namely atazanavir and carfilzomib, were selected; the binding energy values of these drugs with OVA were -59.20 and -55.93 kcal/mol, respectively. The K values of the interaction of the two drugs with OVA/DNA were in the range of 10-10 M, and the binding affinity of the drugs was stronger with OVA than with DNA. Hydrogen bonds and van der Waals forces were very important for the binding between drugs and OVA through molecular docking studies, and it was consistent with experimental results (ΔH < 0, ΔH < 0). The synchronous fluorescence spectrum showed that the interaction caused a change to the original structure of OVA, and atazanavir had a greater effect on OVA than carfilzomib. CD spectrum analysis also demonstrated that the conformation of OVA changed slightly. The interaction between atazanavir and DNA was mainly driven by hydrophobic forces (ΔH > 0 and ΔH > 0), whereas the major interaction forces involved in the binding of carfilzomib with DNA were hydrogen bonds and van der Waals forces. DNA melting studies, UV-visible spectroscopy, CD spectroscopy and viscosity measurements established that the interaction between the drugs and DNA was groove binding.
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http://dx.doi.org/10.1016/j.saa.2021.119673DOI Listing
July 2021

Outcome of endovascular treatment within and beyond 6 h without perfusion software.

Sci Rep 2021 Mar 5;11(1):5342. Epub 2021 Mar 5.

Department of Neurology, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou, China.

Endovascular treatment (EVT) has been accepted as the standard of care for patients with acute ischemic stroke. The aim of the present study was to compare clinical outcomes of patients who received EVT within and beyond 6 h from symptom onset to groin puncture without perfusion software in Guangdong district, China. Between March 2017 and May 2018, acute ischemic stroke patients who received EVT from 6 comprehensive stroke centers, were enrolled into the registry study. In this subgroup study, we included all patients who had acute proximal large vessel occlusion in the anterior circulation. The demographic, clinical and neuroimaging data were collected from each center. A total of 192 patients were included in this subgroup study. They were divided into two groups: group A (n = 125), within 6 h; group B (n = 67), 6-24 h from symptom onset to groin puncture. There were no substantial differences between these two groups in terms of 90 days favorable outcome (modified Rankin scale [mRS] ≤ 2, P = 0.051) and mortality (P = 0.083), and the risk of symptomatic intracranial hemorrhage at 24 h (P = 0.425). The NIHSS (median 16, IQR12-20, group A; median 12, IQR8-18, group B; P = 0.009) and ASPECTS (median 10, IQR8-10, group A; median 9, IQR8-10, group B; P = 0.034) at baseline were higher in group A. The anesthesia method (general anesthesia, 21.3%, group A vs. 1.5% group B, P = 0.001) were also statistically different between the two groups. The NIHSS and ASPECTS were higher, and general anesthesia was also more widely used in group A. Clinical outcomes were not significantly different within 6 h versus 6-24 h from symptom onset to groin puncture in this real world study.
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http://dx.doi.org/10.1038/s41598-021-84857-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935958PMC
March 2021

Synthesis of Rottlerone Analogues and Evaluation of Their α-Glucosidase and DPP-4 Dual Inhibitory and Glucose Consumption-Promoting Activity.

Molecules 2021 Feb 15;26(4). Epub 2021 Feb 15.

China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China.

Our previous study found that desmethylxanthohumol () inhibited α-glucosidase in vitro. Recently, further investigations revealed that dehydrocyclodesmethylxanthohumol () and its dimer analogue rottlerone () exhibited more potent α-glucosidase inhibitory activity than . The aim of this study was to synthesize a series of rottlerone analogues and evaluate their α-glucosidase and DPP-4 dual inhibitory activity. The results showed that compounds and irreversibly and potently inhibited α-glucosidase (IC = 0.22 and 0.12 μM) and moderately inhibited DPP-4 (IC = 23.59 and 26.19 μM), respectively. In addition, compounds and significantly promoted glucose consumption, with the activity of at 0.2 μM being comparable to that of metformin at a concentration of 1 mM.
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http://dx.doi.org/10.3390/molecules26041024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919492PMC
February 2021

Depletion of insulin-like growth factor 1 receptor increases radiosensitivity in colorectal cancer.

J Gastrointest Oncol 2020 Dec;11(6):1135-1145

Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China.

Background: Although radiation therapy for advanced colorectal cancer (CRC) is very effective in some patients, treatment resistance limits its efficacy. Insulin-like growth factor 1 receptor (IGF1R) can affect tumor responsiveness and sensitivity to radiation in several cancer types. Herein, we studied the underlying function of IGF1R in the resistance of advanced CRC to radiation therapy and the possible use of drugs targeting IGF1R to overcome this resistance in patients with CRC.

Methods: Differences in the expression levels of the IGF1R were assessed in CRC samples from patients who were radiosensitive or radioresistant. Two radio-resistant colorectal cancer cell lines, SW480 and HT29, were selected for studies, and the involvement of the IGF1R in their radiation resistance was elucidated by suppressing its expression through a targeted siRNA and through the use of a specific IGF1R inhibitor, BMS-754807. We assessed radiosensitivity in these human CRC cells lines by examining their proliferation and colony formation, as well as cell cycle analysis. Activation of the Akt pathway was assessed using western blotting.

Results: Compared with tissues from radiosensitive patients, higher IGF1R expression levels were found in patients with radiation-resistant colorectal cancer, while BMS-754807 had improved radiosensitivity and reversed radiation tolerance in both colorectal cancer cell lines. Pre-treatment with BMS-754807 prior to irradiation inhibited Akt phosphorylation, induced cell cycle arrest, and increased DNA damage. Therefore, the IGF1R contributes to radiation resistance of CRC cells .

Conclusions: This study supports the notion that the radiosensitivity of radiation-resistant colorectal cancer cells can be enhanced by directly targeting IGF1R expression or activity. Ultimately, the combination of radiotherapy with IGF1R targeted inhibitors could potentially increase its effectiveness in the treatment of advanced colorectal cancer.
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http://dx.doi.org/10.21037/jgo-20-210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807270PMC
December 2020

Metal-Free Trifluoromethylthiolation of Arylazo Sulfones.

J Org Chem 2021 Jan 22;86(1):1292-1299. Epub 2020 Dec 22.

Tianjin Key Laboratory of Structure and Performance for Functional Molecules, College of Chemistry, Tianjin Normal University, Tianjin 300387, People's Republic of China.

A visible-light-driven protocol for the synthesis of aryl trifluoromethyl thioethers under photocatalyst- and metal-free conditions has been pursued. The procedure exploits the peculiar properties of arylazo sulfones (having electron-rich or electron-poor substituents on the (hetero)aromatic ring) as photochemical precursors of aryl radicals and -trifluoromethyl arylsulfonothioates as easy-to-handle trifluoromethylthiolating agents.
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http://dx.doi.org/10.1021/acs.joc.0c02669DOI Listing
January 2021

pH-Responsive Host-Guest Complexations Between a Water-Soluble Pillar[6]arene Dodecyl-Ammonium Chloride and Aromatic Sulfonic Acids.

Front Chem 2020 15;8:588201. Epub 2020 Sep 15.

Henan International Joint Laboratory of Rare Earth Composite Materials, School of Materials and Chemical Engineering, Henan University of Engineering, Zhengzhou, China.

In the present work, new host-guest binding motifs based on a water-soluble pillar[6]arene dodecyl-ammonium chloride (CP6) with two aromatic sulfonic acids in aqueous media were fabricated. In accordance with the integrated results of H NMR, 2D NOESY, and florescence titration experiments, it was demonstrated that the host-guest binding of CP6 with the two aromatic sulfonic acids in aqueous solution not only has high binding constants but also has pH-responsiveness.
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http://dx.doi.org/10.3389/fchem.2020.588201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533581PMC
September 2020

RACO-1 modulates Hippo signalling in oesophageal squamous cell carcinoma.

J Cell Mol Med 2020 10 7;24(20):11912-11921. Epub 2020 Sep 7.

Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.

Oesophageal cancer is one of the most lethal malignancies worldwide, whereas the 5-year survival is less than 20%. Although the detailed carcinogenic mechanisms are not totally clear, recent genomic sequencing data showed dysregulation of Hippo signalling could be a critical factor for oesophageal squamous cell carcinoma (ESCC) progression. Therefore, understanding of the molecular mechanisms that control Hippo signalling activity is of great importance to improve ESCC diagnostics and therapeutics. Our current study revealed RACO-1 as an inhibitory protein for YAP/TEAD axis. Depletion of RACO-1 increases the protein level of YAP and expression of YAP/TEAD target gene. Besides, RACO-1 silencing could promote ESCC cell invasion and migration, which effect could be rescued by YAP depletion in ESCC cells. Immunoprecipitation showed that RACO-1 associated with YAP and promote ubiquitination and degradation of YAP at k48 poly-ubiquitination site. Our research discovered a new regulator of Hippo signalling via modulating YAP stability. RACO-1 could be a promising factor, which serves cancer diagnostics and therapeutics in ESCC patients.
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http://dx.doi.org/10.1111/jcmm.15811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579699PMC
October 2020

Regulation of Hippo/YAP signaling and Esophageal Squamous Carcinoma progression by an E3 ubiquitin ligase PARK2.

Theranostics 2020 25;10(21):9443-9457. Epub 2020 Jul 25.

Xinxiang Key Laboratory for Molecular Therapy of Cancer, Xinxiang Medical University, Xinxiang 453003, Henan Province, P.R. China.

Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed cancer types in China. Recent genomic sequencing analysis indicated the over-activation of Hippo/YAP signaling might play important roles for the carcinogenic process and progression for ESCC patients. However, little is known about the molecular mechanisms that controls Hippo signaling activity in ESCC. Our previous studies indicated that PLCE1-an important risk factor for ESCC-linked to ESCC progression through snail signaling, during this period, we found PARK2 was an important downstream target of PLCE1-snail axis. PARK2 was decreased in ESCC human samples, and correlated with good prognosis in ESCC patients. Further research showed that PARK2 could inhibit YAP, which functions as key downstream effectors of the Hippo pathway. Here, we aim to reveal the molecular mechanisms of PARK2 modulated Hippo pathway in ESCC. To evaluate the function of PARK2 in ESCC, we used a tissue microarray (TMA) of 223 human ESCC patients and immunohistochemistry to analyze the correlation between PARK2 expression and clinicopathologic variables. Depletion of endogenous PARK2 and YAP from ESCC cells using CRISPR/Cas9 technologies. Flow cytometry and EdU cell proliferation assay were used to detect proliferation of ESCC cells. Nude mice subcutaneous injection and Ki-67 staining were used to evaluate tumor growth . Migration and invasion assays were performed. In addition, lung metastasis models in mice were used to validate the function of PARK2 . Identification of PARK2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. The RNA-seq analysis results were validated through quantitative real-time PCR (qRT-PCR) analysis. The protein half-life of YAP was analyzed by Cycloheximide assay, and the TEAD activity was detected by Luciferase reporter assays. Clinical sample of ESCC revealed that low PARK2 expression correlated with late tumor stage (P < 0.001), poor differentiation (P < 0.04), lymph node (P < 0.001) and distant metastasis (P = 0.0087). Multivariate Cox proportional regression analysis further revealed that PARK2 expression (P = 0.032) is an independent prognostic factor for the overall survival of ESCC patients. Besides, the immunohistochemistry results showed that PARK2 negatively correlated with YAP protein level (P 0.001). PARK2 depletion promotes ESCC progression both through Hippo/YAP axis, while PARK2 overexpression suppresses ESCC tumor progression by Hippo signaling. Co-IP and ubiquitination assays revealed that PARK2 could interact with YAP in the cytosol and promotes YAP K48-linked ubiquitination at K90 sites. Clinical sample analysis and mechanistic study have validated PARK2 as a tumor suppressor for ESCC. Multivariate Cox proportional regression analysis further revealed that PARK2 is an independent prognostic factor for the overall survival of ESCC patients. Cellular and molecular mechanisms in this study showed that PARK2 associated with YAP protein in the cytosol, promoted YAP ubiquitination and proteasome-dependent degradation in ESCC cells. Therefore, as a novel modulator for Hippo signaling, modulation of PARK2 activity or gene expression level could be an appealing strategy to treat esophageal.
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http://dx.doi.org/10.7150/thno.46078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449928PMC
June 2021

Retraction Note: Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma.

J Exp Clin Cancer Res 2020 08 19;39(1):164. Epub 2020 Aug 19.

Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266021, China.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13046-020-01668-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437172PMC
August 2020

CORM-3 Regulates Microglia Activity, Prevents Neuronal Injury, and Improves Memory Function During Radiation-induced Brain Injury.

Curr Neurovasc Res 2020 ;17(4):464-470

Department of Neurology, Zengcheng District People's Hospital of Guangzhou, Guangdong 511300, China.

Objective: This study aims to explore in detail, the mechanism of the carbon monoxide releasing molecule-3 (CORM-3) in regulating the activity of microglia (MG) in the treatment of radiation brain injury (RBI).

Methods: The brain injury models of BV2 cells and Balb/C mice were established and randomly divided into three groups: the normal control group (CON), the single radiation group (RAD), and the radiation plus CORM-3 intervention group (RAD+CORM). Immunofluorescence was used to observe the effects on activation of the MG. The expressions of inflammatory factors, such as intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS), were detected by Western blot. Neuron apoptosis and regeneration in the radiation brain injury (RBI) model were detected by neuronal nuclear antigen (NeuN)+TUNEL and NeuN+BrdU double staining. A Morris water maze was used to assess the spatial learning and memory of the mice.

Results: Within 48 h after radiation, CORM-3 inhibited activation of the MG, blocked the phosphorylation of P38, and increased the expression of ICAM-1 and iNOS. Therefore, CORM-3 might alleviate MG-mediated neuronal apoptosis and promote neural regeneration in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. CORM-3 could increase the swimming distance and platform-stay time of the mice in the target platform quadrant after radiation.

Conclusion: CORM-3 could effectively improve the inflammatory response induced by activation of the MG, reduce neuronal apoptosis, promote neural regeneration, and improve the learning and memory performance of mice after radiation.
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http://dx.doi.org/10.2174/1567202617999200730213259DOI Listing
January 2020

Comparison of non-schistosomal colorectal cancer and schistosomal colorectal cancer.

World J Surg Oncol 2020 Jul 1;18(1):149. Epub 2020 Jul 1.

Department of Pathology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Qingpu District Central Hospital, No.1158 Gongyuan East Road, Qingpu District, Shanghai, 201700, People's Republic of China.

Aim: The purpose of this study was to compare clinicopathological features of patients with non-schistosomal and schistosomal colorectal cancer to explore the effect of schistosomiasis on colorectal cancer (CRC) patients' clinical outcomes.

Methods: Three hundred fifty-one cases of CRC were retrospectively analyzed in this study. Survival curves were constructed by using the Kaplan-Meier (K-M) method. Univariate and multivariate Cox proportional hazard regression models were performed to identify associations with outcome variables.

Results: Colorectal cancer patients with schistosomiasis (CRC-S) were significantly older (P < 0.001) than the patients without schistosomiasis (CRC-NS). However, there were no significant differences between CRC-S and CRC-NS patients in other clinicopathological features. Schistosomiasis was associated with adverse overall survival (OS) upon K-M analysis (P = 0.0277). By univariate and multivariate analysis, gender (P = 0.003), TNM stage (P < 0.001), schistosomiasis (P = 0.025), lymphovascular invasion (P = 0.030), and lymph nodes positive for CRC (P < 0.001) were all independent predictors in the whole cohort. When patients were stratified according to clinical stage and lymph node metastasis state, schistosomiasis was also an independent predictor in patients with stage III-IV tumors and in patients with lymph node metastasis, but not in patients with stage I-II tumors and in patients without lymph node metastasis.

Conclusion: Schistosomiasis was significantly correlated with OS, and it was an independent prognostic factor for OS in the whole cohort. When patients were stratified according to clinical stage and lymph node metastasis state, schistosomiasis was still an independently unfavorable prognosis factor for OS in patients with stage III-IV tumors or patients with lymph node metastasis.
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http://dx.doi.org/10.1186/s12957-020-01925-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330999PMC
July 2020

Calix[n]arene/Pillar[n]arene-Functionalized Graphene Nanocomposites and Their Applications.

Front Chem 2020 12;8:504. Epub 2020 Jun 12.

School of Materials and Chemical Engineering, Henan University of Engineering, Zhengzhou, China.

Calix[n]arenes and pillar[n]arenes, which contain repeating units of phenol and methane, are class of synthetic cyclic supramolecules. Their rigid structure, tunable cavity size, flexible functionalization, and rich host-guest properties make them ideal surface modifiers to construct functional hybrid materials. Introduction of the calix[n]arene/pillar[n]arene species to the graphene may bring new interesting or enhanced physicochemical/biological properties by combining their individual characteristics. Reported methods for the surface modification of graphene with calix[n]arene/pillar[n]arene utilize either covalent or non-covalent approaches. This mini-review presents the recent advancements in the functionalization of graphene nanomaterials with calix[n]arene/pillar[n]arene and their applications. At the end, the future outlook and challenges for the continued research of calix[n]arene/pillar[n]arene-functionalized graphene nanohybrids in the development of applied nanoscience are thoroughly discussed.
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http://dx.doi.org/10.3389/fchem.2020.00504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304259PMC
June 2020

Facile One-Step Electrodeposition Preparation of Cationic Pillar[6]arene-Modified Graphene Films on Glassy Carbon Electrodes for Enhanced Electrochemical Performance.

Front Chem 2020 4;8:430. Epub 2020 Jun 4.

School of Materials and Chemical Engineering, Henan University of Engineering, Zhengzhou, China.

In the present work, we have developed a facile one-step route for preparing electrochemically reduced graphene oxide-cationic pillar[6]arene (ErGO-CP6) nanocomposite films on glassy carbon electrodes (GCEs) directly from graphene oxide-cationic pillar[6]arene (GO-CP6) colloidal solution by using a pulsed electrodeposition technique. The electrocatalytic activity of ErGO-CP6 was examined by studying the oxidations of five purine bases [adenine (A), guanine (G), xanthine (X), hypoxanthine (HX), and uric acid (UA)]. It enhanced the oxidation currents of A, G, X, HX, and UA when compared to unmodified ErGO films and bare GCE, which is considered to be the synergetic effects of the graphene (excellent electrical properties and large surface area) and CP6 molecules (high inclusion complexation and enrichment capability).
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http://dx.doi.org/10.3389/fchem.2020.00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287394PMC
June 2020

PALB2 as a potential prognostic biomarker for colorectal cancer.

Comput Biol Chem 2020 May 20;87:107289. Epub 2020 May 20.

Department of Pathology, Qingpu Branch of Zhongshan Hospital, Fudan University, No. 1158 East Park Road, Qingpu District, Shanghai 200032, PR China; Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 201700, PR China. Electronic address:

Partner and localizer of BRCA2 (PALB2) is regarded as a colorectal cancer (CRC) risk gene, but the prognostic implication of PALB2 in CRC remains unclear. In this study, we evaluate the prognostic value of the gene copy number alteration (CNA) and mRNA expression of PALB2 in The Cancer Genome Atlas (TCGA) database, and then validated with our database. We downloaded the copy number and mRNA data of PALB2 from TCGA database and examined the relationship among the genetic alterations, expression levels and survival outcomes. Gene ontology (GO) analysis was performed to study the function of PALB2. cBioPortal database was used to explore the potential co-expression genes of PALB2. There were 6.3% (37 of 582) CRC patients diagnosed as PALB2 gene deletion. The PALB2 deletion group expressed significantly lower of PALB2 mRNA than the non-deletion group (P < 0.001). Survival analysis showed that PALB2 deletion was significantly associated with shorter disease-free survival (DFS) (P = 0.026) and overall survival (OS) (P = 0.028). Low mRNA expression of PALB2 correlated with shorter OS (P < 0.001). Multivariate analysis also confirmed that PALB2 deletion and low mRNA expression of PALB2 were independent prognostic factors of poor OS in CRC (P = 0.019, 0.034, respectively). In validation cohort, negative expression of PALB2 was associated with shorter OS (P = 0.006) in stage I patients. Multivariate analysis confirmed that negative expression of PALB2 was a poor-prognostic factor (P = 0.002). GO analysis and co-expression analysis investigated that PALB2 is primarily involved in the DNA repair process. These results suggest that PALB2 gene copy number deletion and low mRNA expression could be novel prognostic biomarkers for CRC.
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http://dx.doi.org/10.1016/j.compbiolchem.2020.107289DOI Listing
May 2020

Design of BRC analogous peptides based on the complex BRC8-RAD51 and the preliminary study on the peptide structures.

Amino Acids 2020 May 16;52(5):831-839. Epub 2020 May 16.

School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou, 450001, China.

BRCA2 is an important tumor suppressor gene that plays a critical role in preserving the stability of cellular genetic information, participating in DNA repair by engaging in binding interactions with RAD51 proteins. However, the lack of structural data on BRCA2 and RAD51 makes the study of their interaction mechanism still a great challenge. We characterize the structure of the BRC8-RAD51 complex using ZDOCK protein docking software and identify the potential non-conserved active site of BRC8 via virtual alanine scanning, utilizing the obtained results to synthesize BRC8, its six analogous peptides (BRC8-1 to BRC8-6), and critical peptide fragment of RAD51 (RAD51(231-260)) by Fmoc solid-phase synthesis. The analogous peptides are found to exhibit a secondary structure significantly different from that of BRC8 by circular dichroism spectroscopy, which indicates that mutation sites determined by computer-aided simulation correspond to key amino acid residues substantially affecting polypeptide structure. On the other hand, the secondary structure of RAD51(231-260) was also considerably influenced by its interaction with BRC8 and analogs, e.g., the fraction of the α-helical structure in RAD51(231-260) increased to 23.6, 15.1, and 13.5% upon interaction with BRC8-1, BRC8-3, and BRC8-6, respectively. The results show that the properties of C-terminal amino acid residues significantly influence peptide-peptide interactions, in agreement with the results of virtual alanine scanning. Therefore, computer-aided simulation was confirmed to be a technique that is useful for narrowing down the range of sites responsible for interactions between peptides or proteins, and provides new inspirations for the design of peptides with strong interactions.
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http://dx.doi.org/10.1007/s00726-020-02856-xDOI Listing
May 2020

The prognostic role of c-MYC amplification in schistosomiasis-associated colorectal cancer.

Jpn J Clin Oncol 2020 Apr;50(4):446-455

Department of Pathology, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China.

Objective: The purpose of this study was to explore the prognostic role of c-MYC amplification in colorectal cancer, particularly in schistosomiasis-associated colorectal cancer.

Methods: Three hundred and fifty four cases of colorectal cancer, which were from Qingpu Branch of Zhongshan Hospital affiliated to Fudan University, were retrospectively analyzed in a tissue microarray (TMA) format, with fluorescence in situ hybridization (FISH) assay and immunohistochemistry (IHC).

Results: c-MYC gene amplification was found in 14.1% (50 out of 354) of patients with colorectal cancer and was correlated with old age (P = 0.028), positive lymph node metastasis (P = 0.004) and advanced stage tumors (P = 0.002). The overexpression of c-MYC was closely associated with the amplification status (P = 0.023). Kaplan-Meier survival curves for overall survival (OS) showed a statistically significant difference for patients with c-MYC amplification in full cohort of colorectal cancer, stage III-IV set and patients with lymph node metastasis (P = 0.002, 0.034, 0.012, respectively). Further analysis found c-MYC amplification associated with poorer survival in the subgroup of colorectal cancer with schistosomiasis (CRC-S, P < 0.001), but not in colorectal cancer without schistosomiasis (CRC-NS, P = 0.155). By multivariate analysis, c-MYC amplification was an independent poor-prognostic factor in CRC-S set (P = 0.046).

Conclusions: Our study firstly found c-MYC amplification could predict poor prognosis in schistosomiasis-associated colorectal cancer, but not in colorectal cancer without schistosomiasis.
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http://dx.doi.org/10.1093/jjco/hyz210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160914PMC
April 2020

Metal-Free sp C-SCF Coupling Reactions between Cycloketone Oxime Esters and -trifluoromethyl 4-Methylbenzenesulfonothioate.

Org Lett 2020 02 16;22(3):863-866. Epub 2020 Jan 16.

China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology , Tianjin University of Science & Technology , Tianjin , China , 300457.

A novel sp C-SCF coupling reaction between cycloketone oxime esters and -trifluoromethyl 4-methylbenzenesulfonothioate was achieved. Ethanol was found to facilitate this transformation by trapping the sulfonyl cation. The metal-free and photocatalyst-free reaction conditions, as well as the broad substrate scope, make this a green protocol for the synthesis of SCF-substituted nitriles.
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http://dx.doi.org/10.1021/acs.orglett.9b04343DOI Listing
February 2020

SHARPIN Inhibits Esophageal Squamous Cell Carcinoma Progression by Modulating Hippo Signaling.

Neoplasia 2020 02 26;22(2):76-85. Epub 2019 Dec 26.

Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China; Center for Cancer Research, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China; Xinxiang Key Laboratory for Molecular Therapy of Cancer, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China. Electronic address:

Esophageal cancer is one of the leading malignancies worldwide, while around sixty percent of newly diagnosed cases are in China. In recent years, genome-wide sequencing studies and cancer biology studies show that Hippo signaling functions a critical role in esophageal squamous cell carcinoma (ESCC) progression, which could be a promising therapeutic targets in ESCC treatment. However, the detailed mechanisms of Hippo signaling dys-regulation in ESCC remain not clear. Here we identify SHARPIN protein as an endogenous inhibitor for YAP protein. SHARPIN depletion significantly decreases cell migration and invasion capacity in ESCC, which effects could be rescued by further YAP depletion. Depletion SHARPIN increases YAP protein level and YAP/TEAD target genes, such as CTGF and CYR61 in ESCC. Immuno-precipitation assay shows that SHARPIN associates with YAP, promoting YAP degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Our study reveals a novel post-translational mechanism in modulating Hippo signaling in ESCC. Overexpression or activation of SHARPIN could be a promising strategy to target Hippo signaling for ESCC patients.
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http://dx.doi.org/10.1016/j.neo.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939053PMC
February 2020

Design, synthesis and interaction of BRC4 analogous peptides with RAD51(241-260).

Amino Acids 2020 Mar 24;52(3):361-369. Epub 2019 Dec 24.

Shaanxi Key Laboratory of Natural Products and Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Yangling, 712100, China.

Breast cancer susceptibility gene 2 (BRCA2) is an important tumor suppressor, which is participated in repair of damaged DNA by its highly conserved BRC repeat motifs regulating RAD51 protein homologous recombination and thereby preventing cell carcinogenesis. In this study, the BRCA2(1524-1548)-RAD51(241-260) complex structure was obtained based on PDB bank data 1N0W, which provided the basis for site-specific mutation of BRCA2(1524-1548). The BRC4 and BRC4 analogous peptides were synthesized, and the interaction between BRC peptide and RAD51(241-260) was studied by fluorescence spectroscopy, circular dichroism spectroscopy and microscale thermophoresis (MST). The results of circular dichroism showed that the changes in secondary structures of RAD51(241-260) occurred after adding BRC4 analogous peptides, and the α-helix content increased significantly. Fluorescence spectral data demonstrated that the model of BRC peptide binding to RAD51(241-260) was static quenching, and the binding constants of BRC4, P1, P2, P4 with RAD51(241-260) were 1.647 × 10 L mol, 2.532 × 10 L mol, 3.161 × 10 L mol, 1.705 × 10 L mol, respectively. The results of MST indicated that P2 and RAD51(241-260) have better affinity for dissociation constant 44.286 μM. The strongest affinity between P2 and RAD51(241-260) indicated that the mutation of amino acid residue constituting BRC α-helix affects the structure and interaction of BRC peptide and RAD51(241-260).
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http://dx.doi.org/10.1007/s00726-019-02813-3DOI Listing
March 2020

Metal-Free Difluoromethylselenolation of Arylamines Under Visible-Light Photocatalysis.

J Org Chem 2020 Jan 20;85(2):1224-1231. Epub 2019 Dec 20.

College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Key laboratory of Inorganic-Organic Hybrid Functional Material Chemistry, Ministry of Education , Tianjin Normal University , Tianjin 300387 , China.

A novel visible-light photocatalytic difluoromethylselenolation of aryl amines via generation of aryldiazonium salts was achieved using Se-(difluoromethyl) 4-methylbenzenesulfonoselenoate, which was synthesized for the first time. The reagent is readily accessible and shelf-stable. The metal-free reaction conditions and the broad substrate scope provide a green protocol for the efficient and rapid introduction of the difluoromethylselenylether group.
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http://dx.doi.org/10.1021/acs.joc.9b02535DOI Listing
January 2020

Recent advances in the development of cyclin-dependent kinase 7 inhibitors.

Eur J Med Chem 2019 Dec 22;183:111641. Epub 2019 Aug 22.

Unité de Technologies Chimiques et Biologiques pour la Santé, Université Paris Descartes UMR-S 1022 Inserm, 4 avenue de l'Observatoire, Paris, 75006, France. Electronic address:

Cyclin dependent kinase 7 (CDK7) plays a double role as it activates several other cyclin dependent kinases and participates to the initiation of transcription. This kinase is overexpressed in various types of tumors. Relatively few selective CDK7 inhibitors have been up to now disclosed. Most of these inhibitors belong to two chemical families: pyrazolopyrimidines and pyrazolotriazines on one side and pyrimidines on another side. They also differ by their molecular mechanism of action. Some are acting as competitive inhibitors and some others are covalent inhibitors. With these tools, the understanding of the potential therapeutic interest of CDK7 inhibitors in cancer is rapidly growing. They display antiproliferative activity against various types of tumors and leukemia and synergies have been identified. Two inhibitors are undergoing clinical testing. The most potent compounds inhibit a large number of cell-lines with IC < 200 nM.
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http://dx.doi.org/10.1016/j.ejmech.2019.111641DOI Listing
December 2019

Total synthesis of wikstrol A and wikstrol B.

Org Biomol Chem 2019 09 20;17(35):8206-8213. Epub 2019 Aug 20.

China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Key Laboratory of Industrial Microbiology of Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China.

The first total synthesis of wikstrol A and wikstrol B was achieved by employing aldol reaction, Sharpless asymmetric dihydroxylation, regioselective iodination, Sonogashira coupling, and rhodium-catalyzed oxidative coupling as key steps. The structure of the key intermediate for wikstrol A was confirmed via its derivative by single-crystal X-ray analysis.
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http://dx.doi.org/10.1039/c9ob01219bDOI Listing
September 2019

PEP-FOLD design, synthesis, and characteristics of finger-like polypeptides.

Spectrochim Acta A Mol Biomol Spectrosc 2020 Jan 19;224:117401. Epub 2019 Jul 19.

School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou 450001, China.

Polypeptides with finger-like structures can often intercalate into the grooves of DNA, thereby affecting DNA repair or activating gene transcription, both of which are crucial for the regulation of physiological processes. Their conserved amino acid sequence and simple structure have provided useful elements for the design and assembly of functional molecules. In this paper, using the CH zinc finger domain and the PEP-FOLD3 online simulation platform 11 polypeptides containing 22 amino acid residues were designed. In addition, the CD spectroscopy was combined with the fluorescence spectroscopy to study the polypeptide structures and their interaction with DNA. Results showed that although addition of zinc ions affected the polypeptide structure, particularly of the polypeptides A4, B1, and B3, zinc ion was not an essential factor for increasing polypeptide-DNA interactions. Our study revealed an increase in the interaction strength between mutated polypeptides and DNA, suggesting that mutations disrupt polypeptide structure, and polypeptides interact with DNA by groove and electrostatic binding. Mutations at the 12th and 15th amino acid residues had the greatest effect. The stronger binding between A2 or B2 and DNA indicates that the polypeptide has a spatial structure that can stably interact with DNA. The structure and characteristics of these polypeptide domains can provide information for the design and development of new polypeptide functional molecules, which could have potential significance and applications. However, this information also suggests that there are many challenges facing polypeptide design due to the synergistic effects between the side chains of amino acid residues.
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http://dx.doi.org/10.1016/j.saa.2019.117401DOI Listing
January 2020

Visible-Light-Driven Synthesis of Arylstannanes from Arylazo Sulfones.

Org Lett 2019 Jul 17;21(13):5187-5191. Epub 2019 Jun 17.

PhotoGreen Lab, Department of Chemistry , University of Pavia , V. Le Taramelli 12 , Pavia 27100 , Italy.

The visible-light-driven preparation of (hetero)aryl stannanes was carried out under both photocatalyst- and metal-free conditions via irradiation of arylazo sulfones in the presence of hexaalkyldistannanes. The reaction shows a high efficiency and a wide substrates scope. The resulting crude organotin derivatives can be directly employed in a Stille protocol.
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http://dx.doi.org/10.1021/acs.orglett.9b01788DOI Listing
July 2019

Polydatin prevents the induction of secondary brain injury after traumatic brain injury by protecting neuronal mitochondria.

Neural Regen Res 2019 Sep;14(9):1573-1582

Department of Treatment Center for Traumatic Injuries, the Third Affiliated Hospital of Southern Medical University, Academy of Orthopedics, Guangdong Province; Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou, Guangdong Province, China.

Polydatin is thought to protect mitochondria in different cell types in various diseases. Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury. To investigate the protective effect of polydatin after traumatic brain injury, a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults. Rat models were intraperitoneally injected with polydatin (30 mg/kg) or the SIRT1 activator SRT1720 (20 mg/kg, as a positive control to polydatin). At 6 hours post-traumatic brain injury insults, western blot assay was used to detect the expression of SIRT1, endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side. Flow cytometry was used to analyze neuronal mitochondrial superoxide, mitochondrial membrane potential and mitochondrial permeability transition pore opened. Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy. Our results showed that after treatment with polydatin, release of reactive oxygen species in neuronal mitochondria was markedly reduced; swelling of mitochondria was alleviated; mitochondrial membrane potential was maintained; mitochondrial permeability transition pore opened. Also endoplasmic reticulum stress related proteins were inhibited, including the activation of p-PERK, spliced XBP-1 and cleaved ATF6. SIRT1 expression and activity were increased; p38 phosphorylation and cleaved caspase-9/3 activation were inhibited. Neurological scores of treated rats were increased and the mortality was reduced compared with the rats only subjected to traumatic brain injury. These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria. The mechanisms may be linked to increased SIRT1 expression and activity, which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway. This study was approved by the Animal Care and Use Committee of the Southern Medical University, China (approval number: L2016113) on January 1, 2016.
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http://dx.doi.org/10.4103/1673-5374.255972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557083PMC
September 2019

Divalent oseltamivir analogues as potent influenza neuraminidase inhibitors.

Carbohydr Res 2019 May 1;477:32-38. Epub 2019 Apr 1.

Research Centre of Modern Analytical Technology, Tianjin University of Science & Technology, No. 29, 13th Avenue, TEDA, Tianjin, 300457, China; China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, No. 29, 13th Avenue, TEDA, Tianjin, 300457, China. Electronic address:

A panel of divalent oseltamivir and guanidino oseltamivir analogues with esterification on the carboxyl acid group as potent inhibitors of influenza virus neuraminidase was prepared via click reaction. The primary structure activity relationship study demonstrated that appropriate distance between two oseltamivir monomers around 30 Å can crosslink two adjacent neuraminidase tetramers on the virion surface and result in highly effective NA inhibitors against three strains of influenza virus and H7N9 virus like particle. This strategy also provides a basis for the multivalent modification on oseltamivir.
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http://dx.doi.org/10.1016/j.carres.2019.03.012DOI Listing
May 2019

Acid/base- and base/acid-switchable complexation between anionic-/cationic-pillar[6]arenes and a viologen ditosylate salt.

Org Biomol Chem 2019 05;17(18):4430-4434

School of Materials and Chemical Engineering, Henan University of Engineering, Zhengzhou, 450006, China.

Two new host-guest complexes between water-soluble anionic pillar[6]arene (WP6) or cationic pillar[6]arene (CP6) and a viologen ditosylate salt G·2TsO were constructed, among which one formed from WP6 and G2+ ions can be controlled by the sequential addition of an acid and a base (HCl and NaOH, respectively), whereas the other fabricated from CP6 and TsO- ions can be switched through the sequential addition of basic and acidic reagents (NaOH and HCl, respectively).
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http://dx.doi.org/10.1039/c9ob00398cDOI Listing
May 2019

Autophagy induction by xanthoangelol exhibits anti-metastatic activities in hepatocellular carcinoma.

Cell Biochem Funct 2019 Apr 18;37(3):128-138. Epub 2019 Mar 18.

China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.

Xanthoangelol (XAG), a prenylated chalcone isolated from the Japanese herb Angelica keiskei Koidzumi, has been reported to exhibit antineoplastic properties. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC), and the relevant mechanisms are not known. Herein, we evaluated the effect of XAG against HCC in vitro and in vivo. Although XAG treatment did not significantly reduce the viability of the Hep3B and Huh7 cell lines, it suppressed cell migration, invasion, and EMT. This anti-metastatic effect of XAG was due to induction of autophagy, because treatment with the autophagy inhibitor 3-methyadenine (3-MA) or knockdown of the pro-autophagy Beclin-1 effectively abrogated the XAG-induced suppression of metastasis. Mechanistically, XAG induced autophagy via activation of the AMPK/mTOR signaling pathway, and XAG treatment dramatically increased the expression of p-AMPK while decreasing p-mTOR expression. In addition, blocking AMPK/mTOR axis with compound C abrogated the autophagy-mediated inhibition of metastasis. The murine model of HCC metastasis also showed that XAG effectively reduced the number of metastatic pulmonary nodules. Taken together, our results revealed that autophagy via the activation of AMPK/mTOR pathway is essential for the anti-metastatic effect of XAG against HCC. These findings not only contribute to our understanding of the anti-tumor activity of XAG but also provide a basis for its clinical application in HCC. Before this study, evidence of XAG on HCC was purely anecdotal; present study provides the first comprehensive assessments of XAG on HCC metastasis and investigates its underlying mechanism. Results suggest that XAG exerts anti-metastatic properties against HCC through inducing autophagy which is mediated by the activation of AMPK/mTOR signaling pathway. This research extends our knowledge about the antineoplastic properties of XAG and suggests that induction autophagy may represent future treatment strategies for metastatic HCC.
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http://dx.doi.org/10.1002/cbf.3374DOI Listing
April 2019

Effect of purple yam flour substitution for wheat flour on in vitro starch digestibility of wheat bread.

Food Chem 2019 Jun 16;284:118-124. Epub 2019 Jan 16.

Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China. Electronic address:

This study aimed to investigate the effect of purple yam (Dioscorea alata L.) flour substitution for wheat flour on in vitro starch digestibility of wheat bread. The enzyme-resistant starch content increased from 34.9% for wheat flour bread to 41.3% for bread made with 70% wheat flour and 30% purple yam flour. Meanwhile, the content of rapidly digestible starch and slowly digestible starch decreased with the addition of purple yam flour in the bread. The results from differential scanning calorimetry, X-ray diffraction, polarized light and scanning electron microscopy showed that purple yam starch granules were not completely disrupted during bread baking. The fluorescence intensity of α-amylase and amyloglucosidase was reduced in bread made with purple yam flour. The decreased digestibility of starch in bread made with purple yam flour was due to the relatively intact starch granules from purple yam flour and possibly an inhibitory effect on digestive enzymes by purple yam flour.
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http://dx.doi.org/10.1016/j.foodchem.2019.01.025DOI Listing
June 2019
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