bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects
Authors: Okabe Keisuke , Yaku Keisuke , Uchida Yoshiaki , Fukamizu Yuichiro , Sato Toshiya , Sakurai Takanobu , Tobe Kazuyuki , Nakagawa Takashi 
Published: April 2022

Nicotinamide mononucleotide (NNM) is an orally bioavailable NAD+ precursor that has demonstrated beneficial effects against aging and aging-associated diseases in animal models. NMN is ultimately converted to NAD+, a redox cofactor that mediates many metabolic enzymes. NAD+ also serves as the substrate for poly(ADP-ribose) polymerase (PARP) and sirtuins, and regulates various biological processes, such as metabolism, DNA repair, gene expression, and stress responses. Previous mouse models showed that NMN administration can increase NAD+ in various organs and ameliorate aging-related diseases, such as obesity, diabetes, heart failure, stroke, kidney failure, and Alzheimer’s disease through NAD+-mediated pathways. However, evidence of its effect on humans is still scarce. In this study, we conducted a placebo-controlled, randomized, double blind, parallel-group trial to investigate the safety of orally administered NMN and its efficacy to increase NAD+ levels in thirty healthy subjects. Healthy volunteers received 250 mg/day of NMN (n = 15) or placebo (n = 15) for 12 weeks, and physiological and laboratory tests were performed during this period. In addition, NAD+ and its related metabolites in whole blood were examined. Oral supplementation of NMN for 12 weeks caused no abnormalities in physiological and laboratory tests, and no obvious adverse effects were observed. NAD+ levels in whole blood were significantly increased after NMN administration. We also observed the significant rise in nicotinic acid mononucleotide (NAMN) levels, but not in NMN. We also found that the increased amount of NAD+ was strongly correlated with pulse rate before the administration of NMN. These results suggest that oral administration of NMN is a safe and practical strategy to boost NAD+ levels in humans.Clinical Trial Registration: JRCT [https://jrct.niph.go.jp/], identifier: [jRCTs041200034].
Preoperative Prediction of Perineural Invasion Status of Rectal Cancer Based on Radiomics Nomogram of Multiparametric Magnetic Resonance Imaging
Authors: Zhang Yang , Peng Jiaxuan , Liu Jing , Ma Yanqing , Shu Zhenyu 
Published: April 2022

ObjectivesTo compare the predictive performance of different radiomics signatures from multiparametric magnetic resonance imaging (mpMRI), including four sequences when used individually or combined, and to establish and validate an optimal nomogram for predicting perineural invasion (PNI) in rectal cancer (RC) patients.MethodsOur retrospective study included 279 RC patients without preoperative antitumor therapy (194 in the training dataset and 85 in the test dataset) who underwent preoperative mpMRI scan between January 2017 and January 2021. Among them, 72 cases were PNI-positive. Then, clinical and radiological variables were collected, including carcinoembryonic antigen (CEA), radiological tumour stage (T1-4), lymph node stage (N0-2) and so on. Quantitative radiomics features were extracted and selected from oblique axial T2-weighted imaging (T2WI), T1-weighted imaging (T1WI), apparent diffusion coefficient (ADC), and enhanced T1WI (T1CE) sequences. The clinical model was constructed by integrating the final selected clinical and radiological variables. The radiomics signatures included four single-sequence signatures and one fusion signature were built using the respective remaining optimized features. And the nomogram was constructed based on the independent predictors by using multivariable logistic regression. The area under curve (AUC), DeLong test, calibration curve, and decision curve analysis (DCA) were used to evaluate the performance.ResultsUltimately, 20 radiomics features were retained from the four sequences—T1WI (n = 4), T2WI (n = 5), ADC (n = 5), and T1CE (n = 6)—to construct four single-sequence radiomics signatures and one fusion radiomics signature. The fusion radiomics signature performed better than four single-sequence radiomics signatures and clinical model (AUCs of 0.835 and 0.773 vs. 0.680-0.737 and 0.666-0.709 in the training and test datasets, respectively). The nomogram constructed by incorporating CEA, tumour stage and rad-score performed best, with AUCs of 0.869 and 0.864 in the training and test datasets, respectively. Delong test showed that the nomogram was significantly different from the clinical model and four single-sequence radiomics signatures (P &lt; 0.05). Moreover, calibration curves demonstrated good agreement, and DCA highlighted benefits of the nomogram.ConclusionsThe comprehensive nomogram can preoperatively and noninvasively predict PNI status, provide a convenient and practical tool for treatment strategy, and help optimize individualized clinical decision-making in RC patients.
An Efficient Nomogram for Discriminating Intrahepatic Cholangiocarcinoma From Hepatocellular Carcinoma: A Retrospective Study
Authors: Si Yuan-Quan , Wang Xiu-Qin , Pan Cui-Cui , Wang Yong , Lu Zhi-Ming 
Published: April 2022

ObjectiveThis study aims to establish a nomogram and provide an effective method to distinguish between intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC).MethodsA total of 1,591 patients with HCC or ICC hospitalized at Shandong Provincial Hospital between January 2016 and August 2021 were included and randomly divided into development and validation groups in a ratio of 3:1. Univariate and multivariate analyses were performed to determine the independent differential factors between HCC and ICC patients in the development cohort. By combining these independent differential factors, the nomogram was established for discriminating ICC from HCC. The accuracy of the nomogram was estimated by using receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Furthermore, the predictive nomogram was assessed in the internal testing set.ResultsThrough multivariate analysis, independent differential factors between HCC and ICC involved hepatitis B virus (HBV), logarithm of alpha-fetoprotein (Log AFP), logarithm of protein induced by vitamin K absence or antagonist-II (Log PIVKA-II), logarithm of carbohydrate antigen 199 (Log CA199), and logarithm of carbohydrate antigen 125 (Log CA125). A nomogram was finally established by incorporating these five independent differential factors. Comparing a model of conventional tumor biomarkers including AFP and CA199, the nomogram showed a better distinction between ICC and HCC. The area under the ROC curve (AUC) of ICC diagnosis was 0.951 (95% CI, 0.938–0.964) for the nomogram. The results were consistent in the validation cohort with an AUC of 0.958 (95% CI, 0.938–0.978). After integrating patient preferences into the analysis, the DCA showed that using this nomogram to distinguish ICC and HCC increased more benefit compared with the conventional model.ConclusionAn efficient nomogram has been established for the differential diagnosis between ICC and HCC, which may facilitate the detection and diagnosis of ICC. Further use of the nomogram in multicenter investigations will confirm the practicality of the tool for future clinical application.
Multiple Metastases of the Liver and Lung After Breast-Conserving Surgery for Ductal Carcinoma In Situ Without Microinvasion of the Breast: A Case Report and Literature Review
Authors: Wang Zhen , Zhang Xinyang , Ren Huiyang , Zhang Lei , Chen Bo 
Published: April 2022

BackgroundDuctal carcinoma in situ (DCIS) is a non-invasive disease that rarely causes distant metastasis. It is extremely rare for patients diagnosed with DCIS without microinvasion to develop distant metastasis in the absence of ipsilateral or contralateral breast recurrence. This is the first case report of multiple liver and lung metastases from DCIS after breast-conserving surgery and radiotherapy.Case PresentationA 45-year-old woman who was diagnosed with DCIS and received breast-conserving surgery, radiotherapy, and sequential endocrine therapy developed multiple metastases in the liver and lung despite not having bilateral breast recurrence at the 62-month follow-up. Comprehensive advanced breast cancer therapy was administered but did not prevent the progression of metastatic foci in the liver.ConclusionsThis case shows the poor potential outcome in DCIS. Further research should be conducted on metastasis in DCIS; reexamination and monitoring are indispensable for patients diagnosed with DCIS.
Cyclin-Dependent Kinase 6 Identified as the Target Protein in the Antitumor Activity of Tetrastigma hemsleyanum
Authors: Wei Chaoguang , Zhao Yuxiang , Ji Tao , Sun Yong , Cai Xudong , Peng Xin 
Published: April 2022

BackgroundTetrastigma hemsleyanum (T. hemsleyanum) is widely used as an adjuvant drug for tumor therapy but its antitumor therapeutic targets and molecular mechanisms have remained unclear. The prediction and analysis of natural products has previously used only network pharmacology methods to identify potential target proteins from public databases. In this study, we use comprehensive bioinformatics analysis and experimental verification to determine the antitumor mechanism of T. hemsleyanum.MethodsNetwork pharmacology analysis was used to predict the potential in vivo target proteins of T. hemsleyanum. The expression matrix and clinical data to perform an analysis of hub genes were collected from the TCGA and GTEx databases, specifically the analysis of expression, prognosis, tumor immune cell infiltration analysis, immune checkpoint genes, microsatellite instability, tumor mutational burden, tumor neoantigen, and immune microenvironment, which identify the roles and biological functions of the hub genes in pan-cancer. Finally, gene set enrichment analysis was used to verify the biological processes and signaling pathways involved in the pan-cancer expression profile.ResultsWe found 124 potential in vivo target proteins of T. hemsleyanum through network pharmacological analysis, and five hub genes (AKR1C1, MET, PTK2, PIK3R1, and CDK6) were then screened by protein–protein interaction (PPI) network analysis and molecular complex detection analysis (MCODE). Experimental intervention with an aqueous extract of T. hemsleyanum verified that these hub genes are the target proteins involved in the regulation of T. hemsleyanum in cells. A pan-cancer analysis then confirmed that CDK6 and MET are potential targets upon which T. hemsleyanum may exert antitumor action, especially in ACC, CESC, LGG, and PAAD. The CDK6 protein targeted by T. hemsleyanum is also involved in the immune and mutation process of pan-cancer, especially in the regulation of immune cell infiltration, immune checkpoint gene expression, microsatellite instability, tumor mutation burdens, and tumor neoantigens. Together, these analyses show that T. hemsleyanum affects tumor immune regulation and genomic stability. Finally, a gene set enrichment analysis confirmed that T. hemsleyanum regulates the cell cycle checkpoint.ConclusionsWe found that T. hemsleyanum can behave as an antitumor agent by acting as a potential cell cycle checkpoint inhibitor in CDK6-driven tumors, such as ACC, CESC, LGG, and PAAD, and that it acts as a tyrosine kinase receptor inhibitor that inhibits the expression of the proto-oncogene MET. Combined with an analysis of immune and mutation correlations in pan-cancer, we determined that T. hemsleyanum may function biologically as an immune regulator and interfere with the stability of the tumor genome, which is worthy of further study.
Compassionate Use of Yuanjiang Decoction, a Traditional Chinese Medicinal Prescription, for Symptomatic Bradyarrhythmia
Authors: Wan-Tong Zhang , Bao-Chen Zhu , Zhao Liu , Xu-Jie Wang , Rui Gao , Ning Xiao , Wei Tang , Yu-Fei Wu , Miles Phoebe , Wei-Liang Weng , Hao-Xiang Lin , Qiu-Yan Li 
Published: April 2022

Background: No effective medication is available for symptomatic bradyarrhythmia, particularly in low socioeconomic status (SES) population.Objective: To explore the safety and efficacy of Yuanjiang decoction, a traditional Chinese medicinal prescription, for symptomatic bradyarrhythmia on a compassionate-use basis.Methods: This compassionate-use study was conducted in Beijing, China between January 2019 and January 2020. Eligible participants were recruited and treated with Yuanjiang decoction (composed of 6 Chinese herbal medicines), 200 ml twice daily for 16 weeks. Analyses were done with the intention-to-treat (ITT) approach. The primary outcome measure was the proportion of participants who achieved a favorable treatment outcome at 16 weeks.Results: As of January 2020, 184 patients were included. After 16-weeks treatment, 12 participants were lost to contact while 21 participants were terminated from this study, with a drop-out rate of 17.93%. The most common treatment-related adverse events were xerostomia (6.52%), constipation (6.45%) and sleepiness (3.26%). The proportion of participants with favorable treatment outcome was 65.22% at 4 weeks, 59.78% at 8 weeks (OR: 1.11, 95% CI: 0.71–1.73), 61.41% at 12 weeks (OR: 1.16, 95% CI: 0.92–1.45) and 60.87% at 16 weeks (OR: 1.15, 95% CI: 0.98–1.35). In the multifactor regression analysis, the favorable treatment outcome at 16 weeks was significantly associated with completing at least 8 weeks treatment (OR: 2.053, 95% CI: 1.064–3.560), while unfavorable treatment outcome was significantly associated with an atrioventricular block (OR: 0.255, 95% CI: 0.083–0.784), current smoking (OR: 0.343, 95% CI: 0.027–0.487), and syncope in the month before treatment (OR: 0.321, 95%CI: 0.114–0.904).Conclusion: This compassionate-use study showed encouraging outcomes of treatment with Yuanjiang decoction, without serious adverse events. This study identified several key factors that may affect outcomes. These findings helped inform the design and assess the feasibility of a large-scale randomized clinical trial.
The Genus Alternanthera: Phytochemical and Ethnopharmacological Perspectives
Authors: Singla Rajeev K. , Dhir Vivek , Madaan Reecha , Kumar Deepak , Singh Bola Simranjit , Bansal Monika , Kumar Suresh , Dubey Ankit Kumar , Singla Shailja , Shen Bairong 
Published: April 2022

Ethnopharmacological relevance:The genusAlternanthera(Amaranthaceae) comprises 139 species including 14 species used traditionally for the treatment of various ailments such as hypertension, pain, inflammation, diabetes, cancer, microbial and mental disorders.Aim of the review:To search research gaps through critical assessment of pharmacological activities not performed to validate traditional claims of various species ofAlternanthera.This review will aid natural product researchers in identifyingAlternantheraspecies with therapeutic potential for future investigation.Materials and methods:Scattered raw data on ethnopharmacological, morphological, phytochemical, pharmacological, toxicological, and clinical studies of various species of the genusAlternantherahave been compiled utilizing search engines like SciFinder, Google Scholar, PubMed, Science Direct, and Open J-Gate for 100 years up to April 2021.Results:Few species ofAlternantheragenus have been exhaustively investigated phytochemically, and about 129 chemical constituents related to different classes such as flavonoids, steroids, saponins, alkaloids, triterpenoids, glycosides, and phenolic compounds have been isolated from 9 species. Anticancer, antioxidant, antibacterial, CNS depressive, antidiabetic, analgesic, anti-inflammatory, and immunomodulator effects have been explored in the twelve species of the genus. A toxicity study has been conducted on 3 species and a clinical study on 2 species.Conclusions:The available literature on pharmacological studies ofAlternantheraspecies reveals that few species have been selected based on ethnobotanical surveys for scientific validation of their traditional claims. But most of these studies have been conducted on uncharacterized and non-standardized crude extracts. A roadmap of research needs to be developed for the isolation of new bioactive compounds fromAlternantheraspecies, which can emerge out as clinically potential medicines.
Evaluation of Wound Healing and Antibacterial Potential of Greyia radlkoferi Szyszyl. Ethanolic Leaf Extract
Authors: Loggenberg Samantha Rae , Twilley Danielle , De Canha Marco Nuno , Meyer Debra , Mabena Ephraim Cebisa , Lall Namrita 
Published: April 2022

Angiogenesis is an essential mechanism in both physiological and pathological functions, such as wound healing and cancer metastasis. Several growth factors mediate angiogenesis, including vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). This study evaluated the potential wound healing activity of Greyia radlkoferi Szyszyl (GR) and its effect on growth factors regulating angiogenesis. The ethanolic leaf extract of GR was evaluated for antibacterial activity against wound associated bacteria; Staphylococcus aureus and Pseudomonas aeruginosa. It exhibited antibacterial activity against two strains of S. aureus (ATCC 25293 and ATCC 6538) displaying a minimum inhibitory concentration (MIC) at 250 and 500 μg/ml, respectively. The antioxidant activity of the extract was investigated for nitric oxide (NO) scavenging activity and showed a fifty percent inhibitory concentration (IC50) of 1266.5 ± 243.95 μg/ml. The extract was further investigated to determine its effect on the proliferation and modulation of growth factors secreted by human keratinocytes (HaCaT). Its effect on wound closure was evaluated using the scratch assay, where non-toxic concentrations were tested, as determined by the antiproliferative assay against HaCat cells (IC50 &gt; 400 μg/ml). Results showed that the extract significantly inhibited wound closure, with a percentage closure of 60.15 ± 1.41% (p &lt; 0.05) and 49.52 ± 1.43% (p &lt; 0.01) at a concentration of 50 and 100 μg/ml, respectively, when compared to the 0.25% Dimethyl sulfoxide vehicle control (65.86 ± 1.12%). Quantification of secreted growth factors from cell-free supernatant, collected from the scratch assay, revealed that the extract significantly decreased the concentration of platelet-derived growth factor (PDGF-AA) at both 50 (p &lt; 0.05) and 100 μg/ml (p &lt; 0.001) (443.08 ± 77.36 and 178.98 ± 36.60 pg/ml) when compared to the 0.25% DMSO vehicle control (538.33 ± 12.64 pg/ml). Therefore, whilst the extract showed antibacterial activity against wound associated bacteria, it did not induce wound healing but rather showed a significant inhibition of wound closure, which was confirmed by the inhibition of PDGF-AA, a major growth factor involved in angiogenesis. Therefore, the GR extract, should be considered for further investigation of anti-angiogenic and anti-metastatic properties against cancer cells.
Efficacy, Safety, and Retention Rate of Extended-Release Divalproex Versus Conventional Delayed-Release Divalproex: A Meta-Analysis of Controlled Clinical Trials
Authors: Zhang Chen Qi , Li Hong Yan , Wan Yong , Bai Xue Yang , Gan Lu , Wang Juan , Sun Hong Bin 
Published: April 2022

Purpose: A novel once-daily divalproex-extended release (ER) dose formulation has been developed; this formulation prolongs the therapeutic serum levels of the drug, compared with the twice-daily conventional divalproex-delayed release (DR) formulation. This study aimed to systematically examine and compare the efficacy, safety, and retention rates of the ER divalproex (VPA-ER) and conventional DR divalproex (VPA-DR) formulations.Methods: Randomized control trials (RCTs) reporting the efficacy, adverse events (AEs), and medication compliance of ER and DR divalproex were searched in online databases, including PubMed, Embase, and Cochrane Library databases, by searching MeSH words and term words. Observational studies with potential biases were excluded. The meta-analysis was performed using Stata 16.0 software.Findings: Thirteen RCTs, involving 1,028 participants, were included in this meta-analysis. Efficacy, AEs, and drug retention rates were the main study outcomes. According to our study, VPA-ER presented clinically significant benefits compared with the placebo in the population with bipolar disorder (BD) (39.5% versus 27.2%, p &lt; 0.001). A similar efficacy of VPA-ER and VPA-DR in controlling seizures was observed in epilepsy patients (87.4% versus 86.5%, p = 0.769). A significantly lower incidence of AEs was reported in the VPA-ER group than in the placebo group (26.8% versus 34.8%, p = 0.003). By contrast, there was no evidence of difference in safety between VPA-ER and VPA-DR (29.4% versus 30.5%, p = 0.750). In addition, the drug retention rate was significantly lower in the VPA-ER group than in the placebo group (76.0% versus 82.7%, p = 0.020), especially in migraine patients (p = 0.022) and in patients who were treated for fewer than 4 weeks (p = 0.018).Implications: The efficacy of VPA-ER was significantly superior to that of the placebo treatment, which provided efficacy similar to that of conventional VPA-DR. VPA-ER is well tolerated with a low rate of AEs compared to the placebo. In addition, the acceptable medicine compliance of VPA-ER was conducive to the long-term maintenance treatment of chronic diseases. Although we analyzed open labels and crossover design RCTs, large-scale multicenter studies on the efficacy and medicine compliance of new ER formulations with less AEs are required to validate our conclusion.
Icariin: A Potential Molecule for Treatment of Knee Osteoarthritis
Authors: Zhang Juntao , Fan Fangyang , Liu Aifeng , Zhang Chao , Li Qi , Zhang Chenglong , He Feng , Shang Man 
Published: April 2022

Background: Knee osteoarthritis (KOA) is a degenerative disease that develops over time. Icariin (ICA) has a positive effect on KOA, although the mechanism is unknown. To investigate drug-disease connections and processes, network pharmacology is commonly used. The molecular mechanisms of ICA for the treatment of KOA were investigated using network pharmacology, molecular docking and literature research approaches in this study.Methods: We gathered KOA-related genes using the DisGeNET database, the OMIM database, and GEO microarray data. TCMSP database, Pubchem database, TTD database, SwissTargetPrediction database, and Pharmmapper database were used to gather ICA-related data. Following that, a protein-protein interaction (PPI) network was created. Using the Metascape database, we performed GO and KEGG enrichment analyses. After that, we built a targets-pathways network. Furthermore, molecular docking confirms the prediction. Finally, we looked back over the last 5 years of literature on icariin for knee osteoarthritis to see if the findings of this study were accurate.Results: core targets relevant to KOA treatment include TNF, IGF1, MMP9, PTGS2, ESR1, MMP2 and so on. The main biological process involved regulation of inflammatory response, collagen catabolic process, extracellular matrix disassembly and so on. The most likely pathways involved were the IL-17 signaling pathway, TNF signaling pathway, Estrogen signaling pathway.Conclusion: ICA may alleviate KOA by inhibiting inflammation, cartilage breakdown and extracellular matrix degradation. Our study reveals the molecular mechanism of ICA for the treatment of KOA, demonstrating its potential value for further research and as a new drug.