bluuebunny/crossref_metadata_2025 huggingface dataset:
CDK4/6 inhibitors improve the anti-tumor efficacy of lenvatinib in hepatocarcinoma cells
Authors: Digiacomo Graziana , Fumarola Claudia , La Monica Silvia , Bonelli Mara , Cavazzoni Andrea , Galetti Maricla , Terenziani Rita , Eltayeb Kamal , Volta Francesco , Zoppi Silvia , Bertolini Patrizia , Missale Gabriele , Alfieri Roberta , Petronini Pier Giorgio
Published: July 2022

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with a poor prognosis and limited treatment options. Considering that alterations of the CDK4/6-cyclin D-Rb pathway occur frequently in HCC, we tested the efficacy of two CDK4/6 inhibitors, abemaciclib and ribociclib, in combination with lenvatinib, a multi-kinase inhibitor approved as first-line therapy for advanced HCC, in a panel of HCC Rb-expressing cell lines. The simultaneous drug combinations showed a superior anti-proliferative activity as compared with single agents or sequential schedules of treatment, either in short or in long-term experiments. In addition, the simultaneous combination of abemaciclib with lenvatinib reduced 3D cell growth, and impaired colony formation and cell migration. Mechanistically, these growth-inhibitory effects were associated with a stronger down-regulation of c-myc protein expression. Depending on the HCC cell model, reduced activation of MAPK, mTORC1/p70S6K or src/FAK signaling was also observed. Abemaciclib combined with lenvatinib arrested the cells in the G1 cell cycle phase, induced p21 accumulation, and promoted a stronger increase of cellular senescence, associated with elevation of β-galactosidase activity and accumulation of ROS, as compared with single treatments. After drug withdrawal, the capacity of forming colonies was significantly impaired, suggesting that the anti-tumor efficacy of abemaciclib and lenvatinib combination was persistent.

Our pre-clinical results demonstrate the effectiveness of the simultaneous combination of CDK4/6 inhibitors with lenvatinib in HCC cell models, suggesting that this combination may be worthy of further investigation as a therapeutic approach for the treatment of advanced HCC.
A deep learning model based on dynamic contrast-enhanced magnetic resonance imaging enables accurate prediction of benign and malignant breast lessons
Authors: Chen Yanhong , Wang Lijun , Luo Ran , Wang Shuang , Wang Heng , Gao Fei , Wang Dengbin
Published: July 2022

Objectives

The study aims to investigate the value of a convolutional neural network (CNN) based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting malignancy of breast lesions.

Methods

We developed a CNN model based on DCE-MRI to characterize breast lesions. Between November 2018 and October 2019, 6,165 slices of 364 lesions (234 malignant, 130 benign) in 364 patients were pooled in the training/validation set. Lesions were semi-automatically segmented by two breast radiologists using ITK-SNAP software. The standard of reference was histologic consequences. Algorithm performance was evaluated in an independent testing set of 1,560 slices of 127 lesions in 127 patients using weighted sums of the area under the curve (AUC) scores.

Results

The area under the receiver operating characteristic (ROC) curve was 0.955 for breast cancer prediction while the accuracy, sensitivity, and specificity were 90.3, 96.2, and 79.0%, respectively, in the slice-based method. In the case-based method, the efficiency of the model changed by adjusting the standard for the number of positive slices. When a lesion with three or more positive slices was determined as malignant, the sensitivity was above 90%, with a specificity of nearly 60% and an accuracy higher than 80%.

Conclusion

The CNN model based on DCE-MRI demonstrated high accuracy for predicting malignancy among the breast lesions. This method should be validated in a larger and independent cohort.
Paclitaxel Plus Cetuximab as Induction Chemotherapy for Patients With Locoregionally Advanced Head and Neck Squamous Cell Carcinoma Unfit for Cisplatin-Based Chemotherapy
Authors: Marín-Jiménez Juan A. , Oliva Marc , Peinado Martín Paloma , Cabezas-Camarero Santiago , Plana Serrahima Maria , Vázquez Masedo Gonzalo , Lozano Borbalas Alicia , Cabrera Martín María N. , Esteve Anna , Iglesias Moreno María C. , Vilajosana Altamis Esther , Arribas Hortigüela Lorena , Taberna Sanz Miren , Pérez-Segura Pedro , Mesía Ricard
Published: July 2022

Objectives

Induction chemotherapy (ICT) followed by definitive treatment is an accepted non-surgical approach for locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, ICT remains a challenge for cisplatin-unfit patients. We evaluated paclitaxel and cetuximab (P-C) as ICT in a cohort of LA-HNSCC patients unfit for cisplatin.

Materials and Methods

This is a retrospective analysis of patients with newly diagnosed LA-HNSCC considered unfit for cisplatin-based chemotherapy (age >70 and/or ECOG≥2 and/or comorbidities) treated with weekly P-C followed by definitive radiotherapy and cetuximab (RT-C) between 2010 and 2017. Toxicity and objective response rate (ORR) to ICT and RT-C were collected. Median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Cox regression analysis was performed to determine baseline predictors of OS and PFS.

Results

A total of 57 patients were included. Grade 3–4 toxicity rate to ICT was 54.4%, and there was a death deemed treatment-related (G5). P-C achieved an ORR of 66.7%, including 12.3% of complete responses (CR). After P-C, 45 patients (78.9%) continued with concomitant RT-C. Twenty-six patients (45.6%) achieved a CR after definitive treatment. With a median follow-up of 21.7 months (range 1.2–94.6), median OS and PFS were 22.9 months and 10.7 months, respectively. The estimated 2-year OS and PFS rates were 48.9% and 33.7%, respectively. Disease stage had a negative impact on OS (stage IVb vs. III–IVa: HR = 2.55 [1.08–6.04], p = 0.03), with a trend towards worse PFS (HR = 1.92 [0.91–4.05], p = 0.09). Primary tumor in the larynx was associated with improved PFS but not OS (HR = 0.45 [0.22–0.92], p = 0.03, and HR = 0.69 [0.32–1.54], p = 0.37, respectively).

Conclusion

P-C was a well-tolerated and active ICT regimen in this cohort of LA-HNSCC patients unfit for cisplatin-based chemotherapy. P-C might represent a valid ICT option for unfit patients and may aid patient selection for definitive treatment.
Application of random forest based on semi-automatic parameter adjustment for optimization of anti-breast cancer drugs
Authors: Liu Jiajia , Zhou Zhihui , Kong Shanshan , Ma Zezhong
Published: July 2022

The optimization of drug properties in the process of cancer drug development is very important to save research and development time and cost. In order to make the anti-breast cancer drug candidates with good biological activity, this paper collected 1974 compounds, firstly, the top 20 molecular descriptors that have the most influence on biological activity were screened by using XGBoost-based data feature selection; secondly, on this basis, take pIC50 values as feature data and use a variety of machine learning algorithms to compare, soas to select a most suitable algorithm to predict the IC50 and pIC50 values. It is preliminarily found that the effects of Random Forest, XGBoost and Gradient-enhanced algorithms are good and have little difference, and the Support vector machine is the worst. Then, using the Semi-automatic parameter adjustment method to adjust the parameters of Random Forest, XGBoost and Gradient-enhanced algorithms to find the optimal parameters. It is found that the Random Forest algorithm has high accuracy and excellent anti over fitting, and the algorithm is stable. Its prediction accuracy is 0.745. Finally, the accuracy of the results is verified by training the model with the preliminarily selected data, which provides an innovative solution for the optimization of the properties of anti- breast cancer drugs, and can provide better support for the early research and development of anti-breast cancer drugs.
The long-term outcomes of preterm infants receiving non-invasive high-frequency oscillatory ventilation
Authors: Li Yan , Mo Yan , Yao Liping , Wei Qiufen , Meng Danhua , Tan Wei , Pan Xinnian
Published: July 2022

Objective

To investigate the clinical outcomes of preterm infants who received non-invasive high-frequency oscillatory ventilation following extubation in a neonatal intensive care unit.

Methods

Infants born between 25 and 34 weeks of gestation with a birth weight of <1,500 g, who were admitted into the neonatal intensive care unit of Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, China, requiring mechanical ventilation on admission were randomized to the non-invasive high-frequency ventilation group, nasal intermittent positive pressure ventilation group, or nasal continuous positive airway pressure group following extubation. Their respiratory and neurodevelopmental outcomes were assessed at 12 and 24 months of corrected age.

Results

Among 149 preterm infants who underwent randomization, 139 completed their treatment in the neonatal intensive care unit (45, 47, 47 in the non-invasive high-frequency ventilation group, nasal intermittent positive pressure ventilation group, or nasal continuous positive airway pressure group, respectively), 113 were assessed at 12-month corrected age, and 110 of 113 were assessed again at 24-month corrected age. There were no differences in the number of times bronchitis, pneumonia, wheezing episodes, and re-hospitalization rates appeared due to respiratory diseases among the three groups (P > 0.05); the pulmonary function tests at 12-month corrected age showed respiratory rate, tidal volume, inspiratory time/expiratory time, time to peak expiratory flow/expiratory time, volume at peak expiratory flow/expiratory volume, expiratory flow at 25, 50, and 75% tidal volume were all similar among infants from the 3 groups (P > 0.05). There were no differences in the rates of neurodevelopmental impairment among the three groups at 24-month corrected age (P > 0.05).

Conclusion

As post-extubation respiratory support in preterm infants, non-invasive high-frequency ventilation did not increase the rates of long-term respiratory morbidities and neurodevelopmental impairment compared with nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure.
Testing a Family Supportive End of Life Care Intervention in a Chinese Neonatal Intensive Care Unit: A Quasi-experimental Study With a Non-randomized Controlled Trial Design
Authors: Zhang Rong , Tang Qian , Zhu Li-hui , Peng Xiao-ming , Zhang Na , Xiong Yue-e , Chen Mu-hua , Chen Ke-liang , Luo Dan , Li Xun , Latour Jos M.
Published: July 2022

Background:

Neonatal death often occurs in tertiary Neonatal Intensive Care Units (NICUs). In China, end-of-life-care (EOLC) does not always involve parents.

Aim

The aim of this study is to evaluate a parent support intervention to integrate parents at the end of life of their infant in the NICU.

Methods

A quasi-experimental study using a non-randomized clinical trial design was conducted between May 2020 and September 2021. Participants were infants in an EOLC pathway in the NICU and their parents. Parents were allocated into a family supportive EOLC intervention group or a standard EOLC group based on their wishes. The primary outcomes depression (Edinburgh Postnatal Depression Scale for mothers; Hamilton Depression rating scale for fathers) and Satisfaction with Care were measured 1 week after infants' death. Student t-test for continuous variables and the Chi-square test categorical variables were used in the statistical analysis.

Results

In the study period, 62 infants died and 45 infants and 90 parents were enrolled; intervention group 20 infants, standard EOLC group 25 infants. The most common causes of death in both groups were congenital abnormalities (n = 20, 44%). Mean gestational age of infants between the family supportive EOLC group and standard EOLC group was 31.45 vs. 33.8 weeks (p = 0.234). Parents between both groups did not differ in terms of age, delivery of infant, and economic status. In the family support group, higher education levels were observed among mother (p = 0.026) and fathers (p = 0.020). Both mothers and fathers in the family supportive EOLC group had less depression compared to the standard EOLC groups; mothers (mean 6.90 vs. 7.56; p = 0.017) and fathers (mean 20.7 vs. 23.1; p < 0.001). Parents reported higher satisfaction in the family supportive EOLC group (mean 88.9 vs. 86.6; p < 0.001).

Conclusions

Supporting parents in EOLC in Chinese NICUs might decreased their depression and increase satisfaction after the death of their infant. Future research needs to focus on long-term effects and expand on larger populations with different cultural backgrounds.

Clinical Trial Registration

www.ClinicalTrials.gov, identifier: NCT05270915.
Congenital etiologies of exocrine pancreatic insufficiency
Authors: Scheers Isabelle , Berardis Silvia
Published: July 2022

Congenital exocrine pancreatic insufficiency is a rare condition. In a vast majority of patients, exocrine dysfunction occurs as part of a multisystemic disease, the most prevalent being cystic fibrosis and Shwachman-Bodian-Diamond syndrome. Recent fundamental studies have increased our understanding of the pathophysiology of these diseases. Exocrine pancreatic dysfunction should be considered in children with failure to thrive and fatty stools. Treatment is mainly supportive and consists of pancreatic enzyme replacement and liposoluble vitamins supplementation.
The safety of blinatumomab in pediatric patients with acute lymphoblastic leukemia: A systematic review and meta-analysis
Authors: Marrapodi Maria Maddalena , Mascolo Annamaria , di Mauro Gabriella , Mondillo Gianluca , Pota Elvira , Rossi Francesca
Published: July 2022

Background

Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that has proven efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Despite its efficacy, it has also been associated with the development of potentially serious adverse events such as the cytokine release syndrome (CRS) and neurologic events. The present meta-analysis aimed to assess the safety profile of blinatumomab in terms of serious adverse events, CRS, and neurologic events (such as seizure and encephalopathy) in pediatric patients with B-cell ALL.

Methods and findings

A systematic review was conducted in Pubmed up to December 10, 2021 to retain pediatric clinical trials on blinatumomab. A random effect meta-analysis approach was used. This study followed the PRISMA statement. Four out of the 255 initial references were selected, of which 2 were phase 1/2 clinical trials and 2 phase 3 clinical trials. Blinatumomab was associated with a lower risk of serious adverse events (Risk ratio RR, 0.56; 95% CI, 0.32–0.99), febrile neutropenia (RR, 0.13; 95% CI, 0.06–0.26), infection (RR, 0.40; 95% CI, 0.29–0.56), and grade ≥ 3 adverse events (RR, 0.79; 95% CI, 0.67–0.93) compared to chemotherapy. No difference in the risk of CRS (RR, 8.37; 95% CI, 0.27–260.97) and seizure (RR, 6.43; 95% CI, 0.79–53.08) was observed between groups, while for encephalopathy a higher risk was associated with blinatumomab compared to chemotherapy (RR, 8.90; 95% CI, 1.08–73.29).

Conclusion

Our data support the good safety profile of bliantumomab in treating pediatric patients with B-ALL.
Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease Models
Authors: Poirier Andrée-Anne , Côté Mélissa , Jarras Hend , Litim Nadhir , Lamontagne-Proulx Jérôme , Al-Sweidi Sara , Morissette Marc , Lachhab Asmaa , Pelletier Martin , Di Paolo Thérèse , Soulet Denis
Published: July 2022

Gastrointestinal disorders in Parkinson’s disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.
The Use of the Target Trial Approach in Perinatal Pharmacoepidemiology: A Scoping Review Protocol
Authors: Leal Lisiane Freitas , Grandi Sonia Marzia , Mota Daniel Marques , Ferreira Paulo José Gonçalves , Gore Genevieve , Platt Robert William
Published: July 2022

Background: Pregnant and postpartum women have been historically excluded from clinical trials, with data on the safety of drugs relying on observational research. Methodological concerns regarding the timing and dosing of medications, data sources, study designs, and methods used for estimating associations are still problematic in observational studies. Answering causal questions is even more complex. Despite the increased interest in emulating target trials using observational data, little is known about this approach in perinatal pharmacoepidemiology.

Objective: This scoping review protocol aims to describe the methodology for assessing the available literature concerning emulating target trials for studying outcomes in women exposed to medications in the preconception, perinatal, or postpartum periods.

Methods and Analysis: We will follow the methods detailed in the Joanna Briggs Institute reviewer’s manual. We will adopt the six-stage framework recommended by Arksey and O'Malley and Levac and others. Web scraping techniques will be used for identifying relevant studies. Two authors will select articles based on the title and abstract, with discrepancies resolved by consensus, by a third reviewer. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews flow diagram will be presented to reflect the search process. We will use existing statements to identify quality gaps in the current literature. Variables related to the content for perinatal pharmacoepidemiologic research will be included. The Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) will guide the assessment of the target trial emulation (i.e., treatment strategies compared, assignment procedures, follow-up period, outcome, and causal contrasts).

Discussion: Data regarding the safety of drugs taken, prior to and during pregnancy and while lactating are lacking and it is necessary to understand how we can answer these questions using rigorous methods in observational research. Through this scoping review, we intend to understand to what extent the target trial approach is being used in perinatal pharmacoepidemiology and provide recommendations to improve its use in this field.

Ethics and Dissemination: Secondary data from published scientific articles will be used, not requiring approval by the Research Ethics Committee with human beings. Findings will be submitted to a peer-reviewed journal.
Efficacy and safety of intravenous acetaminophen (2 g/day) for reducing opioid consumption in Chinese adults after elective orthopedic surgery: A multicenter randomized controlled trial
Authors: Yin Feng , Ma Wei , Liu Qiao , Xiong Liu-Lin , Wang Ting-Hua , Li Qian , Liu Fei
Published: July 2022

Background: Acetaminophen is an important component of a multimodal analgesia strategy to reduce opioid consumption and pain intensity after an orthopedic surgery. The opioid-sparing efficacy of intravenous acetaminophen has been established at a daily dose of 4 g. However, it is still unclear for the daily dose of 2 g of acetaminophen, which is recommended by the China Food and Drug Administration Center for Drug Evaluation, in terms of its efficacy and safety.

Objectives: This study aimed to evaluate the efficacy and safety of intravenous acetaminophen at a daily dose of 2 g for reducing opioid consumption and pain intensity after orthopedic surgery.

Methods: In this multicenter, randomized, double-blind, placebo-controlled phase III trial, 235 patients who underwent orthopedic surgery were randomly assigned to receive intravenous acetaminophen 500 mg every 6 h or placebo. Postoperative morphine consumption, pain intensity at rest and during movement, and adverse events were analysed.

Results: For the mean (standard deviation) morphine consumption within 24 h after surgery, intravenous acetaminophen was superior to placebo both in the modified intention-to-treat analysis [8.7 (7.7) mg vs. 11.2 (9.2) mg] in the acetaminophen group and the placebo group, respectively. Difference in means: 2.5 mg; 95% confidence interval, 0.25 to 4.61; p = 0.030), and in the per-protocol analysis (8.3 (7.0) mg and 11.7 (9.9) mg in the acetaminophen group and the placebo group, respectively. Difference in means: 3.4 mg; 95% confidence interval: 1.05 to 5.77; p = 0.005). The two groups did not differ significantly in terms of pain intensity and adverse events.

Conclusion: Our results suggest that intravenous acetaminophen at a daily dose of 2 g can reduce morphine consumption by Chinese adults within the first 24 h after orthopedic surgery, but the extent of reduction is not clinically relevant.

Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT02811991].
Therapeutic Effect of Ultrasound Combined With Porous Lipid Clioquinol/PLGA Microbubbles on Ferroptosis in HL-1 Cardiac Cell Induced by Isoproterenol Attack
Authors: Li Nana , Dong Lei , Shen Yuanyuan , Wang Yongling , Chang Liansheng , Wu Hongwei , Chang Yuqiao , Li Menghao , Li Dan , Li Zhaoyi , He Mei , Li Cheng , Wei Yao , Xie Haiqin , Wang Feng
Published: July 2022

In recent years, studies have shown a close relationship between cardiomyocyte death and ferroptosis. Clioquinol (CQ) can inhibit ferroptosis. Porous lipid-poly (lactic-co-glycolic acid) (PLGA) microbubbles (MBs) were prepared by double emulsification (W1/O/W2) using 1,2-dioctadecanoyl-sn-glycero-3-phophocholine and PLGA as raw materials. Porous lipid-PLGA MBs were used as carriers to prepare CQ/PLGA MBs containing CQ. CQ/PLGA had the advantages of high drug loading, good biocompatibility, and sustained release. Our results showed that CQ/PLGA improved the effect of CQ and reduced its cytotoxicity. Under low-frequency ultrasound with certain parameters, CQ/PLGA showed steady-state cavitation, which increased the membrane permeability of mouse cardiomyocyte HL-1 to a certain extent and further prevented the process of ferroptosis in mouse cardiomyocyte HL-1.
Flavonoid Group of Smilax glabra Roxb. Regulates the Anti-Tumor Immune Response Through the STAT3/HIF-1 Signaling Pathway
Authors: Guo Yingxue , Mao Weiye , Jin Lu , Xia Linying , Huang Jie , Liu Xia , Ni Ping , Shou Qiyang , Fu Huiying
Published: July 2022

Background:Smilax glabra Roxb. (SGR) is a widely used traditional Chinese medicine, which has known effects of enhancing immunity. However, its anti-tumor effects and mechanism of action are still unclear.

Methods: We selected MMTV-PyMT mice to determine the anti-tumor efficacy of SGR ethyl acetate (SGR-EA). First, flow cytometry was used to detect the number of immune cells in the mice tumor microenvironment. Furthermore, M2 polarization of macrophages was stimulated in vitro, and the expressions of macrophage M1/M2 surface markers and mRNA were as determined. Finally, we carried out a network pharmacology analysis on the active components of SGR-EA and in vitro experiments to verify that SGR-EA regulated the hypoxia-inducible factor (HIF)-1 signaling pathway to modulate the anti-tumor immune response by resetting M2 macrophages toward the M1 phenotype which inhibited tumor growth and lung metastasis in the mice.

Result: SGR-EA inhibited tumor growth and lung metastasis in the mice. Tumor-associated macrophages switched from M2 to the tumor-killing M1 phenotype and promoted the recruitment of CD4+ and CD8+ T cells in the tumor microenvironment. In vitro, SGR-EA significantly inhibited the polarization of macrophages into M2 macrophages and increased the number of M1 macrophages. In addition, following an intervention with SGR-EA, the expression of the HIF-1 signaling pathway-related proteins stimulated by interleukin-4 in macrophages was significantly inhibited.

Conclusion: SGR-EA played an anti-tumor role by inhibiting the activation of the HIF-1 signaling pathway and response by resetting tumor-associated macrophages toward the M1 phenotype.
Effects of 6-Hydroxykaempferol: A Potential Natural Product for Amelioration of Tendon Impairment
Authors: Mok Tsz Ngai , He Qiyu , Zhang Xiaoxi , Sin Tat Hang , Wang Huajun , Hou Huige , Pan Jinghua , Zheng Xiaofei , Zha Zhengang , Li Jieruo
Published: July 2022

Tendon impairment is a common injury associated with impairment of range of motion and pain. Currently, evidence has confirmed that natural herbs contribute to orthopedics and have shown excellent results in the clinical management of tendon impairment. Shujin Huoxue tablet (SHT) and its complex prescriptions are regularly used in tendon rupture therapy with positive results. This study aimed to discover the potential molecules that promote tendon healing. The Chinese traditional medicine system pharmacological database analysis platform (TCMSP) is the primary resource. The Traditional Chinese Medicine Integrated Database and Encyclopedia of Traditional Chinese Medicine database were used as secondary databases. The GeneCards database was used to search for reported tendinopathy-related genes by keywords. Functions of the targeted genes were analyzed using Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes. Protein–protein interaction information was extracted from the STRING database. Docking study, MTT assay, quantitative real-time PCR, and migration assays were performed to obtain a better understanding of the herbs according to cell function to test the basic pharmacological action in vitro. A total of 104 disease nodes, 496 target gene nodes, 35 ingredient nodes, and one drug node were extracted. According to the TCMSP database, 6-hydroxykaempferol, which reportedly promotes the proliferation of microvascular endothelial cells, is a molecule found in SHT. We found that it promoted the proliferation and migration of tendon fibroblasts and elevated tendon repair-related gene expression. Purified 6-hydroxykaempferol promoted the proliferation and migration of tendon fibroblasts and increased their mRNA expression in tendon proliferation.
Nitidine Chloride Alleviates Inflammation and Cellular Senescence in Murine Osteoarthritis Through Scavenging ROS
Authors: Lin Changjian , Ge Lujie , Tang Luping , He Yuzhe , Moqbel Safwat Adel Abdo , Xu Kai , Ma Diana , Zhou Xing , Ran Jisheng , Wu Lidong
Published: July 2022

Osteoarthritis (OA) is one of the most common chronic musculoskeletal disorder worldwide, representing a major source of disability, pain and socioeconomic burden. Yet the effective pharmaceutical treatments applied in the clinical works are merely symptomatic management with uncertainty around their long-term safety and efficacy, namely no drugs currently are capable of modulating the biological progression of OA. Here, we identified the potent anti-inflammatory as well as anti-oxidative properties of Nitidine Chloride (NitC), a bioactive phytochemical alkaloid extracted from natural herbs, in IL-1β-treated rat articular chondrocytes (RACs), LPS-stimulated RAW 264.7 and rat osteoarthritic models in vivo. We demonstrated NitC remarkably inhibited the production of inflammatory mediators including COX2 and iNOS, suppressed the activation of MAPK and NF-κB cell signaling pathway and reduced the expression of extracellular matrix (ECM) degrading enzymes including MMP3, MMP9 and MMP13 in IL-1β-treated RACs. Several emerging bioinformatics tools were performed to predict the underlying mechanism, the result of which indicated the potential reactive oxygen species (ROS) clearance potential of NitC. Further, NitC exhibited its anti-oxidative potential through ameliorating cellular senescence in IL-1β-treated RACs and decreasing NLRP3 inflammasomes activation in LPS-stimulated RAW 264.7 via scavenging ROS. Additionally, X-ray, micro-CT and other experiments in vivo demonstrated that intra-articular injection of NitC significantly alleviated the cartilage erosion, ECM degradation and subchondral alterations in OA progression. In conclusion, the present study reported the potent anti-inflammatory and anti-oxidative potential of NitC in OA biological process, providing a promising therapeutic agent for OA management.
Nucleotide-Binding Oligomerization Domain 1/Toll-Like Receptor 4 Co-Engagement Promotes Non-Specific Immune Response Against K562 Cancer Cells
Authors: Guzelj Samo , Jakopin Žiga
Published: July 2022

Nucleotide-binding oligomerization domain 1 (NOD1) receptor and Toll-like receptor 4 (TLR4) belong to the family of pattern recognition receptors. Interactions between these receptors profoundly shape the innate immune responses. We previously demonstrated that co-stimulation of peripheral blood mononuclear cells (PBMCs) with D-glutamyl-meso-diaminopimelic acid (iE-DAP)-based NOD1 agonists and lipopolysaccharide (LPS), a TLR4 agonist, synergistically increased the cytokine production. Herein, we postulate that stimulation of NOD1 alone or a combined stimulation of NOD1 and TLR4 could also strengthen PBMC-mediated cytotoxicity against cancer cells. Initially, an in-house library of iE-DAP analogs was screened for NOD1 agonist activity to establish their potency in HEK-Blue NOD1 cells. Next, we showed that our most potent NOD1 agonist SZZ-38 markedly enhanced the LPS-induced cytokine secretion from PBMCs, in addition to PBMC- and natural killer (NK) cell-mediated killing of K562 cancer cells. Activation marker analysis revealed that the frequencies of CD69+, CD107a+, and IFN-γ+ NK cells are significantly upregulated following NOD1/TLR4 co-stimulation. Of note, SZZ-38 also enhanced the IFN-γ-induced PBMC cytotoxicity. Overall, our findings provide further insight into how co-engagement of two pathways boosts the non-specific immune response and attest to the importance of such interplay between NOD1 and TLR4.
Vicious LQT induced by a combination of factors different from hERG inhibition
Authors: Xu Xinping , Yin Yue , Li Dayan , Yao Binwei , Zhao Li , Wang Haoyu , Wang Hui , Dong Ji , Zhang Jing , Peng Ruiyun
Published: July 2022

Clinically, drug-induced torsades de pointes (TdP) are rare events, whereas the reduction of the human ether-à-go-go-related gene (hERG) current is common. In this study, we aimed to explore the specific factors that contribute to the deterioration of hERG inhibition into malignant ventricular arrhythmias. Cisapride, a drug removed from the market because it caused long QT (LQT) syndrome and torsade de pointes (TdP), was used to induce hERG inhibition. The effects of cisapride on the hERG current were evaluated using a whole-cell patch clamp. Based on the dose-response curve of cisapride, models of its effects at different doses (10, 100, and 1,000 nM) on guinea pig heart in vitro were established. The effects of cisapride on electrocardiogram (ECG) signals and QT interval changes in the guinea pigs were then comprehensively evaluated by multi-channel electrical mapping and high-resolution fluorescence mapping, and changes in the action potential were simultaneously detected. Cisapride dose-dependently inhibited the hERG current with a half inhibitory concentration (IC50) of 32.63 ± 3.71 nM. The complete hERG suppression by a high dose of cisapride (1,000 nM) prolonged the action potential duration (APD), but not early after depolarizations (EADs) and TdP occurred. With 1 μM cisapride and lower Mg2+/K+, the APD exhibited triangulation, dispersion, and instability. VT was induced in two of 12 guinea pig hearts. Furthermore, the combined administration of isoproterenol was not therapeutic and increased susceptibility to ventricular fibrillation (VF) development. hERG inhibition alone led to QT and ERP prolongation and exerted an anti-arrhythmic effect. However, after the combination with low concentrations of magnesium and potassium, the prolonged action potential became unstable, triangular, and dispersed, and VT was easy to induce. The combination of catecholamines shortened the APD, but triangulation and dispersion still existed. At this time, VF was easily induced and sustained.
Detecting drug-drug interactions between therapies for COVID-19 and concomitant medications through the FDA adverse event reporting system
Authors: Jeong Eugene , Nelson Scott D. , Su Yu , Malin Bradley , Li Lang , Chen You
Published: July 2022

Background: COVID-19 patients with underlying medical conditions are vulnerable to drug-drug interactions (DDI) due to the use of multiple medications. We conducted a discovery-driven data analysis to identify potential DDIs and associated adverse events (AEs) in COVID-19 patients from the FDA Adverse Event Reporting System (FAERS), a source of post-market drug safety.

Materials and Methods: We investigated 18,589 COVID-19 AEs reported in the FAERS database between 2020 and 2021. We applied multivariate logistic regression to account for potential confounding factors, including age, gender, and the number of unique drug exposures. The significance of the DDIs was determined using both additive and multiplicative measures of interaction. We compared our findings with the Liverpool database and conducted a Monte Carlo simulation to validate the identified DDIs.

Results: Out of 11,337 COVID-19 drug-Co-medication-AE combinations investigated, our methods identified 424 signals statistically significant, covering 176 drug-drug pairs, composed of 13 COVID-19 drugs and 60 co-medications. Out of the 176 drug-drug pairs, 20 were found to exist in the Liverpool database. The empirical p-value obtained based on 1,000 Monte Carlo simulations was less than 0.001. Remdesivir was discovered to interact with the largest number of concomitant drugs (41). Hydroxychloroquine was detected to be associated with most AEs (39). Furthermore, we identified 323 gender- and 254 age-specific DDI signals.

Conclusion: The results, particularly those not found in the Liverpool database, suggest a subsequent need for further pharmacoepidemiology and/or pharmacology studies.
A Novel Anti-Cancer Therapy: CRISPR/Cas9 Gene Editing
Authors: Chen Xin-Zhu , Guo Rong , Zhao Cong , Xu Jing , Song Hang , Yu Hua , Pilarsky Christian , Nainu Firzan , Li Jing-Quan , Zhou Xin-Ke , Zhang Jian-Ye
Published: July 2022

Cancer becomes one of the main causes of human deaths in the world due to the high incidence and mortality rate and produces serious economic burdens. With more and more attention is paid on cancer, its therapies are getting more of a concern. Previous research has shown that the occurrence, progression, and treatment prognosis of malignant tumors are closely related to genetic and gene mutation. CRISPR/Cas9 has emerged as a powerful method for making changes to the genome, which has extensively been applied in various cell lines. Establishing the cell and animal models by CRISPR/Cas9 laid the foundation for the clinical trials which possibly treated the tumor. CRISPR-Cas9-mediated genome editing technology brings a great promise for inhibiting migration, invasion, and even treatment of tumor. However, the potential off-target effect limits its clinical application, and the effective ethical review is necessary. The article reviews the molecular mechanisms of CRISPR/Cas9 and discusses the research and the limitation related to cancer clinical trials.
Class IIa histone deacetylase inhibition ameliorates acute kidney injury by suppressing renal tubular cell apoptosis and enhancing autophagy and proliferation
Authors: Li Jialu , Yu Chao , Shen Fengchen , Cui Binbin , Liu Na , Zhuang Shougang
Published: July 2022

Expression and function of histone deacetylases (HDACs) vary with cell types and pathological conditions. Our recent studies showed that pharmacological targeting class IIa HDACs attenuated renal fibrosis, but the effect of class IIa HDAC inhibition on acute kidney injury (AKI) remains unknown. In this study, we found that four class IIa HDACs (4, 5, 7, 9) were highly expressed in the kidney of folic acid (FA) and ischemia/reperfusion (I/R)-induced AKI in mice. Administration of TMP269, a potent and selective class IIa HDAC inhibitor, improved renal function and reduced tubular cell injury and apoptosis, with concomitant suppression of HDAC4 and elevation of acetyl-histone H3. Mechanistical studies showed that TMP269 treatment inhibited FA and I/R-induced caspase-3 cleavage, Bax expression and p53 phosphorylation. Conversely, TMP269 administration preserved expression of E-cadherin, BMP7, Klotho and Bcl-2 in injured kidneys. Moreover, TMP269 was effective in promoting cellular autophagy as indicated by increased expression of Atg7, beclin-1, and LC3II, and promoted renal tubular cell proliferation as shown by increased number of proliferating cell nuclear antigen-positive cells and expression of cyclin E. Finally, blocking class IIa HDACs inhibited FA-and I/R-induced phosphorylation of extracellular signal-regulated kinases 1 and 2, and p38, two signaling pathways associated with the pathogenesis of AKI. Collectively, these results suggest that pharmacological inhibition of class IIa HDACs protects against AKI through ameliorating apoptosis, enhancing autophagy and promoting proliferation of renal tubular cells by targeting multiple signaling pathways.
Metabonomic analysis of abnormal sphingolipid metabolism in rheumatoid arthritis synovial fibroblasts in hypoxia microenvironment and intervention of geniposide
Authors: Ke Jiang-Tao , Zhang Heng , Bu Yan-Hong , Gan Pei-Rong , Chen Fang-Yuan , Dong Xin-Tong , Wang Yan , Wu Hong
Published: July 2022

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by a joint hypoxia microenvironment. Our previous untargeted metabolomics study found that sphingolipid (SPL) metabolism was abnormal in the joint synovial fluid samples from adjuvant arthritis (AA) rats. Geniposide (GE), an iridoid glycoside component of the dried fruit of Gardenia jasminoides Ellis, is commonly used for RA treatment in many Asian countries. At present, the mechanism of GE in the treatment of RA, especially in the joint hypoxia microenvironment, is not entirely clear from the perspective of SPL metabolism. The purpose of this research was to explore the potential mechanism of abnormal SPL metabolism in RA joint hypoxia microenvironment and the intervention effect of GE, through the untargeted metabolic analysis based on the ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Arthritis index, foot swelling and histopathology were used to assess whether the AA rat model was successfully established. The SPLs extracts collected from AA rats’ synovial tissue, serum and rheumatoid arthritis synovial fibroblasts (RASFs, MH7A cells, hypoxia/normoxia culture) were analyzed by metabolomics and lipdomics approach based on UPLC-Q-TOF/MS, to identify potential biomarkers associated with disorders of GE regulated RA sphingolipid metabolism. As a result, 11 sphingolipid metabolites related to RA were screened and identified. Except for galactosylceramide (d18:1/20:0), GE could recover the change levels of the above 10 sphingolipid biomarkers in varying degrees. Western blotting results showed that the changes in ceramide (Cer) level regulated by GE were related to the down-regulation of acid-sphingomyelinase (A-SMase) expression in synovial tissue of AA rats. To sum up, this research examined the mechanism of GE in the treatment of RA from the perspective of SPL metabolism and provided a new strategy for the screening of biomarkers for clinical diagnosis of RA.
Pleiotropic ZmICE1 Is an Important Transcriptional Regulator of Maize Endosperm Starch Biosynthesis
Authors: Liu Hanmei , Wang Yongbin , Liu Lijun , Wei Bin , Wang Xieqin , Xiao Qianlin , Li Yangping , Ajayo Babatope Samuel , Huang Yubi
Published: July 2022

Starch, the major component of cereal grains, affects crop yield and quality and is widely used in food and industrial applications. The biosynthesis of maize starch is a complex process involving a series of functional enzymes. However, the sophisticated regulatory mechanisms of starch biosynthetic genes have not been fully elaborated. The basic/helix-loop-helix (bHLH) transcription factors are widely distributed in eukaryotes and participate in many physiological processes. In this study, 202 bHLH encoding genes were identified in the maize genome by Blast method. ZmICE1 gene, which belongs to the ICE subfamily of the bHLH family, was obtained and expressed mainly in maize filling endosperm and co-expressed with 14 starch biosynthesis genes. Based on the comparative analyses across different plant species, we revealed that the gene structures and protein domains of the ICE subfamily were conserved between monocots and dicots, suggesting their functional conservation feature. Yeast activation and subcellular localization assays suggested that ZmICE1 had transcriptional activation activity and localized in the nucleus. Yeast one-hybrid assays confirmed that ZmICE1 could directly bind to the promoters of ZmSSIIa and ZmGBSSI. Transient gene expression analysis in maize endosperm revealed that ZmICE1 positively regulated the expression of ZmSSIIa, but inhibited the expression of ZmGBSSI. Our results indicated that ZmICE1 could function as a regulator of maize starch biosynthesis.
Short waterlogging events differently affect morphology and photosynthesis of two cucumber (Cucumis sativus L.) cultivars
Authors: Olorunwa Omolayo J. , Adhikari Bikash , Brazel Skyler , Popescu Sorina C. , Popescu George V. , Barickman T. Casey
Published: July 2022

Waterlogging induces growth and developmental changes in sensitive crops such as cucumber (Cucumis sativus L.) during early plant development. However, information on the physiological mechanisms underpinning the response of cucumber plants to waterlogging conditions is limited. Here, we investigated the effects of 10-day waterlogging stress on the morphology, photosynthesis, and chlorophyll fluorescence parameters in two cultivars of cucumber seedlings. Waterlogging stress hampered cultivars’ growth, biomass accumulation, and photosynthetic capacity. Both cultivars also developed adventitious roots (ARs) after 10 days of waterlogging (DOW). We observed differential responses in the light- and carbon-dependent reactions of photosynthesis, with an increase in light-dependent reactions. At the same time, carbon assimilation was considerably inhibited by waterlogging. Specifically, the CO2 assimilation rate (A) in leaves was significantly reduced and was caused by a corresponding decrease in stomatal conductance (gs). The downregulation of the maximum rate of Rubisco efficiency (Vcmax) and the maximum rate of photosynthetic electron transport (Jmax) were non-stomatal limiting factors contributing to A reduction. Exposure of cucumber to 10 DOW affected the PSII photochemistry by downregulating the PSII quantum yield (ΦPSII). The redox state of the primary quinone acceptor in the lake model (1-qL), a measure of the regulatory balance of the light reactions, became more oxidized after 10 DOW, indicating enhanced electron sink capacity despite a reduced A. Overall, the results suggest that waterlogging induces alterations in the photochemical apparatus efficiency of cucumber. Thus, developing cultivars that resist inhibition of PSII photochemistry while maintaining carbon metabolism is a potential approach for increasing crops’ tolerance to waterlogged environments.
Benchmarking organic electrochemical transistors for plant electrophysiology
Authors: Armada-Moreira Adam , Diacci Chiara , Dar Abdul Manan , Berggren Magnus , Simon Daniel T. , Stavrinidou Eleni
Published: July 2022

Plants are able to sense and respond to a myriad of external stimuli, using different signal transduction pathways, including electrical signaling. The ability to monitor plant responses is essential not only for fundamental plant science, but also to gain knowledge on how to interface plants with technology. Still, the field of plant electrophysiology remains rather unexplored when compared to its animal counterpart. Indeed, most studies continue to rely on invasive techniques or on bulky inorganic electrodes that oftentimes are not ideal for stable integration with plant tissues. On the other hand, few studies have proposed novel approaches to monitor plant signals, based on non-invasive conformable electrodes or even organic transistors. Organic electrochemical transistors (OECTs) are particularly promising for electrophysiology as they are inherently amplification devices, they operate at low voltages, can be miniaturized, and be fabricated in flexible and conformable substrates. Thus, in this study, we characterize OECTs as viable tools to measure plant electrical signals, comparing them to the performance of the current standard, Ag/AgCl electrodes. For that, we focused on two widely studied plant signals: the Venus flytrap (VFT) action potentials elicited by mechanical stimulation of its sensitive trigger hairs, and the wound response of Arabidopsis thaliana. We found that OECTs are able to record these signals without distortion and with the same resolution as Ag/AgCl electrodes and that they offer a major advantage in terms of signal noise, which allow them to be used in field conditions. This work establishes these organic bioelectronic devices as non-invasive tools to monitor plant signaling that can provide insight into plant processes in their natural environment.
Why Do Trump's Authoritarian Followers Resist COVID-19 Authorities? Because They Are Not Really Authoritarian Followers
Authors: Hibbing John R.
Published: July 2022

People's responses to the threat posed by COVID-19 varied widely. In direct contradiction to the popular theory that Trump supporters prefer to submit to powerful people, Trump's most enthusiastic followers actually were the most vocal in resisting the urgings of authorities to get vaccinated and to wear masks. I explain this anomaly by showing that Trump's followers are driven less by a desire for authority and more by a desire to be secure from the threats human outsiders pose to society's historically dominant racial, language, religious, and cultural group. Far from being authoritarians, the followers of leaders such as Donald Trump stridently oppose all authority figures who divert attention from what they believe are the real threats: immigrants, powerful foreign enemies, diversity, terrorists, and criminals. From this perspective, it is unsurprising that those with a securitarian orientation would not take seriously authorities who are concerned with the threat posed by an mRNA virus.