bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of neuronal injury transcriptional response identifies CTCF and YY1 as co-operating factors regulating axon regeneration
Authors: Avraham Oshri , Le Jimmy , Leahy Kathleen , Li Tiandao , Zhao Guoyan , Cavalli Valeria
Published: August 2022

Injured sensory neurons activate a transcriptional program necessary for robust axon regeneration and eventual target reinnervation. Understanding the transcriptional regulators that govern this axon regenerative response may guide therapeutic strategies to promote axon regeneration in the injured nervous system. Here, we used cultured dorsal root ganglia neurons to identify pro-regenerative transcription factors. Using RNA sequencing, we first characterized this neuronal culture and determined that embryonic day 13.5 DRG (eDRG) neurons cultured for 7 days are similar to e15.5 DRG neurons in vivo and that all neuronal subtypes are represented. This eDRG neuronal culture does not contain other non-neuronal cell types. Next, we performed RNA sequencing at different time points after in vitro axotomy. Analysis of differentially expressed genes revealed upregulation of known regeneration associated transcription factors, including Jun, Atf3 and Rest, paralleling the axon injury response in vivo. Analysis of transcription factor binding sites in differentially expressed genes revealed other known transcription factors promoting axon regeneration, such as Myc, Hif1α, Pparγ, Ascl1a, Srf, and Ctcf, as well as other transcription factors not yet characterized in axon regeneration. We next tested if overexpression of novel candidate transcription factors alone or in combination promotes axon regeneration in vitro. Our results demonstrate that expression of Ctcf with Yy1 or E2f2 enhances in vitro axon regeneration. Our analysis highlights that transcription factor interaction and chromatin architecture play important roles as a regulator of axon regeneration.
Nutrition and mental health: A review of current knowledge about the impact of diet on mental health
Authors: Grajek Mateusz , Krupa-Kotara Karolina , Białek-Dratwa Agnieszka , Sobczyk Karolina , Grot Martina , Kowalski Oskar , Staśkiewicz Wiktoria
Published: August 2022

Applied psychopharmacotherapy and psychotherapy do not always bring the expected results in the treatment of mental disorders. As a result, other interventions are receiving increasing attention. In recent years, there has been a surge in research on the effects of nutrition on mental status, which may be an important aspect of the prevention of many mental disorders and, at the same time, may lead to a reduction in the proportion of people with mental disorders. This review aims to answer whether and to what extent lifestyle and related nutrition affect mental health and whether there is scientific evidence supporting a link between diet and mental health. A review of the scientific evidence was conducted based on the available literature by typing in phrases related to nutrition and mental health using the methodological tool of the PubMed database. The literature search yielded 3,473 records, from which 356 sources directly related to the topic of the study were selected, and then those with the highest scientific value were selected according to bibliometric impact factors. In the context of current changes, urbanization, globalization, including the food industry, and changes in people’s lifestyles and eating habits, the correlations between these phenomena and their impact on mental state become important. Knowledge of these correlations creates potential opportunities to implement new effective dietary, pharmacological, therapeutic, and above all preventive interventions. The highest therapeutic potential is seen in the rational diet, physical activity, use of psychobiotics, and consumption of antioxidants. Research also shows that there are nutritional interventions that have psychoprotective potential.
Effects of two triterpenoids from Nigella sativa seeds on insulin resistance of 3T3-L1 adipocytes
Authors: Wei Jinfeng , Wang Baoguang , Chen Yixiao , Wang Qiuyi , Ahmed Adel F. , Cui Lili , Xi Xuefeng , Kang Wenyi
Published: August 2022

Insulin resistance (IR) is a physiological abnormality that occurs when insulin fails to activate the signal transduction pathway in target organs. It was found that supplementation of Nigella sativa seeds with oral antidiabetic medicines helps improve blood glucose control by enhanced β cells activity and alleviation of IR. However, the activities and related mechanisms of phytochemicals from N. sativa seeds have not been thoroughly explored. In this study, the effects of two triterpenoids, 3-O-[β-D-xylopyranose-(1→3)-α-L-rhamnose-(1→2)-α-L-arabinose]-28-O-[α-L-rhamnose-(1→4)-β-D-glucopyranose-L-(1→6)-β-D-glucopyranose]-hederagenin (Hxrarg) and 3-O-[β-D-xylopyranose-(1→3)-α-L-rhamnose-(1→2)-α-L-arabinose]-hederagenin (Hxra), on IR were studied by 3T3-L1 adipocytes model. The results demonstrated that Hxrarg and Hxra inhibited maturation of 3T3-L1 preadipocytes, dramatically stimulated glucose uptake of IR-3T3-L1 adipocytes, promoted transcription of IRS, AKT, PI-3K, and GLUT4 mRNA. Western Blot results suggested that Hxrarg and Hxra were able to markedly up-regulate expression of p-IRS, p-AKT, PI-3K, and GLUT4 proteins. These findings could provide a basic foundation for the continued development and application of N. sativa in medicine and functional foods.
FOXM1 is regulated by DEPDC1 to facilitate development and metastasis of oral squamous cell carcinoma
Authors: Qiu Jing , Tang Yongping , Liu Lan , Yu Jiangbo , Chen Zhenggang , Chen Hao , Yuan Rongtao
Published: August 2022

The Disheveled, EGL-10, Pleckstrin domain containing 1 (DEPDC1) is a new oncogene that has recently been described. The mechanisms and functions of its expression are yet to be determined in oral squamous cell carcinoma (OSCC). In the present study, the impact of DEPDC1 on the growth and development of OSCC was investigated using animal models, cell lines and human tissue samples. Elevated DEPDC1 expression within cancer cell lines and human OSCC has been identified. Mechanistic examination showed that restored DEPDC1 expression in vivo and in vitro stimulated OSCC tumour development. In addition, FOXM1 interacts with DEPDC1 as indicated by co-immunoprecipitation and immunofluorescence testing. Functionally, DEPDC1 facilitated Wnt/β-catenin signal transduction and β-catenin protein nuclear expression. In summary, the DEPDC1, interacting with FOXM1 via Wnt/β-catenin signaling, the closely regulated OSCC pathogenesis, suggesting that targeting the novel DEPDC1/FOXM1/β-catenin complex is an essential OSCC therapeutic approach.
Comprehensive germline and somatic genomic profiles of Chinese patients with biliary tract cancer
Authors: Yu Haipeng , Xu Yan , Gao Wei , Li Mei , He Ji’an , Deng Xiaoqian , Xing Wenge
Published: August 2022

Background

Biliary tract cancer (BTC) is an uncommon but highly lethal malignancy with poor clinical outcomes. To promote the development of precision medicine for BTC, uncovering its genomic profile becomes particularly important. However, studies on the genomic feature of Chinese BTC patients remain insufficient.

Methods

A total of 382 Chinese patients with BTC were enrolled in this study, including 71 with intrahepatic cholangiocarcinoma (ICC), 194 with extrahepatic cholangiocarcinoma (ECC), and 117 with gallbladder carcinoma (GBC). Genetic testing was performed by utilizing the next-generation sequencing (NGS) of 499 cancer-related genes and the results were compared to those of Western BTC patients (MSKCC cohorts).

Results

The most prevalent genes were TP53 (51.6%), ARID1A (25.9%), KMT2C (24.6%), NCOR1 (17%), SMAD4 (15.2%), KRAS (14.9%), KMT2D (14.9%), ATM (14.1%), and APC (13.9%) in Chinese BTC patients. TP53, SMAD4, and APC were more prevalent in GBC, ECC, and ICC, respectively. In addition, 10.5% of Chinese BTC patients harbored pathogenic or likely pathogenic (P/LP) germline alterations in 41 genes, which were mainly related to DNA damage repair (DDR). Additionally, the genomic features of Chinese and Western BTC tumors were similar, with the exception of the notable difference in the prevalence of TP53, KRAS, IDH1, KMT2C, and SMAD4. Notably, Chinese BTC patients had high prevalence (57.1%) of actionable alterations, especially for those with ECC, and half (192/382) of them had somatic DDR alterations, with the prevalence of deleterious ones being significantly higher than their Western counterparts. Twenty-three percent of patients had a higher tumor mutational burden (TMB-H, over 10 mutations/MB), and TMB was significantly higher in those with deleterious DDR alterations and/or microsatellite instability-high. The most common mutational signature in BTC patients was Signature 1, and interestingly, Signatures 1, 4, and 26 were significantly associated with higher TMB level, but not with the survival of patients who had received immunotherapy in pan-cancer.

Conclusion

Our study elaborated the distinct germline and somatic genomic characteristics of Chinese BTC patients and identified clinically actionable alterations, highlighting the possibility for the development and application of precision medicine.
A cuproptosis and copper metabolism–related gene prognostic index for head and neck squamous cell carcinoma
Authors: Zhang Shuaiyuan , Zhang Lujin , Lu Huanzi , Yao Yihuan , Liu Xiaoyong , Hou Jingsong
Published: August 2022

Background

The purpose of this study was to identify the prognostic value of cuproptosis and copper metabolism–related genes, to clarify their molecular and immunological characteristics, and to elucidate their benefits in head and neck squamous cell carcinoma (HNSCC).

Methods

The details of human cuproptosis and copper metabolism–related genes were searched and filtered from the msigdb database and the latest literature. To identify prognostic genes associated with cuproptosis and copper metabolism, we used least absolute shrinkage and selection operator regression, and this coefficient was used to set up a prognostic risk score model. HNSCC samples were divided into two groups according to the median risk. Afterwards, the function and immune characteristics of these genes in HNSCC were analyzed.

Results

The 14-gene signature was constructed to classify HNSCC patients into low-risk and high-risk groups according to the risk level. In the The Cancer Genome Atlas (TCGA) cohort, the overall survival (OS) rate of the high-risk group was lower than that of the low-risk group (P < 0.0001). The area under the curve of the time-dependent Receiver Operator Characteristic (ROC) curve assessed the good performance of the genetic signature in predicting OS and showed similar performance in the external validation cohort. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment assays and Protein-Protein Interaction (PPI) protein networks have been used to explore signaling pathways and potential mechanisms that were markedly active in patients with HNSCC. Furthermore, the 14 cuproptosis and copper metabolism-related genes were significantly correlated with the immune microenvironment, suggesting that these genes may be linked with the immune regulation and development of HNSCC.

Conclusions

Our results emphasize the significance of cuproptosis and copper metabolism as a predictive biomarker for HNSCC, and its expression levels seem to be correlated with immune- related features; thus, they may be a possible biomarker for HNSCC prognosis.
LncRNA-ENST00000543604 exerts a tumor-promoting effect via miRNA 564/AEG-1 or ZNF326/EMT and predicts the prognosis of and chemotherapeutic effect in colorectal cancer
Authors: Wang Weimin , Zhou Zhen , Dai Xiaojun , Wang Haibo , Jin Jun , Min Ke , Wang Yunfan , Lv Mengying , Liu Yanqing , Zhou Yan
Published: August 2022

Objectives

Colorectal cancer(CRC) is a common malignant tumor. Recent studies have found that lncRNAs play an important role in the occurrence and development of colorectal cancer.

Methods

Based on high-throughput sequencing results of fresh CRC tissues and adjacent tissues, we identified lncRNA-ENST00000543604 (lncRNA 604) as the research object by qRT-PCR in CRC tissues and cells. We explored the mechanism of lncRNA 604 action by using luciferin reporter, qRT-PCR and Western blot assays. Kaplan-Meier survival analysis and a Cox regression model were used to analyze the correlation of lncRNA 604 and its regulatory molecules with the prognosis of and chemotherapy efficacy in CRC patients.

Results

In this study, we found that the expression levels of lncRNA 604 were increased in CRC. LncRNA 604 could promote CRC cell proliferation and metastasis through the miRNA 564/AEG-1 or ZNF326/EMT signaling axis in vivo and in vitro. LncRNA 604 could predict the prognosis of CRC and was an independent negative factor. LncRNA 604 exerted a synergistic effect with miRNA 564 or ZNF326 on the prognosis of CRC. LncRNA 604 could improve chemoresistance by increasing the expression of AEG-1, NF-κB, and ERCC1.

Conclusions

Our study demonstrated that lncRNA 604 could promote the progression of CRC via the lncRNA 604/miRNA 564/AEG-1/EMT or lncRNA 604/ZNF326/EMT signaling axis. LncRNA 604 could improve chemoresistance by increasing drug resistance protein expression.
Surgery and chemotherapy cannot improve the survival of patients with early-stage mucosa-associated lymphoid tissue derived primary pulmonary lymphoma
Authors: Lin Huahang , Zhou Ke , Peng Zhiyu , Liang Linchuan , Cao Jie , Mei Jiandong
Published: August 2022

Background

To date, there is no treatment consensus on mucosa-associated lymphoid tissue (MALT) derived primary pulmonary lymphoma (PPL).

Methods

We identified patients with early-stage MALT-type PPL from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program database. The patients were divided into four groups according to treatment modalities: None of surgery or chemotherapy (None) group, Surgery alone group, Chemotherapy alone (Chemo alone) group, and Surgery plus chemotherapy (Surgery + chemo) group. Overall survival (OS) and cancer-specific survival (CSS) were study endpoints. We performed Cox regression analyses, propensity score-matched analyses (PSM) and Kaplan-Meier (KM) survival curves to compare the survival among different groups.

Results

A total of 953 patients were included in our analysis with 302, 403, 175, and 73 cases in the None, Surgery alone, Chemo alone, and Surgery + chemo groups, respectively. In this cohort, the estimated 3-year, 5-year and 10-year OS rates were 86.95%, 78.91%, and 55.89%, respectively. Meanwhile, the estimated 3-year, 5-year and 10-year CSS rates were 96.71%, 93.73%, and 86.84%, respectively. Multivariate Cox regression analyses demonstrated that increasing age, tumors located in the lower lobe, and stage II were significant predictors of poorer OS while increasing age and tumors located in the bilateral lungs were associated with lower CSS. After PSM analyses, the KM survival curves showed no significant differences in OS or CSS among the four groups.

Conclusion

Early-stage MALT-type PPL is indolent in nature. Neither surgery, chemotherapy nor a combination of surgery and chemotherapy can improve OS and CSS, suggesting that “watch and wait” may be a reasonable alternative.
Prediction of survival in oropharyngeal squamous cell carcinoma using machine learning algorithms: A study based on the surveillance, epidemiology, and end results database
Authors: Kim Su Il , Kang Jeong Wook , Eun Young-Gyu , Lee Young Chan
Published: August 2022

Background

We determined appropriate survival prediction machine learning models for patients with oropharyngeal squamous cell carcinoma (OPSCC) using the “Surveillance, Epidemiology, and End Results” (SEER) database.

Methods

In total, 4039 patients diagnosed with OPSCC between 2004 and 2016 were enrolled in this study. In particular, 13 variables were selected and analyzed: age, sex, tumor grade, tumor size, neck dissection, radiation therapy, cancer directed surgery, chemotherapy, T stage, N stage, M stage, clinical stage, and human papillomavirus (HPV) status. The T-, N-, and clinical staging were reconstructed based on the American Joint Committee on Cancer (AJCC) Staging Manual, 8th Edition. The patients were randomly assigned to a development or test dataset at a 7:3 ratio. The extremely randomized survival tree (EST), conditional survival forest (CSF), and DeepSurv models were used to predict the overall and disease-specific survival in patients with OPSCC. A 10-fold cross-validation on a development dataset was used to build the training and internal validation data for all models. We evaluated the predictive performance of each model using test datasets.

Results

A higher c-index value and lower integrated Brier score (IBS), root mean square error (RMSE), and mean absolute error (MAE) indicate a better performance from a machine learning model. The C-index was the highest for the DeepSurv model (0.77). The IBS was also the lowest in the DeepSurv model (0.08). However, the RMSE and RAE were the lowest for the CSF model.

Conclusions

We demonstrated various machine-learning-based survival prediction models. The CSF model showed a better performance in predicting the survival of patients with OPSCC in terms of the RMSE and RAE. In this context, machine learning models based on personalized survival predictions can be used to stratify various complex risk factors. This could help in designing personalized treatments and predicting prognoses for patients.
The role of the bone microenvironment in regulating myeloma residual disease and treatment
Authors: Dadzie Terry G. , Green Alanna C.
Published: August 2022

Multiple myeloma is an incurable haematological cancer. The increase in targeted therapies has improved the number of myeloma patients achieving a complete response and improved progression-free survival following therapy. However, a low level of disease or minimal residual disease (MRD) still persists which contributes to the inevitable relapse in myeloma patients. MRD has been attributed to the presence of dormant myeloma cells and their subsequent reactivation, which is controlled by the microenvironment and specialised niches within the bone marrow. This contributes to the evasion of the immune system and chemotherapy, eventually leading to relapse. The growth of myeloma tumours are heavily dependent on environmental stimuli from the bone marrow microenvironment, and this plays a key role in myeloma progression. The bone microenvironment also plays a critical role in myeloma bone disease and the development of skeletal-related events. This review focuses on the bone marrow microenvironment in relation to myeloma pathogenesis and cancer dormancy. Moreover, it reviews the current therapies targeting the bone microenvironment to treat myeloma and myeloma bone disease. Lastly, it identifies novel therapeutic targets for myeloma treatment and the associated bone disease.
Metabolic model of necrotizing enterocolitis in the premature newborn gut resulting from enteric dysbiosis
Authors: Casaburi Giorgio , Wei Jingjing , Kazi Sufyan , Liu Junlin , Wang Kewei , Tao Guo-Zhong , Lin Po-Yu , Dunn James C. Y. , Henrick Bethany M. , Frese Steven A. , Sylvester Karl G.
Published: August 2022

Necrotizing enterocolitis (NEC) is a leading cause of premature newborn morbidity and mortality. The clinical features of NEC consistently include prematurity, gut dysbiosis and enteral inflammation, yet the pathogenesis remains obscure. Herein we combine metagenomics and targeted metabolomics, with functional in vivo and in vitro assessment, to define a novel molecular mechanism of NEC. One thousand six hundred and forty seven publicly available metagenomics datasets were analyzed (NEC = 245; healthy = 1,402) using artificial intelligence methodologies. Targeted metabolomic profiling was used to quantify the concentration of specified fecal metabolites at NEC onset (n = 8), during recovery (n = 6), and in age matched controls (n = 10). Toxicity assays of discovered metabolites were performed in vivo in mice and in vitro using human intestinal epithelial cells. Metagenomic and targeted metabolomic analyses revealed significant differences in pyruvate fermentation pathways and associated intermediates. Notably, the short chain fatty acid formate was elevated in the stool of NEC patients at disease onset (P = 0.005) dissipated during recovery (P = 0.02) and positively correlated with degree of intestinal injury (r2 = 0.86). In vitro, formate caused enterocyte cytotoxicity in human cells through necroptosis (P < 0.01). In vivo, luminal formate caused significant dose and development dependent NEC-like injury in newborn mice. Enterobacter cloacae and Klebsiella pneumoniae were the most discriminatory taxa related to NEC dysbiosis and increased formate production. Together, these data suggest a novel biochemical mechanism of NEC through the microbial production of formate. Clinical efforts to prevent NEC should focus on reducing the functional consequences of newborn gut dysbiosis associated metabolic pathways.
Effect of ranibizumab on retinopathy of prematurity: A meta-analysis
Authors: Wang Zhibin , Zhang Zhaobo , Wang Yue , Di Yu
Published: August 2022

The primary objective of this study was to systematically evaluate the clinical efficacy of intravitreal ranibizumab injection in the treatment for retinopathy of prematurity (ROP) in infants. The MEDLINE (PubMed), Embase, China Biology Medicine disc, Cochrane Library, Web of Science, WanFang Data, CNKI, and CQVIP databases were searched to collect randomized controlled trials (RCTs) comparing the efficacy of ranibizumab with laser treatment in ROP. The retrieval time was from 2007, on which ranibizumab was approved until 12 January 2022. Data were extracted based on predetermined inclusion and exclusion criteria. Two investigators employed QUADAS-2 to independently assess the quality of all eligible original studies. Following quality evaluation, we also performed a meta-analysis using STATA v 15.1 and RevMan v 5.4 and funnel plots were used to detect publication bias. A total of five RCTs were included in the meta-analysis. In this study, the regression rate of retinal neovascularization was used as the index of therapeutic effectiveness. According to the results, the retinal neovascularization regression rate of the intravitreal ranibizumab injection group was statistically higher than that of the laser therapy group [risk ratio (RR) = 1.26, 95% confidence interval (CI): 1.18–1.35]; however, the incidence of adverse events, including recurrence and complications, was not different between them (RR = 0.73, 95%CI: 0.19–2.80). Therefore, intravitreal ranibizumab injection may be more clinically effective than laser therapy in the treatment for ROP. The safety and efficacy of ranibizumab in the long-term treatment for ROP needs further investigation.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, CRD42022296387
Qingfei Jiedu decoction inhibits PD-L1 expression in lung adenocarcinoma based on network pharmacology analysis, molecular docking and experimental verification
Authors: Pan Junjie , Yang Hongkuan , Zhu Lihong , Lou Yafang , Jin Bo
Published: August 2022

Objective: We aim at investigating the molecular mechanisms through which the Qingfei Jiedu decoction (QFJDD) regulates PD-L1 expression in lung adenocarcinoma (LUAD).

Methods: Bioactive compounds and targets of QFJDD were screened from TCMSP, BATMAN-TCM, and literature. Then, GeneCard, OMIM, PharmGKB, Therapeutic Target, and DrugBank databases were used to identify LUAD-related genes. The protein-protein interaction (PPI) network was constructed using overlapping targets of bioactive compounds in LUAD with the Cytoscape software and STRING database. The potential functions and pathways in which the hub genes were enriched by GO, KEGG, and DAVID pathway analyses. Molecular docking of bioactive compounds and key genes was executed via AutoDock Vina. Qualitative and quantitative analyses of QFJDD were performed using UPLC-Q-TOF-MS and UPLC. Expressions of key genes were determined by qRT-PCR, immunoreactivity score (IRS) of PD-L1 was assessed by immunohistochemistry (IHC), while the CD8+PD-1+T% derived from spleen tissues of Lewis lung cancer (LLC) bearing-mice was calculated using flow cytometry (FCM).

Results: A total of 53 bioactive compounds and 288 targets of QFJDD as well as 8151 LUAD associated genes were obtained. Further, six bioactive compounds, including quercetin, luteolin, kaempferol, wogonin, baicalein, and acacetin, and 22 hub genes were identified. The GO analysis showed that the hub genes were mainly enriched in DNA or RNA transcription. KEGG and DAVID pathway analyses revealed that 20 hub genes were primarily enriched in virus, cancer, immune, endocrine, and cardiovascular pathways. The EGFR, JUN, RELA, HIF1A, NFKBIA, AKT1, MAPK1, and MAPK14 hub genes were identified as key genes in PD-L1 expression and PD-1 checkpoint pathway. Moreover, ideal affinity and regions were identified between core compounds and key genes. Notably, QFJDD downregulated EGFR, JUN, RELA, HIF1A, NFKBIA, and CD274 expressions (p < 0.05), while it upregulated AKT1 and MAPK1 (p < 0.05) levels in A549 cells. The PD-L1 IRS of LLC tissue in the QFJDD high dose (Hd) group was lower than model group (p < 0.01). CD8+PD-1+T% was higher in the QFJDD Hd group than in normal and model groups (p < 0.05).

Conclusion: QFJDD downregulates PD-L1 expression and increases CD8+PD-1+T% via regulating HIF-1, EGFR, JUN and NFκB signaling pathways. Therefore, QFJDD is a potential treatment option for LUAD.
The change of drug utilization in China’s public healthcare institutions under the “4 + 7” centralized drug procurement policy: Evidence from a natural experiment in China
Authors: Lu Jiancheng , Long Hongfei , Shen Yuan , Wang Jing , Geng Xin , Yang Ying , Mao Zongfu , Li Jinghua
Published: August 2022

Background: Improving drug accessibility and rational drug use are major challenges for China’s healthcare reform. In 2018, the Chinese government introduced a novel nationwide policy of centralized drug procurement for off-patent drugs, focusing on improving drug utilization patterns of public medical institutions.

Objective: To estimate the impacts of the Chinese centralized drug procurement policy (the so-called “4 + 7” policy) on drug utilization in public medical institutions.

Methods: A retrospective natural experimental design and difference-in-difference method were applied using cross-region data extracted from the national procurement database. Eleven “4 + 7” pilot cities (intervention group) and eleven non-pilot provinces (control group) were matched. In addition, “4 + 7” policy-related drugs (n = 116) were selected as study samples, including 25 drugs in the 4 + 7” procurement List (“4 + 7” List drugs) and their alternative drugs (n = 91) that have not yet been covered by centralized procurement policy. Then, the “4 + 7” List drugs were divided into bid-winning and non-winning drugs according to the bidding results, and they were sorted into generic and original drugs. Defined daily dose (DDD) was used to standardize the quantity of drugs used.

Results: In the 1-year procurement period, the overall completion rate of agreed procurement volume reached 191.4% in pilot cities. Owing to policy impact, the consumption increased by 405.31% in bid-winning drugs (β = 1.62, p < 0.001) and decreased by 62.28% (β = −0.98, p < 0.001) in non-winning drugs. The overall use proportion of bid-winning drugs increased from 17.03% to 73.61% with statistical significance (β = 1.48, p < 0.001), and increments were also detected in all healthcare settings, regions, and anatomical therapeutic chemical (ATC) categories (all p-values < 0.05). Generics and originators were detected with 67.53% increment (β = 0.52, p < 0.001) and 26.88% drop (β = −0.31, p = 0.006) in consume volume. The use proportion of generics increased from 59.23% to 78.44% with significance (β = 0.24, p < 0.001), as well as in tertiary hospitals (β = 0.31), secondary hospitals (β = 0.23), and primary healthcare centers (β = 0.11) (all p-values < 0.001). The use proportion of relatively quality-guaranteed drugs (i.e. bid-winning and original drugs) increased from 56.69% to 93.61% with significance (β = 0.61, p < 0.001), and similar increments were also detected in all healthcare settings, regions, and ATC categories (all p-values < 0.05).

Conclusion: Healthcare providers demonstrated good compliance with the “4 + 7” policy in completing contracted procurement volume. Centralized drug procurement policy promoted drug consumption gradually concentrated on bid-winning drugs, generic drugs, and more importantly, quality-guaranteed drugs.
Flavonol glycoside complanatoside A requires FOXO/DAF-16, NRF2/SKN-1, and HSF-1 to improve stress resistances and extend the life span of Caenorhabditis elegans
Authors: Tan Lin , Zheng Zhuo-Ya , Huang Lv , Jin Zhong , Li Su-Lian , Wu Gui-Sheng , Luo Huai-Rong
Published: August 2022

Aging is associated with the increased risk of most age-related diseases in humans. Complanatoside A (CA) is a flavonoid compound isolated from the herbal medicine Semen Astragali Complanati. CA was reported to have potential anti-inflammatory and anti-oxidative activities. In this study, we investigated whether CA could increase the stress resistance capability and life span of Caenorhabditis elegans. Our results showed that CA could extend the longevity of C. elegans in a dosage-dependent manner, while 50 μM of CA has the best effect and increased the life span of C. elegans by about 16.87%. CA also improved the physiological functions in aging worms, such as enhanced locomotor capacity, and reduced the accumulation of the aging pigment. CA could also reduce the accumulation of toxic proteins (α-synuclein and β-amyloid) and delay the onset of neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, in models of C. elegans. Further investigation has revealed that CA requires DAF-16/FOXO, SKN-1, and HSF-1 to extend the life span of C. elegans. CA could increase the antioxidation and detoxification activities regulated by transcription factor SKN-1 and the heat resistance by activating HSF-1 that mediated the expression of the chaperone heat shock proteins. Our results suggest that CA is a potential antiaging agent worth further research for its pharmacological mechanism and development for pharmaceutical applications.
Oroxylin A ameliorates AKI-to-CKD transition through maintaining PPARα-BNIP3 signaling-mediated mitochondrial homeostasis
Authors: Yao Mengying , Qin Shaozong , Xiong Jiachuan , Xin Wang , Guan Xu , Gong Shuiqin , Chen Jing , Liu Yong , Zhang Bo , Zhao Jinghong , Huang Yinghui
Published: August 2022

Background: Acute kidney injury (AKI) occurs in approximately 7–18% of all hospitalizations, but there are currently no effective drug therapy for preventing AKI or delaying its progression to chronic kidney disease (CKD). Recent studies have shown that Scutellaria baicalensis, a traditional Chinese herb, could attenuate cisplatin-induced AKI, although the mechanism remains elusive. Further, it is unknown whether its major active component, Oroxylin A (OA), can alleviate kidney injury.

Methods: The therapeutic effect of OA was evaluated by using ischemia-reperfusion (IR) and cisplatin mediated-AKI mice and HK-2 cells under hypoxia-reoxygenation (HR) conditions. HE staining, transmission electron microscopy, flow cytometry, immunofluorescence, qPCR, Western blot, PPARα inhibitor, BNIP3 siRNA and ChIP assay were used to explore the role and mechanism of OA in AKI.

Results: OA ameliorated tubular damage and dramatically decreased serum creatinine (Scr) and urea nitrogen (BUN), and the expressions of renal injury markers (Kim-1, Ngal) in AKI mice induced by both IR injury and cisplatin, as well as attenuating AKI-to-CKD transition. In vitro experiments showed that OA alleviated HR-induced mitochondrial homeostasis imbalance in renal tubular epithelial cells. Mechanistically, OA dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 expression reversed the protection of OA against HR-mediated mitochondrial injury. Network pharmacological analysis and experimental validation suggested that OA enhanced BNIP3 expression via upregulating the expression of peroxisome proliferator activated receptor alpha (PPARα), which induced the transcription of BNIP3 via directly binding to its promoter region. Both in vitro and in vivo experiments confirmed that the renoprotective effect of OA was dramatically reduced by GW6471, a PPARα antagonist.

Conclusion: Our findings revealed that OA ameliorates AKI-to-CKD transition by maintaining mitochondrial homeostasis through inducing PPARα-BNIP3 signaling pathway, indicating that OA may serve as a candidate therapeutic strategy for alleviating AKI and CKD.
Nalidixic acid potentiates the antitumor activity in sorafenib-resistant hepatocellular carcinoma via the tumor immune microenvironment analysis
Authors: Liu Zhi-Yong , Zhang Dan-Ying , Lin Xia-Hui , Sun Jia-Lei , Abuduwaili Weinire , Zhang Guang-Cong , Xu Ru-Chen , Wang Fu , Yu Xiang-Nan , Shi Xuan , Deng Bin , Dong Ling , Weng Shu-Qiang , Zhu Ji-Min , Shen Xi-Zhong , Liu Tao-Tao
Published: August 2022

Sorafenib resistance is often developed and impedes the benefits of clinical therapy in hepatocellular carcinoma (HCC) patients. However, the relationship between sorafenib resistance and tumor immune environment and adjuvant drugs for sorafenib-resistant HCC are not systemically identified. This study first analyzed the expression profiles of sorafenib-resistant HCC cells to explore immune cell infiltration levels and differentially expressed immune-related genes (DEIRGs). The prognostic value of DEIRGs was analyzed using Cox regression and Kaplan–Meier analysis based on The Cancer Genome Atlas. The primary immune cells infiltrated in sorafenib-resistant HCC mice were explored using flow cytometry (FCM). Finally, small-molecule drugs for sorafenib-resistant HCC treatment were screened and validated by experiments. The CIBERSORT algorithm and mice model showed that macrophages and neutrophils are highly infiltrated, while CD8+ T cells are downregulated in sorafenib-resistant HCC. Totally, 34 DEIRGs were obtained from sorafenib-resistant and control groups, which were highly enriched in immune-associated biological processes and pathways. NR6A1, CXCL5, C3, and TGFB1 were further identified as prognostic markers for HCC patients. Finally, nalidixic acid was identified as a promising antagonist for sorafenib-resistant HCC treatment. Collectively, our study reveals the tumor immune microenvironment changes and explores a promising adjuvant drug to overcome sorafenib resistance in HCC.
Bibliometric and visual analysis of blood-testis barrier research
Authors: Shen Yifeng , You Yaodong , Zhu Kun , Fang Chunyan , Yu Xujun , Chang Degui
Published: August 2022

Background: Extensive research on the blood-testis barrier has been undertaken in recent years. However, no systematic bibliometric study has been conducted on this subject. Our research aimed to identify the hotspots and frontiers of blood-testis barrier research and to serve as a guide for future scientific research and decision-making in the field.

Methods: Studies on the blood-testis barrier were found in the Web of Science Core Collection. VOSviewer, CiteSpace, and Microsoft Excel were used to conduct the bibliometric and visual analyses.

Results: We found 942 blood-testis barrier studies published in English between 1992 and 2022. The number of annual publications and citations increased significantly between 2011 and 2022, notably in the United States. China and the United States, the US Population Council, Endocrinology, and Cheng C. Yan were the most productive countries, institution, journal, and author, respectively. The study keywords indicated that blood-testis barrier research involves a variety of compositional features (tight junctions, cytoskeleton, adherens junctions), cell types (Sertoli cells, germ cells, Leydig cells, stem cells), reproductive toxicity (cadmium, nanoparticles, bisphenol-a), and relevant mechanisms (spermatogenesis, apoptosis, oxidative stress, dynamics, inflammation, immune privilege).

Conclusion: The composition and molecular processes of the blood-testis barrier as well as the blood-testis barrier in male infertility patients are the primary research hotspots in this field. In addition, future research will likely focus on treatment and the development of novel medications that target signal pathways in oxidative stress and apoptosis to preserve the blood-testis barrier. Further studies must extend to clinical diagnosis and therapy.
Quantitative evaluation of fast free-hand volumetric ultrasound
Authors: Nikolaev Anton V. , Hansen Hendrik H. G. , Maal Thomas J. J. , van Alfen Nens , de Korte Chris L.
Published: August 2022

Free-hand volumetric ultrasound (FVUS) facilitates 3D US imaging of large anatomical areas. However, this method is user-dependent and image quality, especially in the scan direction (elevational direction), depends on the number of US images acquired per distance unit. This might affect clinical decision making for example in quantitative ultrasound muscle imaging. This study addresses three goals. First, to determine quantitatively below which number of acquisitions per cm (acq/cm) image quality is affected: the acquisition limit. Second, to determine the translation speed used naturally by sonographers. Third, to demonstrate in vivo possible benefits of utilizing plane wave imaging for FVUS, so-called fast FVUS in order to boost translation speed while maintaining quantitative image information. Fast FVUS enables imaging at much higher framerates and hence the acquisition limit is easier met which allows for much faster transducer translation. From an analysis of the contrast and elevational resolution in a phantom, the average acquisition limit was determined to be 33 acq/cm. Above this limit, the quantitative ultrasound information remained unchanged. This would imply that when imaging at 30 frames per second, a common frame-rate of current 2D ultrasound devices, suboptimal imaging quality is obtained above transducer translation speeds of 9.1 mm/s. The median and maximum transducer translation speed observed in 10 sonographers were 15.8 mm/s and 30.1 mm/s, thus above this limit. Finally, we presented a design of fast FVUS that enabled acquiring 200 fps, and hence, would allow imaging up to speeds of 60.6 mm/s. We demonstrated in vivo in tibialis anterior muscles that more anatomical details were visible with fast FVUS which were lost at the typical framerate. These observations support our hypothesis that fast FVUS would be an ideal method for 3D quantitative muscle ultrasound.
Objectively determined physical activity and adiposity measures in adult women: A systematic review and meta-analysis
Authors: Lu Yining , Wiltshire Huw D. , Baker Julien S. , Wang Qiaojun , Ying Shanshan , Li Jianshe , Lu Yichen
Published: August 2022

The prevalence of adiposity is increasing among adult women. Although emerging evidence suggest that all patterns of heightened physical activity (PA) are important to benefit adiposity, the relationship between objectively assessed intensities of PA and adiposity in women has not yet been assessed. Therefore, this systematic review and meta-analysis aims to qualitatively synthesize and quantitatively assess the evidence for any relationship between objectively measured PA and a wide range of adiposity indicators to guide PA prescription in adult women. Four databases (PubMed, Web of Science, Scopus, and the Cochrane library) were searched for eligible studies. 35 studies were included (25 observational and 10 interventional studies), with a total of 9,176 women from 20 countries included. The overall pooled correlation for random effects model (n = 1 intervention and n = 15 cross-sectional studies) revealed that the total volume of physical activity (TPA) was moderately associated with percentage body fat (%BF) (r = −0.59; 95% CI: −1.11, −0.24; p = 0.003). There was a weak but significant association between MVPA with body mass index (BMI), waist circumference (WC), and visceral adiposity. Daily steps were significantly associated with BMI, %BF, WC, and fat mass, with the strongest association with %BF (r = −0.41; 95% CI: −0.66, −0.19; p < 0.001). Walking programs resulting in increasing daily steps only had a significant effect on WC (SMD = −0.35; 95% CI: −0.65, −0.05; p = 0.02). Overall, objectively determined PA in terms of steps, TPA and MVPA were favorably associated with adiposity outcomes. The improvement in adiposity can be achieved by simply accumulating more PA than previously and adiposity is more likely to be benefited by PA performed at higher intensity. Nonetheless, these results should be interpreted with caution as there were a small number of studies included in the meta-analysis and the majority of studies included utilized cross-sectional designs.
Humic Acid Modified by Being Incorporated Into Phosphate Fertilizer Increases Its Potency in Stimulating Maize Growth and Nutrient Absorption
Authors: Jing Jianyuan , Zhang Shuiqin , Yuan Liang , Li Yanting , Chen Chengrong , Zhao Bingqiang
Published: August 2022

Humic acid-enhanced phosphate fertilizer (HAP) is widely applied in Chinese agriculture due to its high efficiency. Although the structural composition and physicochemical properties of humic acid (HA) are significantly altered during HAP production, a clear understanding of the mechanisms underlying the biological effects of HA extracted from HAP fertilizer (PHA) on plant growth is still lacking. In the current study, we extracted PHA from HAP and assessed its effects on the dry biomass, phosphorus (P) and nitrogen (N) uptake, and P absorption rate of maize seedlings when supplied at different concentrations (2.5, 5, 10, and 25 mg C L−1) in the hydroponic culture. The root vigor, root plasma membrane H+-ATPase activity, and root nitrate reductase activity were also determined as the representative indicators of the root capacity for nutrient absorption, and used to clarify the mechanism by which PHA affects the maize growth and nutrient absorption. The results showed that the dry biomass, phosphorus uptake, nitrogen uptake, and average phosphorus absorption rates were significantly higher by 14.7–27.9%, 9.6–35.1%, 17.9–22.4%, and 22.1–31.0%, respectively, in plants treated with 2.5–5 mg C L−1 PHA compared to untreated controls. Application of 10–25 mg C L−1 raw HA resulted in similar stimulatory effects on plant growth and nutrient absorption. However, higher levels of PHA (10–25 mg C L−1) negatively impacted these indicators of plant growth. Furthermore, low PHA or high raw HA concentrations similarly improved root vigor and root plasma membrane H+-ATPase and nitrate reductase (NR) activities. These results indicate that lower concentrations of PHA can stimulate maize seedling growth and nutrient absorption to an extent that is comparable to the effect of higher concentrations of raw HA. Thus, the proportion of HA incorporated into HAP could be lower than the theoretical amount estimated through assays evaluating the biological effects of raw HA.
Transcriptome analysis of the 2,4-dichlorophenoxyacetic acid (2,4-D)-tolerant cotton chromosome substitution line CS-B15sh and its susceptible parental lines G. hirsutum L. cv. Texas Marker-1 and G. barbadense L. cv. Pima 379
Authors: Perez Loida M. , Mauleon Ramil , Arick Mark A. , Magbanua Zenaida V. , Peterson Daniel G. , Dean Jeffrey F. D. , Tseng Te Ming
Published: August 2022

The cotton chromosome substitution line, CS-B15sh, exhibits 41% lower injury from 2,4-D when applied at the field recommended rate of 1.12 kg ae ha−1 (1×) than does Texas Marker-1 (TM-1). CS-B15sh was developed in the genetic background of Gossypium hirsutum L. cv TM-1 and has chromosome introgression on the short arm of chromosome 15 from Gossypium barbadense L. cv. Pima 379. In a previous experiment, we observed reduced translocation of [14C]2,4-D outside the treated leaf tissue in CS-B15sh, which contrasted with an increased translocation of the herbicide in the tissues above and below the treated leaf in TM-1. Our results indicate a potential 2,4-D tolerance mechanism in CS-B15sh involving altered movement of 2,4-D. Here, we used RNA sequencing (RNA-seq) to determine the differential expression of genes between 2,4-D-challenged and control plants of the tolerant (CS-B15sh) and susceptible lines (TM-1 and Pima 379). Several components of the 2,4-D/auxin-response pathway—including ubiquitin E3 ligase, PB1|AUX/IAA, ARF transcription factors, and F-box proteins of the SCFTIR1/AFB complex—were upregulated with at least threefold higher expression in TM-1 compared with CS-B15sh, while both Pima 379 and TM-1 showed the same fold change expression for PB1|AUX/IAA mRNA. Some genes associated with herbicide metabolism, including flavin monooxygenase (Gohir.A01G174100) and FAD-linked oxidase (Gohir.D06G002600), exhibited at least a twofold increase in CS-B15sh than in TM-1 (the gene was not expressed in Pima 379), suggesting a potential relationship between the gene’s expression and 2,4-D tolerance. It is interesting to note that glutathione S-transferase was differentially expressed in both CS-B15sh and Pima 379 but not in TM-1, while cytochrome P450 and other genes involved in the oxidation–reduction process were significantly expressed only in CS-B15sh in response to 2,4-D. Gene set enrichment analysis on the union DEGs of the three cotton genotypes revealed the depletion of transcripts involved in photosynthesis and enrichment of transcripts involved in ABA response and signaling.
Identification of early quassinoid biosynthesis in the invasive tree of heaven (Ailanthus altissima) confirms evolutionary origin from protolimonoids
Authors: Chuang Ling , Liu Shenyu , Biedermann Dave , Franke Jakob
Published: August 2022

The tree of heaven, Ailanthus altissima (MILL.) SWINGLE, is a globally invasive plant known to secrete allelopathic metabolites called quassinoids. Quassinoids are highly modified triterpenoids. So far, nothing has been known about the biochemical basis of quassinoid biosynthesis. Here, based on transcriptome and metabolome data of Ailanthus altissima, we present the first three steps of quassinoid biosynthesis, which are catalysed by an oxidosqualene cyclase and two cytochrome P450 monooxygenases, resulting in the formation of the protolimonoid melianol. Strikingly, these steps are identical to the first steps of the biosynthesis of limonoids, structurally different triterpenoids from sister plant families within the same order Sapindales. Our results are therefore not only important to fully understand the biosynthesis of complex triterpenoids in plants, but also confirm the long-standing hypothesis that quassinoids and limonoids share an evolutionary origin. In addition, our transcriptome data for Ailanthus altissima will be beneficial to other researchers investigating the physiology and ecology of this invasive tree.