bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Meat Subtypes With Colorectal Polyp Prevalence: Finding From the Lanxi Pre-colorectal Cancer Cohort in China
Authors: Chai Xiaoyin , Li Yin , Yin Zihan , Wu Fei , Hu Peiling , Liu Xiaohui , Tong Shuhan , Zhuang Pan , Zhang Yu , Zheng Weifang , Jiao Jingjing
Published: March 2022

Background

Although the detrimental effect of red meat on colorectal cancer (CRC) incidence has been extensively reported, no previous studies have comprehensively linked different meat subtypes with colorectal polyp occurrence. The aim was to assess the association of meat and subtypes with colorectal polyp prevalence for the high-risk CRC Chinese population. Besides, we also focused on the association according to sizes, subsites, and multiplicity of polyps.

Methods

High-risk CRC patients aged 40–80 years were enrolled into the Lanxi Pre-colorectal Cancer Cohort (LP3C) between March 2018 and December 2019. Cross-sectional analyses were conducted by using the baseline data from LP3C. A validated food frequency questionnaire (FFQ) was employed to collect dietary information. Odds ratios (ORs) and 95% confidence intervals (95% CIs) of colorectal polyp prevalence were estimated by multivariate logistic regression.

Results

2,064 colorectal polyp cases were identified among 6,783 eligible participants in the survey of LP3C (March 2018 and December 2019). Total meat intake was positively related to rectum polyp prevalence (Pfor trend = 0.01) but was not linked to total colorectal polyps after multivariable adjustment. For meat subtypes, higher poultry consumption was significantly related to a higher polyp prevalence [ORQ4vs.Q1 (95% CI): 1.20 (1.02–1.42); Pfor trend = 0.03]. Processed red meat intake was linked to an increased small polyp prevalence (Pfor trend = 0.03) while unprocessed red meat had a relation with a higher rectum polyp prevalence (Pfor trend = 0.04). Furthermore, seafood intake had a significant association with a higher multiple polyp prevalence [ORQ4vs.Q1 (95% CI): 1.70 (1.31–2.21); Pfor trend < 0.001].

Conclusion

The finding was that poultry meat consumption was related to a higher polyp prevalence. Besides, total meat consumption, processed and unprocessed red meat consumption, seafood consumption had a positive relation with certain polyp subtypes prevalence. Generally recommending reducing total meat consumption, including poultry, processed and unprocessed red meat, and seafood intake, may prevent colorectal polyps.
Elaeagnus angustifolia Plant Extract Induces Apoptosis via P53 and Signal Transducer and Activator of Transcription 3 Signaling Pathways in Triple-Negative Breast Cancer Cells
Authors: Fouzat Arij , Hussein Ola Jihad , Gupta Ishita , Al-Farsi Halema F. , Khalil Ashraf , Al Moustafa Ala-Eddin
Published: March 2022

Elaeagnus angustifolia (EA) is used as an alternative medicine in the Middle East to manage numerous human diseases. We recently reported that EA flower extract inhibits cell proliferation and invasion of human oral and HER2-positive breast cancer cells. Nevertheless, the outcome of EA extract on triple-negative breast cancer (TNBC) cells has not been explored yet. We herein investigate the effect of the aqueous EA extract (100 and 200 μl/ml) on two TNBC cell lines (MDA-MB-231 and MDA-MB-436) for 48 h and explore its underlying molecular pathways. Our data revealed that EA extract suppresses cell proliferation by approximately 50% and alters cell-cycle progression of these two cancer cell lines. Additionally, EA extract induces cell apoptosis by 40–50%, accompanied by the upregulation of pro-apoptotic markers (Bax and cleaved caspase-8) and downregulation of the anti-apoptotic marker, Bcl-2. Moreover, EA extract inhibits colony formation compared to their matched control. More significantly, the molecular pathway analysis of EA-treated cells revealed that EA extract enhances p53 expression, while inhibiting the expression of total and phosphorylated Signal Transducer and Activator Of Transcription 3 (STAT3) in both cell lines, suggesting p53 and STAT3 are the main key players behind the biological events provoked by the extract in TNBC cells. Our findings implicate that EA flower extract may possess an important potential as an anticancer drug against TNBC.
Comparison of Computed and Acquired DWI in the Assessment of Rectal Cancer: Image Quality and Preoperative Staging
Authors: Xia Yihan , Wang Lan , Wu Zhiyuan , Tan Jingwen , Fu Meng , Fu Caixia , Pan Zilai , Zhu Lan , Yan Fuhua , Shen Hailin , Ma Qianchen , Cai Gang
Published: March 2022

Objective

The aim of the study was to evaluate the computed diffusion-weighted images (DWI) in image quality and diagnostic performance of rectal cancer by comparing with the acquired DWI.

Methods

A total of 103 consecutive patients with primary rectal cancer were enrolled in this study. All patients underwent two DWI sequences, namely, conventional acquisition with b = 0 and 1,000 s/mm2 (aDWIb1,000) and another with b = 0 and 700 s/mm2 on a 3.0T MR scanner (MAGNETOM Prisma; Siemens Healthcare, Germany). The images (b = 0 and 700 s/mm2) were used to compute the diffusion images with b value of 1,000 s/mm2 (cDWIb1,000). Qualitative and quantitative analysis of both computed and acquired DWI images was performed, namely, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and signal intensity ratio (SIR), and also diagnostic staging performance. Interclass correlation coefficients, weighted κ coefficient, Friedman test, Wilcoxon paired test, and McNemar or Fisher test were used for repeatability and comparison assessment.

Results

Compared with the aDWIb1,000 images, the cDWIb1,000 ones exhibited significant higher scores of subjective image quality (all P <0.050). SNR, SIR, and CNR of the cDWIb1,000 images were superior to those of the aDWIb1,000 ones (P <0.001). The overall diagnostic accuracy of computed images was higher than that of the aDWIb1,000 images in T stage (P <0.001), with markedly better sensitivity and specificity in distinguishing T1–2 tumors from the T3–4 ones (P <0.050).

Conclusion

cDWIb1,000 images from lower b values might be a useful alternative option and comparable to the acquired DWI, providing better image quality and diagnostic performance in preoperative rectal cancer staging.
Systemic Deficiency of PTEN Accelerates Breast Cancer Growth and Metastasis
Authors: Chen Jing , Sun Jingjing , Wang Qunfeng , Du Yanze , Cheng Jie , Yi Juan , Xie Bei , Jin Suya , Chen Gang , Wang Lina , Wang Xiaoyuan , Wei Hulai
Published: March 2022

Mutation or loss of the tumor suppressor gene PTEN or its functional status in tumor stromal cells may affect tumor occurrence, development, invasion, and metastasis, in which, however, the role of overall low PTEN expression, mutation, or deletion in the tumor-bearing host has rarely been reported. Breast cancer is a common highly invasive metastatic tumor. We therefore treated mouse breast cancer 4T1 cells with the specific PTEN inhibitor VO-OHpic to study the effects of PTEN suppression or deletion on malignant behavior in vivo and in vitro. VO-OHpic effectively inhibited PTEN gene/protein expression in 4T1 cells, accelerated cell proliferation, and enhanced cell migration and invasion. We also transplanted 4T1 cells with VO-OHpic-inhibited PTEN into mice to create orthotopic and metastatic breast cancer models. The proliferation of 4T1 cells in mouse mammary gland was increased and distant metastasis was enhanced, with metastatic foci in the lung, liver, and intestinal tract. In addition, injection of mice with VO-OHpic to inhibit PTEN in the overall microenvironment accelerated the proliferation of transplanted 4T1 cells and enhanced distant metastasis and the formation of metastatic tumors. Metastatic foci formed in the lung, liver, intestine, thymus, and brain, and PTEN levels in the organ/tissues were negatively associated with the formation of metastatic foci. Similarly, inoculation of PTEN-deficient 4T1 cells into systemic PTEN-inhibited mice further enhanced the orthotopic growth and distant metastasis of 4T1 breast cancer. VO-OHpic inhibition of PTEN in 4T1 cells was also associated with significantly increased phosphorylation of Akt and phosphoinositide 3-kinase (PI3K), suggesting that inhibition of PTEN could activate the PI3K-Akt pathway, as a key signaling pathway regulating cell proliferation and death. These results confirmed that functional loss or deletion of the tumor suppressor gene PTEN significantly enhanced the proliferation, invasion, and metastasis of 4T1 cells. Systemic decrease or deletion of PTEN in the organism or organ/tissue microenvironment was conducive to the proliferation of breast cancer cells in situ and distant metastasis. These results suggest that, as well the PTEN in cancer cells the systemic microenvironment PTEN intensely mediates the proliferation, invasion and metastasis of mouse breast cancer cells via regulating the PI3K-Akt signaling pathway.
Establish of an Initial Platinum-Resistance Predictor in High-Grade Serous Ovarian Cancer Patients Regardless of Homologous Recombination Deficiency Status
Authors: Li Yongmei , Nie Yufei , Guo Hongyan , Guo Hua , Ha Chunfang , Li Yuan
Published: March 2022

Backgrounds

Ovarian cancer (OC) is still the leading aggressive and lethal disease of gynecological cancers, and platinum-based regimes are the standard treatments. However, nearly 20%–30% of patients with OC are initial platinum resistant (IPR), and there is a lack of valid tools to predict whether they will be primary platinum resistant or not prior to chemotherapy.

Methods

Transcriptome data from The Cancer Genome Atlas (TCGA) was downloaded as the training data, and transcriptome data of GSE15622, GSE102073, GSE19829, and GSE26712 were retrieved from Gene Expression Omnibus (GEO) as the validation cohorts. Differentially expressed genes (DEGs) were selected between platinum-sensitive and platinum-resistant patients from the training cohort, and multiple machine-learning algorithms [including random forest, XGboost, and least absolute shrinkage and selection operator (LASSO) regression] were utilized to determine the candidate genes from DEGs. Then, we applied logistic regression to establish the IPR signature based on the expression. Finally, comprehensive clinical, genomic, and survival feature were analyzed to understand the application value of the established IPR signature.

Results

A total of 532 DEGs were identified between platinum-resistant and platinum-sensitive samples, and 11 of them were shared by these three-machine learning algorithms and utilized to construct an IPR prediction signature. The area under receiver operating characteristic curve (AUC) was 0.841 and 0.796 in the training and validation cohorts, respectively. Notably, the prediction capacity of this signature was stable and robust regardless of the patients’ homologous recombination deficiency (HRD) and mutation burden status. Meanwhile, the genomic feature was concordant between samples with high- or low-IPR signature, except a significantly higher prevalence of gain at Chr19q.12 (regions including CCNE1) in the high-IPR signature samples. The efficacy of prediction of platinum resistance of IPR signature successfully transferred to the precise survival prediction, with the AUC of 0.71, 0.72, and 0.66 to predict 1-, 3-, and 5-year survival, respectively. At last, we found a significantly different tumor-infiltrated lymphocytes feature, including lower abundance of CD4+ naive T cells in the samples with high-IPR signature. A relatively lower tumor immune dysfunction and exclusion (TIDE) value and more sensitivity to multiple therapies including Gefitinib may suggest the potency to transfer from platinum-based therapy to immunotherapy or target therapies in patients with high-IPR signature.

Conclusion

Our study established an IPR signature based on the expression of 11 genes that could stably and robustly distinguish OC patients with IPR and/or poor outcomes, which may guide therapeutic regimes tailoring.
GFAPδ: A Promising Biomarker and Therapeutic Target in Glioblastoma
Authors: Radu Roxana , Petrescu George E. D. , Gorgan Radu M. , Brehar Felix M.
Published: March 2022

GFAPδ, the delta isoform of the glial fibrillary acidic protein, is mainly expressed in the subventricular zone of the brain, together with other neural stem cell markers like nestin. The authors of this paper were among the first that described in detail the expression of GFAPδ and its correlation with malignancy and invasiveness in cerebral astrocytoma. Later, several papers confirmed these findings, showing that the alternative splice variant GFAPδ is overexpressed in glioblastoma (CNS WHO grade 4) compared with lower grade gliomas. Other studies suggested that a high GFAPδ/α ratio is associated with a more malignant and invasive behavior of glioma cells. Moreover, the changing of GFAPδ/α ratio affects the expression of high-malignant genes. It is now suggested that discriminating between predominant GFAP isoforms, GFAPδ or GFAPα, is useful for assessing the malignancy state of astrocytoma, and may even contribute to the classification of gliomas. Therefore, the purpose of this paper is to review the literature with emphasize on the role of GFAPδ as a potential biomarker, and as a possible therapeutic target in glioblastoma.
Prenatal Exposure to Air Pollution and Immune Thrombocytopenia: A Nationwide Population-Based Cohort Study
Authors: Yen Hsin-Chien , Lin Chien-Heng , Lin Ming-Chih , Hsu Ya-Chi , Lin Yi-Hsuan
Published: March 2022

Introduction

Immune thrombocytopenia (ITP) is one of the most common hematologic disorders in children. However, its etiology is still unclear. Epidemiological studies have shown that air pollution is a plausible risk factor in stimulation of oxidative stress, induction of inflammation, and onset of autoimmune diseases. The objective of this article is to examine the effects of prenatal exposure to air pollution on the occurrence of immune thrombocytopenia (ITP) in children.

Materials and Methods

This is a nationwide, population-based, matched case-control study. Using data from Taiwan’s Maternal and Child Health Database (MCHD), we identified 427 children with ITP less than 6 years of age and age-matched controls without ITP between 2004 and 2016. Levels of prenatal exposure to air pollutants were obtained from 71 Environmental Protection Administration monitoring stations across Taiwan according to the maternal residence during pregnancy. Patients who had outpatient visits or admission with diagnosis of ITP and subsequently received first-line treatment of intravenous immunoglobulin or oral glucocorticoids were defined as incidence cases.

Results

Prenatal exposure to particulate matter <10 μm (PM10) in diameter and the pollutant standard index (PSI) increased the risk of childhood ITP. Conversely, carbon monoxide (CO) exposure during pregnancy was negatively associated with the development of ITP.

Conclusion

Certain prenatal air pollutant exposure may increase the incidence of ITP in children.
Early Immunomodulatory Effects of Different Natural Surfactant Preparations in Preterms With Respiratory Distress
Authors: Yalaz Mehmet , Tanriverdi Sema , Uygur Özgün , Altun Köroğlu Özge , Azarsiz Elif , Aksu Guzide , Kültürsay Nilgün
Published: March 2022

Background

Respiratory distress syndrome (RDS) is the most common respiratory disease in premature infants. Exogenous natural surfactant preparations are used in the treatment of RDS. In recent years, it has become increasingly evident that surfactant plays an immunoregulatory role.

Objectives

The aim of this study was to evaluate cytokine and chemokine response following three different regimens of natural surfactant treatment in preterm newborns with RDS.

Methods

Premature newborns below 32 weeks of gestation who were intubated for RDS and given early surfactant rescue therapy were included in the study. Newborns were randomly divided into three groups and Beractant 100 mg/kg (B-100), Poractant alfa 100 mg/kg (Pα-100) and Poractant alfa 200 mg/kg (Pα-200) were administered intratracheally. Blood samples and transtracheal aspirates (TA) were collected just before and 4–6 h after the surfactant treatment. Total eosinophil count, inducible T Cell alpha chemoattractant (ITaC), macrophage inflammatory protein 3 beta (MIP3b), interleukins (IL) 5, 8, 9, 10, 13, immunoglobulin E (IgE), interferon gamma (IFN-γ), eotaxin and tumor necrosis factor beta-1 (TGF-β1) were measured from blood and tracheal aspirate samples.

Results

A total of 45 infants, 15 in each group, were included in the study. Mean gestational age, birth weight, antenatal, demographic and clinical characteristics of the study groups were similar. IFNγ concentration and eosinophil counts in TA decreased after surfactant replacement in all groups, especially in the infants treated with Pα-100 and Pα-200. Eotaxin, TGF beta and IL-8 concentrations in TA increased significantly in the infants treated with Pα-100 and Pα-200. IL-9 levels in TA decreased in the B-100 group but increased in the Pα-100 and Pα-200 groups. Blood levels of cytokines and chemokines showed significantly decreased levels of ITaC and MIP3b only in the B-100 group, but no significant change was observed in the Pα-100 and Pα-200 groups.

Conclusion

In our study, the different immunomodulatory effects of natural surfactant preparations on newborn lung is proven. We found that Poractant α, one of the natural surfactant preparations, shifted the lung immune system toward TH2.
Efficacy and Mechanism of Buyang Huanwu Decoction in Patients With Ischemic Heart Failure: A Randomized, Double-Blind, Placebo-Controlled Trial Combined With Proteomic Analysis
Authors: Zhu Mingjun , Wei Jingjing , Li Ying , Wang Yongxia , Ren Junguo , Li Bin , Ma Bo , Wang Xinlu , Qiao Lijie , Zhou Cheng , Liu Jianxun
Published: March 2022

Objective: Buyang Huanwu Decoction (BYHW), a famous herbal prescription in traditional Chinese medicine (TCM), has been used for 200 years for treating ischemic heart failure (IHF). This study aims to assess the efficacy and safety of BYHW combined with guideline-guided pharmacotherapy in patients with IHF and explore the biological mechanism by which BYHW exerts its efficacy.

Methods: In the multicenter, double-blind, randomized controlled trial, a total of 80 patients with IHF were randomized to receive BYHW or placebo for 3 months. The primary efficacy endpoints were New York Heart Association (NYHA) classification, TCM syndrome scores, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), whereas the mechanism exploration endpoints included energy metabolism parameters and coagulation function parameters. In addition, we performed the proteomic study of the serum of patients after treatment by label-free quantification technology to verify the candidate target proteins and pathways.

Results: After 3 months of treatment, the NYHA classification, TCM syndrome scores, and the percentage of subjects with at least 30% reduction in NT-ProBNP were significantly improved in the BYHW group, compared with the control group (p < 0.05); BYHW treatment also significantly regulated blood glucose, blood lipid levels, ameliorated energy metabolism and improved coagulation function parameters. There were no significant differences in safety endpoints between the two groups. In addition, we obtained 56 differentially expressed proteins by proteomics, including 20 upregulated proteins and 36 downregulated proteins. Bioinformatic analysis revealed the mechanism of BYHW treatment was significantly related to complement and coagulation cascades, cholesterol metabolism, NF-kappa B signaling pathway, PI3K-Akt signaling pathway, and metabolic pathways. Among these differentially regulated proteins, fibrinogen gamma (FGG), fibrinogen beta (FGB), Carboxypeptidase B2 (CPB2), Coagulation factor XIII A (F13A1), Intercellular adhesion molecule1 (ICAM1), Apolipoprotein C-II(APOC2), Apolipoprotein C-I(APOC1), and CD44 were found to be signature proteins associated with the efficacy of BYHW against IHF.

Conclusion: BYHW treatment can further improve cardiac dysfunction and clinical symptoms in IHF based on standard therapy without apparent adverse effects. Additionally, BYHW may play a therapeutic role in IHF by improving energy metabolism and regulating coagulation function through multiple targets and pathways.
Efficacy and Adverse Events of PD-1 Inhibitors in Patients With Advanced Urothelial Carcinoma From a Real-World Experience
Authors: Sun Fengze , Wang Dawei , Liu Aina , Wang Tianqi , Zhang Dongxu , Yao Huibao , Sun Kai , Zhou Zhongbao , Lu Guoliang , Wu Jitao
Published: March 2022

Background: Programmed death 1 (PD-1) inhibitors—tislelizumab, toripalimab, camrelizumab, and sintilimab—are used for advanced urothelial carcinoma (UC) in China. To date, the efficacy and adverse events (AEs) of these PD-1 inhibitors have been poorly reported for advanced UC.

Methods: We reviewed 118 patients treated with PD-1 inhibitors for advanced UC from July 2019 to October 2021 at Yantai Yuhuangding Hospital. Patient data were obtained from hospital records and telephone follow-ups. The safety and efficacy of PD-1 inhibitors were assessed by RESIST and Common Terminology Criteria for Adverse Events (version 4.0), respectively.

Results: During a median follow-up period of 6 months, 112 patients (95%) experienced AEs; of these, 104 (88%) were grade 1–2 AEs, and 60 (51%) were grade 3–4 AEs. The most common AE was anemia, and no patients died as a result of treatment. A subanalysis according to treatment method (PD-1 inhibitor vs. PD-1 inhibitor plus chemotherapy) was performed. The incidence of grade 1–2 AEs was not different between the groups (85% vs. 94%), but combination therapy significantly increased grade 3–4 AEs (32% vs. 89%). Monotherapy and combination therapy also did not differ with regard to immune-related AEs of grades 1–2 (13% vs. 22%) or grades 3–4 (1% vs. 6%). In efficacy, complete response was not observed, but 33 patients (28%) had partial response, 30 (25%) had stable disease, and 47 had progressive disease (40%). The overall response and disease control rates were 28% and 53%, respectively. The preliminary efficacy of disease control was better with combination therapy versus monotherapy (78 vs. 43%).

Conclusion: PD-1 inhibitors show promising tolerance and efficacy in advanced UC. PD-1 inhibitors combined with chemotherapy offered better disease control but had more grade 3–4 AEs. The clinical use of combination therapy warrants caution.
Upregulated Linc01836 in Serum Promisingly Serving as a Diagnostic and Prognostic Biomarker for Colorectal Cancer
Authors: Shen Lei , Zong Wei , Feng Wei , Chen Erlin , Ma Shuo , Yuan Jie , Wang Guihua , Gu Xinliang , Shen Xianjuan , Ju Shaoqing
Published: March 2022

Objectives: Colorectal cancer (CRC) is a common carcinoma of the gastrointestinal tract with high incidence and mortality worldwide. Studies have shown that long noncoding RNAs (lncRNAs) play important roles in CRC. Our purpose is to investigate the potential of serum Linc01836 as a diagnostic and prognostic marker in CRC.

Methods: We evaluated the expression of Linc01836 via quantitative real-time polymerase chain reaction (qRT-PCR). The serum CEA, CA19-9, Cyfra21-1, and CA72-4 concentrations were measured by Architect I4000 SR. Receiver operating characteristic (ROC) curves were plotted to estimate the diagnostic value in CRC. Relationship between serum Linc01836 expression and clinicopathological characteristics of CRC cases was analyzed via chi-square test. The underlying mechanism of Linc01836 on the development and prognosis in CRC was predicted by bioinformatic analysis.

Results: The method of qRT-PCR for Linc01836 detection was confirmed with high precision and specificity. Serum Linc01836 expression in CRC patients was significantly higher than that in healthy donors (p < 0.0001) and benign patients (p < 0.0001), and declined after resection (p < 0.01). High expression of Linc01836 was associated with histological stage (p = 0.002) and lymph node metastasis (p = 0.006). In addition, serum Linc01836 could effectively differentiate CRC patients from the healthy folks, with favorable area under the curve (AUC) of 0.809 (95% CI: 0.757–0.861, p < 0.001). What is more, the combination of serum Linc01836, CEA, and Cyfra21-1 could improve diagnostic sensitivity (92.0%). Linc01836 was averagely located in the nucleus and cytoplasm, suggesting that it might participate in CRC progression and prognosis through the crosstalk among lncRNAs, miRNAs, and mRNAs.

Conclusion: Linc01836 may serve as a valuable noninvasive biomarker for population screening, early detection, and clinical surveillance of CRC.
Nutraceuticals in the Modulation of the Intestinal Microbiota: Current Status and Future Directions
Authors: Spisni Enzo , Turroni Silvia , Alvisi Patrizia , Spigarelli Renato , Azzinnari Demetrio , Ayala Dario , Imbesi Veronica , Valerii Maria Chiara
Published: March 2022

Pharmaceutical interest in the human intestinal microbiota has increased considerably, because of the increasing number of studies linking the human intestinal microbial ecology to an increasing number of non-communicable diseases. Many efforts at modulating the gut microbiota have been made using probiotics, prebiotics and recently postbiotics. However, there are other, still little-explored opportunities from a pharmaceutical point of view, which appear promising to obtain modifications of the microbiota structure and functions. This review summarizes all in vitro, in vivo and clinical studies demonstrating the possibility to positively modulate the intestinal microbiota by using probiotics, prebiotics, postbiotics, essential oils, fungus and officinal plants. For the future, clinical studies investigating the ability to impact the intestinal microbiota especially by using fungus, officinal and aromatic plants or their extracts are required. This knowledge could lead to effective microbiome modulations that might support the pharmacological therapy of most non-communicable diseases in a near future.
A Pharmacoinformatics Analysis of Artemisinin Targets and de novo Design of Hits for Treating Ulcerative Colitis
Authors: Tian Rui , Li Yufei , Wang Xiaofeng , Li Jiajun , Li Yingqian , Bei Shaosheng , Li Huashan
Published: March 2022

Ulcerative colitis (UC), as an intractably treated disease, seriously affects the quality of life of patients and has an increase in terms of incidence and prevalence annually. However, due to the lack of a direct etiology and drug-induced side effects, the medical treatment of UC falls into a bottleneck. There are many natural phytochemicals with the potential to regulate immune function in nature. Herein, a potential mechanism of artemisinin in the treatment of UC and potential druggability compounds with an artemisinin peroxide bond were discussed and predicted based on computer-aided drug design (CADD) technology by using the methods of network pharmacology, molecular docking, de novo drug structure design and molecular dynamics through the integration of artemisinin related targets from TCMSP, ChEMBL and HERB databases. The networks were constructed based on 50 artemisinin-disease intersection targets related to inflammation, cytokines, proliferation and apoptosis, showing the importance of GALNT2, BMP7 and TGFBR2 in the treatment of disease, which may be due to the occupation of the ricin B-type lectin domain of GALNT2 by artemisinin compounds or de novo designed candidates. This result could guide the direction of experiments and actual case studies in the future. This study provides a new route for the application of artemisinin and the development of drugs.
A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels
Authors: Valdés-Jiménez Alejandro , Jiménez-González Daniel , Kiper Aytug K. , Rinné Susanne , Decher Niels , González Wendy , Reyes-Parada Miguel , Núñez-Vivanco Gabriel
Published: March 2022

The identification of similar three-dimensional (3D) amino acid patterns among different proteins might be helpful to explain the polypharmacological profile of many currently used drugs. Also, it would be a reasonable first step for the design of novel multitarget compounds. Most of the current computational tools employed for this aim are limited to the comparisons among known binding sites, and do not consider several additional important 3D patterns such as allosteric sites or other conserved motifs. In the present work, we introduce Geomfinder2.0, which is a new and improved version of our previously described algorithm for the deep exploration and discovery of similar and druggable 3D patterns. As compared with the original version, substantial improvements that have been incorporated to our software allow: (i) to compare quaternary structures, (ii) to deal with a list of pairs of structures, (iii) to know how druggable is the zone where similar 3D patterns are detected and (iv) to significantly reduce the execution time. Thus, the new algorithm achieves up to 353x speedup as compared to the previous sequential version, allowing the exploration of a significant number of quaternary structures in a reasonable time. In order to illustrate the potential of the updated Geomfinder version, we show a case of use in which similar 3D patterns were detected in the cardiac ions channels NaV1.5 and TASK-1. These channels are quite different in terms of structure, sequence and function and both have been regarded as important targets for drugs aimed at treating atrial fibrillation. Finally, we describe the in vitro effects of tafluprost (a drug currently used to treat glaucoma, which was identified as a novel putative ligand of NaV1.5 and TASK-1) upon both ion channels’ activity and discuss its possible repositioning as a novel antiarrhythmic drug.
Pterostilbene in Combination With Mitochondrial Cofactors Improve Mitochondrial Function in Cellular Models of Mitochondrial Diseases
Authors: Suárez-Rivero Juan M. , Pastor-Maldonado Carmen J. , Romero-González Ana , Gómez-Fernandez David , Povea-Cabello Suleva , Álvarez-Córdoba Mónica , Villalón-García Irene , Talaverón-Rey Marta , Suárez-Carrillo Alejandra , Munuera-Cabeza Manuel , Sánchez-Alcázar José A.
Published: March 2022

Mitochondrial diseases are genetic disorders caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode mitochondrial structural or functional proteins. Although considered “rare” due to their low incidence, such diseases affect thousands of patients’ lives worldwide. Despite intensive research efforts, most mitochondrial diseases are still incurable. Recent studies have proposed the modulation of cellular compensatory pathways such as mitophagy, AMP-activated protein kinase (AMPK) activation or the mitochondrial unfolded protein response (UPRmt) as novel therapeutic approaches for the treatment of these pathologies. UPRmt is an intracellular compensatory pathway that signals mitochondrial stress to the nucleus for the activation of mitochondrial proteostasis mechanisms including chaperones, proteases and antioxidants. In this work a potentially beneficial molecule, pterostilbene (a resveratrol analogue), was identified as mitochondrial booster in drug screenings. The positive effects of pterostilbene were significantly increased in combination with a mitochondrial cocktail (CoC3) consisting of: pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid and l-carnitine. CoC3 increases sirtuins’ activity and UPRmt activation, thus improving pathological alterations in mutant fibroblasts and induced neurons.
Mechanistic Insights Into Co-Administration of Allosteric and Orthosteric Drugs to Overcome Drug-Resistance in T315I BCR-ABL1
Authors: Zhang Hao , Zhu Mingsheng , Li Mingzi , Ni Duan , Wang Yuanhao , Deng Liping , Du Kui , Lu Shaoyong , Shi Hui , Cai Chen
Published: March 2022

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, driven by the BCR-ABL1 fusion oncoprotein. The discovery of orthosteric BCR-ABL1 tyrosine kinase inhibitors (TKIs) targeting its active ATP-binding pocket, such as first-generation Imatinib and second-generation Nilotinib (NIL), has profoundly revolutionized the therapeutic landscape of CML. However, currently targeted therapeutics still face considerable challenges with the inevitable emergence of drug-resistant mutations within BCR-ABL1. One of the most common resistant mutations in BCR-ABL1 is the T315I gatekeeper mutation, which confers resistance to most current TKIs in use. To resolve such conundrum, co-administration of orthosteric TKIs and allosteric drugs offers a novel paradigm to tackle drug resistance. Remarkably, previous studies have confirmed that the dual targeting BCR-ABL1 utilizing orthosteric TKI NIL and allosteric inhibitor ABL001 resulted in eradication of the CML xenograft tumors, exhibiting promising therapeutic potential. Previous studies have demonstrated the cooperated mechanism of two drugs. However, the conformational landscapes of synergistic effects remain unclear, hampering future efforts in optimizations and improvements. Hence, extensive large-scale molecular dynamics (MD) simulations of wide type (WT), WT-NIL, T315I, T315I-NIL, T315I-ABL001 and T315I-ABL001-NIL systems were carried out in an attempt to address such question. Simulation data revealed that the dynamic landscape of NIL-bound BCR-ABL1 was significantly reshaped upon ABL001 binding, as it shifted from an active conformation towards an inactive conformation. The community network of allosteric signaling was analyzed to elucidate the atomistic overview of allosteric regulation within BCR-ABL1. Moreover, binding free energy analysis unveiled that the affinity of NIL to BCR-ABL1 increased by the induction of ABL001, which led to its favorable binding and the release of drug resistance. The findings uncovered the in-depth structural mechanisms underpinning dual-targeting towards T315I BCR-ABL1 to overcome its drug resistance and will offer guidance for the rational design of next generations of BCR-ABL1 modulators and future combinatory therapeutic regimens.
Polarimetric Imaging Through Scattering Media: A Review
Authors: Li Xiaobo , Han Yilin , Wang Hongyuan , Liu Tiegen , Chen Shih-Chi , Hu Haofeng
Published: March 2022

Imaging in scattering media has been a challenging and important subject in optical science. In scattering media, the image quality is often severely degraded by the scattering and absorption effects owing to the small particles and the resulting nonuniform distribution of the intensity or polarization properties. This study reviews the recent development in polarimetric imaging techniques that address these challenges. Specifically, based on the polarization properties of the backscattering light, polarimetric methods can estimate the intensity level of the backscattering and the transmittance of the media. They can also separate the target signal from the undesired ones to achieve high-quality imaging. In addition, the different designs of the polarimetric imaging systems offer additional metrics, for example, the degree/angle of polarization, to recover images with high fidelity. We first introduce the physical degradation models in scattering media. Secondly, we apply the models in different polarimetric imaging systems, such as polarization difference, Stokes vector, Mueller matrix, and deep learning-based systems. Lastly, we provide a model selection guideline and future research directions in polarimetric imaging.
A 6D Fractional-Order Memristive Hopfield Neural Network and its Application in Image Encryption
Authors: Yu Fei , Kong Xinxin , Chen Huifeng , Yu Qiulin , Cai Shuo , Huang Yuanyuan , Du Sichun
Published: March 2022

This paper proposes a new memristor model and uses pinched hysteresis loops (PHL) to prove the memristor characteristics of the model. Then, a new 6D fractional-order memristive Hopfield neural network (6D-FMHNN) is presented by using this memristor to simulate the induced current, and the bifurcation characteristics and coexistence attractor characteristics of fractional memristor Hopfield neural network is studied. Because this 6D-FMHNN has chaotic characteristics, we also use this 6D-FMHNN to generate a random number and apply it to the field of image encryption. We make a series of analysis on the randomness of random numbers and the security of image encryption, and prove that the encryption algorithm using this 6D-FMHNN is safe and sensitive to the key.
Influence of Nutrient (NPK) Factors on Growth, and Pharmacodynamic Component Biosynthesis of Atractylodes chinensis: An Insight on Acetyl-CoA Carboxylase (ACC), 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGR), and Farnesyl Pyrophosphate Synthase (FPPS) Signaling Responses
Authors: Sun Jin , Luo Haoming , Jiang Yuxin , Wang Lijuan , Xiao Chunping , Weng Lili
Published: March 2022

In the planting of crops, especially medicinal plants, formula fertilization is important for improving the utilization rate of elements, soil quality, crop yield, and quality. Therefore, it is important to study targeted fertilizer application schemes for sustainable agricultural development and environmental protection. In this study, an L9(34) orthogonal design was used to conduct a field experiment to study the effects of NPK combined application on the growth and pharmacodynamic component biosynthesis of Atractylodes chinensis (DC.) Koidz. Results showed that after applying a base fertilizer at the seedling stage (late May), topdressing at the vegetative stage (late June) and fruit stage (late August) was beneficial to the growth and development of A. chinensis. The high concentrations of phosphorus were conducive to the accumulation of yield and effective components, and the best harvest time was after late October. Principal component analysis (PCA) showed that the comprehensive score of T6 treatment was the highest, indicating that the optimal fertilization scheme for the high yield and high quality of A. chinensis was (N2P3K1): N 180, P2O5 225, and K2O 105 kg⋅ha–1. A signaling response analysis showed that during the growth and development of A. chinensis, the T6 fertilization scheme had clear effects on the activity and gene expression of the key enzymes acetyl-CoA carboxylase (ACC) and farnesyl pyrophosphate synthase (FPPS). Under the T4 [(N2P1K2): N 180, P2O5 75, and K2O 210 kg⋅ha–1] fertilization scheme, the activity and gene expression of the key enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) were higher. Moreover, ACC was closely related to the synthesis of the polyacetylene component atractylodin, and FPPS played an important regulatory role in the synthesis of sesquiterpene components atractylenolide II, β-eudesmol, and atractylon. In summary, the high phosphorus fertilization scheme T6 could notably increase the yield of A. chinensis, and promote the accumulation of polyacetylene and sesquiterpene volatile oils by increasing the expression of ACC and FPPS. Therefore, we postulate that the precise application of nutrients (NPK) plays a vital role in the yield formation and quality regulation of A. chinensis.
The Nitrate Transporter MtNPF6.8 Is a Master Sensor of Nitrate Signal in the Primary Root Tip of Medicago truncatula
Authors: Zang Lili , Tarkowski Łukasz Paweł , Morère-Le Paven Marie-Christine , Zivy Michel , Balliau Thierry , Clochard Thibault , Bahut Muriel , Balzergue Sandrine , Pelletier Sandra , Landès Claudine , Limami Anis M. , Montrichard Françoise
Published: March 2022

Nitrate is not only an essential nutrient for plants, but also a signal involved in plant development. We have previously shown in the model legume Medicago truncatula, that the nitrate signal, which restricts primary root growth, is mediated by MtNPF6.8, a nitrate transporter. Nitrate signal also induces changes in reactive oxygen species accumulation in the root tip due to changes in cell wall peroxidase (PODs) activity. Thus, it was interesting to determine the importance of the role of MtNPF6.8 in the regulation of the root growth by nitrate and identify the POD isoforms responsible for the changes in POD activity. For this purpose, we compared in M. truncatula a npf6.8 mutant and nitrate insensitive line deficient in MtNPF6.8 and the corresponding wild and sensitive genotype for their transcriptomic and proteomic responses to nitrate. Interestingly, only 13 transcripts and no protein were differently accumulated in the primary root tip of the npf6.8-3 mutant line in response to nitrate. The sensitivity of the primary root tip to nitrate appeared therefore to be strongly linked to the integrity of MtNPF6.8 which acts as a master mediator of the nitrate signal involved in the control of the root system architecture. In parallel, 7,259 and 493 genes responded, respectively, at the level of transcripts or proteins in the wild type, 196 genes being identified by both their transcript and protein. By focusing on these 196 genes, a concordance of expression was observed for most of them with 143 genes being up-regulated and 51 being down-regulated at the two gene expression levels. Their ontology analysis uncovered a high enrichment in POD genes, allowing the identification of POD candidates involved in the changes in POD activity previously observed in response to nitrate.
Root Reinforcement Improved Performance, Productivity, and Grain Bioactive Quality of Field-Droughted Quinoa (Chenopodium quinoa)
Authors: Toubali Salma , Ait-El-Mokhtar Mohamed , Boutasknit Abderrahim , Anli Mohamed , Ait-Rahou Youssef , Benaffari Wissal , Ben-Ahmed Hela , Mitsui Toshiaki , Baslam Marouane , Meddich Abdelilah
Published: March 2022

Modern agriculture is facing multiple and complex challenges and has to produce more food and fiber to feed a growing population. Increasingly volatile weather and more extreme events such as droughts can reduce crop productivity. This implies the need for significant increases in production and the adoption of more efficient and sustainable production methods and adaptation to climate change. A new technological and environment-friendly management technique to improve the tolerance of quinoa grown to maturity is proposed using native microbial biostimulants (arbuscular mycorrhizal fungi; AMF) alone, in the consortium, or in combination with compost (Comp) as an organic matter source under two water treatments (normal irrigation and drought stress (DS)). Compared with controls, growth, grain yield, and all physiological traits under DS were significantly decreased while hydrogen peroxide, malondialdehyde, and antioxidative enzymatic functions were significantly increased. Under DS, biofertilizer application reverted physiological activities to normal levels and potentially strengthened quinoa’s adaptability to water shortage as compared to untreated plants. The dual combination yielded a 97% improvement in grain dry weight. Moreover, the effectiveness of microbial and compost biostimulants as a biological tool improves grain quality and limits soil degradation under DS. Elemental concentrations, particularly macronutrients, antioxidant potential (1,1-diphenyl-2-picrylhydrazyl radical scavenging activity), and bioactive compounds (phenol and flavonoid content), were accumulated at higher levels in biofertilizer-treated quinoa grain than in untreated controls. The effects of AMF + Comp on post-harvest soil fertility traits were the most positive, with significant increases in total phosphorus (47%) and organic matter (200%) content under drought conditions. Taken together, our data demonstrate that drought stress strongly influences the physiological traits, yield, and quality of quinoa. Microbial and compost biostimulation could be an effective alternative to ensure greater recovery capability, thereby maintaining relatively high levels of grain production. Our study shows that aboveground stress responses in quinoa can be modulated by signals from the microbial/compost-treated root. Further, quinoa grains are generally of higher nutritive quality when amended and inoculated with AMF as compared to non-inoculated and compost-free plants.
High Resolution Quantitative Trait Locus Mapping and Whole Genome Sequencing Enable the Design of an Anthocyanidin Reductase-Specific Homoeo-Allelic Marker for Fruit Colour Improvement in Octoploid Strawberry (Fragaria × ananassa)
Authors: Labadie Marc , Vallin Guillaume , Potier Aline , Petit Aurélie , Ring Ludwig , Hoffmann Thomas , Gaston Amèlia , Munoz-Blanco Juan , Caballero José L. , Schwab Wilfried , Rothan Christophe , Denoyes Béatrice
Published: March 2022

Fruit colour is central to the sensorial and nutritional quality of strawberry fruit and is therefore a major target in breeding programmes of the octoploid cultivated strawberry (Fragaria × ananassa). The red colour of the fruit is caused by the accumulation of anthocyanins, which are water-soluble flavonoids. To facilitate molecular breeding, here we have mapped with high resolution fruit colour quantitative trait loci (QTLs) (COLOUR, scored visually as in selection programmes) and associated flavonoid metabolic QTLs (5 anthocyanins compounds together with 8 flavonols and flavan-3-ols) to specific subgenomes of cultivated strawberry. Two main colour-related QTLs were located on the LG3A linkage group (Fragaria vesca subgenome). Genetic mapping, transcriptome analysis and whole genome sequencing enabled the detection of a homoeo-allelic variant of ANTHOCYANIDIN REDUCTASE (ANR) underlying the major male M3A COLOUR and pelargonidin-3-glucoside (PgGs) QTLs (up to ∼20% of explained variance). Consistent with previously published functional studies, ANR transcript abundance was inversely related with PgGs content in contrasted progeny individuals. Genetic segregation analyses further indicated that a molecular marker designed using an 18 bp deletion found in the 5′UTR of the candidate ANR homoeo-allelic variant is effective in identifying genotypes with intense red fruit colour. Our study provides insights into the genetic and molecular control of colour-related traits in strawberry and further defines a genetic marker for marker-assisted selection of new strawberry varieties with improved colour. The QTLs detected and the underlying candidate genes are different from those described to date, emphasising the importance of screening a wide diversity of genetic resources in strawberry.
Associations Between Sign Language Skills and Resting-State Functional Connectivity in Deaf Early Signers
Authors: Holmer Emil , Schönström Krister , Andin Josefine
Published: March 2022

The processing of a language involves a neural language network including temporal, parietal, and frontal cortical regions. This applies to spoken as well as signed languages. Previous research suggests that spoken language proficiency is associated with resting-state functional connectivity (rsFC) between language regions and other regions of the brain. Given the similarities in neural activation for spoken and signed languages, rsFC-behavior associations should also exist for sign language tasks. In this study, we explored the associations between rsFC and two types of linguistic skills in sign language: phonological processing skill and accuracy in elicited sentence production. Fifteen adult, deaf early signers were enrolled in a resting-state functional magnetic resonance imaging (fMRI) study. In addition to fMRI data, behavioral tests of sign language phonological processing and sentence reproduction were administered. Using seed-to-voxel connectivity analysis, we investigated associations between behavioral proficiency and rsFC from language-relevant nodes: bilateral inferior frontal gyrus (IFG) and posterior superior temporal gyrus (STG). Results showed that worse sentence processing skill was associated with stronger positive rsFC between the left IFG and left sensorimotor regions. Further, sign language phonological processing skill was associated with positive rsFC from right IFG to middle frontal gyrus/frontal pole although this association could possibly be explained by domain-general cognitive functions. Our findings suggest a possible connection between rsFC and developmental language outcomes in deaf individuals.