bluuebunny/crossref_metadata_2025 huggingface dataset:
Emotional Word Processing in Patients With Juvenile Myoclonic Epilepsy
Authors: Rainer Lucas Johannes , Kronbichler Martin , Kuchukhidze Giorgi , Trinka Eugen , Langthaler Patrick Benjamin , Kronbichler Lisa , Said-Yuerekli Sarah , Kirschner Margarita , Zimmermann Georg , Höfler Julia , Schmid Elisabeth , Braun Mario
Published: June 2022

Objective

According to Panksepp's hierarchical emotion model, emotion processing relies on three functionally and neuroanatomically distinct levels. These levels comprise subcortical networks (primary level), the limbic system (secondary level), and the neocortex (tertiary level) and are suggested to serve differential emotional processing. We aimed to validate and extend previous evidence of discrete and dimensional emotion processing in patient with juvenile myoclonic epilepsy (JME).

Methods

We recorded brain activity of patients with JME and healthy controls in response to lexical decisions to words reflecting the discrete emotion fear and the affective dimension negativity previously suggested to rely on different brain regions and to reflect different levels of processing. In all study participants, we tested verbal cognitive functions, as well as the relationship of psychiatric conditions, seizure types and duration of epilepsy and emotional word processing.

Results

In support of the hierarchical emotion model, we found an interaction of discrete emotion and affective dimensional processing in the right amygdala likely to reflect secondary level processing. Brain activity related to affective dimensional processing was found in the right inferior frontal gyrus and is suggested to reflect tertiary level processing. Psychiatric conditions, type of seizure nor mono- vs. polytherapy and duration of epilepsy within patients did not have any effect on the processing of emotional words. In addition, no differences in brain activity or response times between patients and controls were observed, despite neuropsychological testing revealed slightly decreased verbal intelligence, verbal fluency and reading speed in patients with JME.

Significance

These results were interpreted to be in line with the hierarchical emotion model and to highlight the amygdala's role in processing biologically relevant stimuli, as well as to suggest a semantic foundation of affective dimensional processing in prefrontal cortex. A lack of differences in brain activity of patients with JME and healthy controls in response to the emotional content of words could point to unaffected implicit emotion processing in patients with JME.
15-Hydroxyprostaglandin Dehydrogenase Is a Predictor of Stroke-Associated Pneumonia
Authors: Xu Yunfei , Qiao Haoduo , Yang Shun , Zhou Lin , Zhao Yao , Xu Qing , Miao Shuying , Yuan Dun , Zhao Jie , Liu Ying
Published: June 2022

Background and Purpose

Stroke is a serious fatal and disabling disease. Stroke-associated pneumonia (SAP) is the most common complication of stroke, which may further aggravate the stroke. The prevention and early prediction of SAP is a key clinical strategy. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is involved in pneumonia, while its relationship with SAP has yet to be determined. Therefore, we investigated the predictive value of 15-PGDH for SAP and visualized their relationship.

Methods

Stroke patients were recruited and divided into SAP group and Non-SAP group. Baseline demographic and clinical data were obtained from the medical record system, blood samples were collected to detect relevant variables and 15-PGDH levels. Patient characteristics were compared with a t-test. Binary logistic regression analysis was performed to determine the predictive value of 15-PGDH for SAP. Restricted cubic splines (RCS) were performed to visualize the relationship between 15-PGDH and SAP risk. Finally, the SAP patient characteristics between the severe group and mild group were compared.

Results

50 patients were enrolled and divided into SAP group (n = 26) and Non-SAP group (n = 24). 15-PGDH in the SAP group was lower than that in the Non-SAP group (0.258 ± 0.275 vs. 0.784 ± 0.615, p = 0.025). Binary logistic regression analysis revealed that the lower 15-PGDH, the higher the risk of SAP (OR = 0.04, 95%CI, 0.010–0.157, p < 0.001). The RCS model showed the L-shaped relationship between 15-PGDH and SAP.

Conclusions

In stroke patients, serum 15-PGDH is a valuable biomarker for predicting SAP. There is an L-shaped relationship between the level of 15-PGDH and the risk of SAP.
A New Scale for Predicting the Risk of In-hospital Mortality in Patients With Traumatic Spinal Cord Injury
Authors: Gong Yining , Du Jinpeng , Hao Dingjun , He Baorong , Cao Yang , Gao Xiangcheng , Zhang Bo , Yan Liang
Published: June 2022

Purpose

To analyze the relative factors influencing in-hospital mortality in patients with traumatic spinal cord injury (TSCI), and develop a score scale for predicting the risk of in-hospital mortality.

Method

We reviewed the medical records from 59 spine centers in mainland China from 1 January 2018 to 31 December 2018. The inclusion criteria were (1) confirmed diagnosis of TSCI, (2) hospitalization within 7 days of injury, and (3) affecting neurological level from C1 to L1. The exclusion criteria were (1) readmission, and (2) incomplete data. Included patients were classified into the survival and non-survival groups according to their status at discharge. Univariate and multivariate logistic regressions were performed to identify the factors related to in-hospital mortality in patients with TSCI. A new scale was developed, and the mortality rate in each risk group was calculated.

Results

Of the 3,176 participants, 23 (0.7%) died in the hospital, and most of them died from respiratory diseases (17/23, 73.9%). After univariate and multivariate logistic regression analysis, cervical spinal cord injury [odds ratio (OR) = 0.264, 95% confidence interval (CI): 0.076–0.917, P = 0.036], abdominal visceral injury (OR = 3.778, 95% CI: 1.038–13.755, P = 0.044), the American Spinal Injury Association (ASIA) score on admission (A: reference; B:OR = 0.326, 95% CI: 0.093–1.146, P = 0.081; C:OR = 0.070, 95% CI: 0.016–0.308, P < 0.001; D:OR = 0.069, 95% CI: 0.019–0.246, P < 0.001), and surgery (OR = 0.341, 95% CI: 0.146–0.796, P = 0.013) were significantly associated with in-hospital mortality. Scores for each of the four factors were derived according to mortality rates. The sum of the scores from all four factors was included in the scoring system and represented the risk of in-hospital mortality. The in-hospital mortality risk of the low-risk (0–3 points), moderate-risk (4–5 points), and high-risk groups (6–8 points) was 0.3, 2.7, and 9.7%, respectively (P < 0.001).

Conclusions

Cervical spinal cord injury, abdominal visceral injury, ASIA score on admission, and surgery were significantly associated with in-hospital mortality in patients with TSCI and stable condition. The scale system may be beneficial for clinical decision-making and for communicating relevant information to patients and their families.
Current Steering Using Multiple Independent Current Control Deep Brain Stimulation Technology Results in Distinct Neurophysiological Responses in Parkinson’s Disease Patients
Authors: Peeters Jana , Boogers Alexandra , Van Bogaert Tine , Gransier Robin , Wouters Jan , Nuttin Bart , Mc Laughlin Myles
Published: June 2022

Background

Deep brain stimulation (DBS) is an effective neuromodulation therapy to treat people with medication-refractory Parkinson’s disease (PD). However, the neural networks affected by DBS are not yet fully understood. Recent studies show that stimulating on different DBS-contacts using a single current source results in distinct EEG-based evoked potentials (EPs), with a peak at 3 ms (P3) associated with dorsolateral subthalamic nucleus stimulation and a peak at 10 ms associated with substantia nigra stimulation. Multiple independent current control (MICC) technology allows the center of the electric field to be moved in between two adjacent DBS-contacts, offering a potential advantage in spatial precision.

Objective

Determine if MICC precision targeting results in distinct neurophysiological responses recorded via EEG.

Materials and Methods

We recorded cortical EPs in five hemispheres (four PD patients) using EEG whilst employing MICC to move the electric field from the most dorsal DBS-contact to the most ventral in 15 incremental steps.

Results

The center of the electric field location had a significant effect on both the P3 and P10 amplitude in all hemispheres where a peak was detected (P3, detected in 4 of 5 hemispheres, p < 0.0001; P10, detected in 5 of 5 hemispheres, p < 0.0001). Post hoc analysis indicated furthermore that MICC technology can significantly refine the resolution of steering.

Conclusion

Using MICC to incrementally move the center of the electric field to locations between adjacent DBS-contacts resulted in significantly different neurophysiological responses that may allow further precision of the programming of individual patients.
Automatic Detection of High-Frequency Oscillations With Neuromorphic Spiking Neural Networks
Authors: Burelo Karla , Sharifshazileh Mohammadali , Indiveri Giacomo , Sarnthein Johannes
Published: June 2022

Interictal high-frequency oscillations (HFO) detected in electroencephalography recordings have been proposed as biomarkers of epileptogenesis, seizure propensity, disease severity, and treatment response. Automatic HFO detectors typically analyze the data offline using complex time-consuming algorithms, which limits their clinical application. Neuromorphic circuits offer the possibility of building compact and low-power processing systems that can analyze data on-line and in real time. In this review, we describe a fully automated detection pipeline for HFO that uses, for the first time, spiking neural networks and neuromorphic technology. We demonstrated that our HFO detection pipeline can be applied to recordings from different modalities (intracranial electroencephalography, electrocorticography, and scalp electroencephalography) and validated its operation in a custom-designed neuromorphic processor. Our HFO detection approach resulted in high accuracy and specificity in the prediction of seizure outcome in patients implanted with intracranial electroencephalography and electrocorticography, and in the prediction of epilepsy severity in patients recorded with scalp electroencephalography. Our research provides a further step toward the real-time detection of HFO using compact and low-power neuromorphic devices. The real-time detection of HFO in the operation room may improve the seizure outcome of epilepsy surgery, while the use of our neuromorphic processor for non-invasive therapy monitoring might allow for more effective medication strategies to achieve seizure control. Therefore, this work has the potential to improve the quality of life in patients with epilepsy by improving epilepsy diagnostics and treatment.
Dynamic Changes of Brain Activity in Patients With Disorders of Consciousness During Recovery of Consciousness
Authors: Guo Yongkun , Li Ruiqi , Zhang Rui , Liu Chunying , Zhang Lipeng , Zhao Dexiao , Shan Qiao , Wang Xinjun , Hu Yuxia
Published: June 2022

The disorder of brain activity dynamics is one of the main characteristics leading to disorders of consciousness (DOC). However, few studies have explored whether the dynamics of brain activity can be modulated, and whether the dynamics of brain activity can help to evaluate the state of consciousness and the recovery progress of consciousness. In current study, 20 patients with minimally conscious state (MCS) and 13 patients with vegetative state (VS) were enrolled, and resting state electroencephalogram (EEG) data and the coma recovery scale-revised (CRS-R) scores were collected three times before and after high-definition transcranial direct current stimulation (HD-tDCS) treatment. The patients were divided into the improved group and the unimproved group according to whether the CRS-R scores were improved after the treatment, and the dynamic changes of resting state EEG microstate parameters during treatment were analyzed. The results showed the occurrence per second (OPS) of microstate D was significantly different between the MCS group and VS group, and it was positively correlated with the CRS-R before the treatment. After 2 weeks of the treatment, the OPS of microstate D improved significantly in the improved group. Meanwhile, the mean microstate duration (MMD), ratio of time coverage (Cov) of microstate C and the Cov of microstate D were significantly changed after the treatment. Compared with the microstates parameters before the treatment, the dynamic changes of parameters with significant difference in the improved group showed a consistent trend after the treatment. In contrast, the microstates parameters did not change significantly after the treatment in the unimproved group. The results suggest that the dynamics of EEG brain activity can be modulated by HD-tDCS, and the improvement in brain activity dynamics is closely related to the recovery of DOC, which is helpful to evaluate the level of DOC and the progress of recovery of consciousness.
Changes in Adiposity and Cerebrospinal Fluid Biomarkers Following a Modified Mediterranean Ketogenic Diet in Older Adults at Risk for Alzheimer’s Disease
Authors: Brinkley Tina E. , Leng Iris , Register Thomas C. , Neth Bryan J. , Zetterberg Henrik , Blennow Kaj , Craft Suzanne
Published: June 2022

Background

Ketogenic diets have been used to treat both obesity and neurological disorders, including epilepsy and more recently Alzheimer’s disease (AD), likely due to favorable effects on both central and peripheral metabolism. Improvements in body composition have also been reported; however, it is unclear if diet-induced changes in adiposity are related to improvements in AD and related neuropathology.

Purpose

We examined the effects of a Modified Mediterranean Ketogenic (MMK) diet vs. an American Heart Association (AHA) diet on body weight, body composition, and body fat distribution and their association with cerebrospinal fluid (CSF) biomarkers in older adults at risk for AD.

Methods

Twenty adults (mean age: 64.3 ± 6.3 years, 35% Black, 75% female) were randomly assigned to a crossover trial starting with either the MMK or AHA diet for 6 weeks, followed by a 6-week washout and then the opposite diet for 6 weeks. At baseline and after each diet adiposity was assessed by dual-energy x-ray absorptiometry and CSF biomarkers were measured. Linear mixed effect models were used to examine the effect of diet on adiposity. Spearman correlations were examined to assess associations between adiposity and CSF biomarkers.

Results

At baseline there was a high prevalence of overweight/obesity and central adiposity, and higher visceral fat and lower peripheral fat were associated with an adverse CSF biomarker profile. The MMK and AHA diets led to similar improvements in body composition and body fat distribution. Significant correlations were found between changes in adiposity and changes in CSF biomarkers (r’s = 0.63–0.92, p’s < 0.05), with notable differences by diet. Decreases in body fat on the MMK diet were related to changes in Aβ biomarkers, whereas decreases in body fat on the AHA diet were related to changes in tau biomarkers and cholinesterase activity. Interestingly, increases in CSF Aβ on the MMK diet occurred in those with less fat loss.

Conclusion

An MMK diet leads to favorable changes in body composition, body fat distribution, and CSF biomarkers. Our data suggest that modest weight loss that maximizes visceral fat loss and preserves peripheral fat, may have the greatest impact on brain health.

Clinical Trial Registration

[www.ClinicalTrials.gov], identifier [NCT02984540].
Tumor Budding as a Marker for Poor Prognosis and Epithelial–Mesenchymal Transition in Lung Cancer: A Systematic Review and Meta-Analysis
Authors: Thakur Nishant , Ailia Muhammad Joan , Chong Yosep , Shin Ok Ran , Yim Kwangil
Published: June 2022

Introduction

Currently, tumor budding (TB) is considered to predict the prognosis of patients. The prognostic significance of TB has also been explored in patients with lung cancer, but has not been fully clarified. In the present meta-analysis, we evaluated the prognostic significance, clinicopathological value, and relationship with epithelial–mesenchymal transition (EMT) of TB in lung cancer.

Methods

The MEDLINE, EMBASE, and Cochrane databases were searched up to July 7, 2021, for the relevant articles that showed the relationship between TB and prognosis in patients with lung cancer. For statistical analysis, we used pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) to assess the correlation between high-grade TB expression and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), clinicopathological factors, and EMT markers.

Results

A total of 3,784 patients from 10 independent studies were included in the statistical analysis. Our results indicated that high-grade TB was significantly associated with poor OS [HR 1.64 (95% CI, 1.43–1.87)] and DFS [HR 1.65 (95% CI, 1.22–2.25)]. In terms of clinicopathological characteristics, high-grade TB was associated with larger tumor size, higher T and N stage, pleural invasion, vascular invasion, lymphatic invasion, and severe nuclear atypia. Interestingly, smoking showed significant association with high-grade TB, despite the fact that previous studies could not show a significant relationship between them. Furthermore, through our systematic analysis, high-grade TB showed a significant relationship with EMT markers.

Conclusion

Our findings indicate that high-grade TB is associated with a worse prognosis in patients with lung cancer. TB evaluation should be implemented in routine pathological diagnosis, which may guide the patient’s treatment.
A Novel and Easy-to-Promote Prognostic Model for Patients With Uveal Melanoma
Authors: Yue Han , Xu Binbin , Gao Jian , Bi Yingwen , Xue Kang , Guo Jie , Zhang Rui , Ren Hui , Yuan Yifei , Qian Jiang
Published: June 2022

Purpose

To establish an easy and widely applicable prognostic prediction model for uveal melanoma (UM) based on a Chinese population.

Patients and Methods

A total of 295 consecutive cases treated at the Eye & ENT Hospital of Fudan University were included as the primary cohort, and 256 cases were included in the validation cohorts from two external Caucasian databases. Clinicopathological data were collected retrospectively, and nomogram models were formulated based on multivariable analysis. The concordance index (C-index), AUC (area under the Receiver Operating Characteristic, ROC curve), and Brier score were calculated and compared.

Results

Based on the training cohort, a nomogram model was established with five relevant variables: age, tumor size, ciliary body involvement, non-spindle cell type and extra-scleral extension. The C-index was 0.737, the 3- and 5-year AUCs were 0.767 and 0.742, and the Brier scores for 3- and 5-year survival were 0.082 and 0.129, respectively, which showed superior prediction compared to that of the Tumor, Node and Metastasis staging system. The model also displayed good discrimination and calibration in the external validation cohorts. By risk stratification, patients could be divided into low- and high-risk groups, and the overall survival curves displayed significant differences in the training and validation cohorts.

Conclusion

Our nomogram model was simple and accurate at predicting the overall survival of patients with UM. It was established based on Asian patients and proved suitable for Caucasian patients; thus, it has a wide range of potential applications, especially for patients living in less medically developed countries and regions.
Combination of Radiofrequency Ablation With Resiquimod to Treat Hepatocellular Carcinoma Via Inflammation of Tumor Immune Microenvironment and Suppression of Angiogenesis
Authors: Tian Zhou , Hong Baojian , Chen Jianzhong , Tang Zhe
Published: June 2022

Background

Radiofrequency ablation (RFA) destroys tumors through hyperthermic injury, which induces the release of immunogenic intracellular substrates and damages associated molecular patterns (DAMPs) to evoke a systemic immune response, but its therapeutic effect is limited. This study aimed to combine RFA with an immunomodulator, resiquimod (R848), to enhance the RFA-induced antitumor immunity.

Methods

We performed RFA on subcutaneous tumors in immunocompetent mice and intraperitoneally injected R848 to observe the efficacy of the combination therapy. Our research investigated changes in the composition of tumor-infiltrating immune cells in primary and distant tumors by flow cytometry. Natural killer (NK) cell depletion experiment was applied to confirm the role of NK cell in the combination therapy. The expression levels of cytokines and chemokines were detected by real-time quantitative PCR. Immunohistochemical test was conducted to reveal tumor angiogenesis, tumor proliferation, and apoptosis after the different treatments.

Results and Conclusion

Compared with RFA or R848 monotherapy, the combination therapy significantly slowed the tumor growth, prolonged the survival time, and shrank the tumor-draining lymph nodes of tumor-bearing mice. The flow cytometry results showed that tumor-infiltrating immune cells, total T cells, the ratio of CD8+ T and NK cells to CD45+ cells, and functional NK cells were obviously increased after the combined treatment. Distal tumor growth was also suppressed, and the profile of tumor-infiltrating immune cells was remodeled, too. In addition, the additive effect of the combination therapy disappeared after NK cell depletion. Furthermore, immunohistochemical results verified that R848 inhibited tumor angiogenesis in murine liver cancer, and the combination therapy promoted tumor cell apoptosis. In conclusion, our data suggest that RFA combined with R848 stimulated a stronger antitumor immune response and effectively inhibited liver cancer progression in a NK cell-dependent manner. Meanwhile, we confirmed that R848 inhibited tumor angiogenesis and promoted apoptosis in murine liver cancer. Overall, this is a promising therapeutic strategy to improve the efficacy of RFA in the treatment of liver cancer and provides a novel option for combined thermal ablation and immunotherapy.
The Identification of Necroptosis-Related Subtypes, the Construction of a Prognostic Model, and the Characterization of the Tumor Microenvironment in Gliomas
Authors: Ba Yueyang , Su Jiahao , Gao Shuangqi , Liao Zhi , Wu Zhimin , Cao Chengan , Liang Chaofeng , Gong Jin , Guo Ying
Published: June 2022

Necroptosis is a recently discovered form of cell death that plays a vital role in the progression of cancer, the spread of metastases, and the immunologic response to tumors. Due to the dual role of necrotic apoptotic processes in tumor pathogenesis and the heterogeneity of gliomas, the function of necroptosis in the glioma microenvironment is still poorly understood. We characterized the expression of necroptosis-related genes (NRGs) within glioma samples at both the genetic and transcriptional levels, identifying three distinct subtypes. Additionally, we constructed a risk score, which is capable of accurately predicting patient prognosis, correlates with tumor mutation burden (TMB), tumor stem cell index (CSC), immune checkpoints, and predicts tumor drug sensitivity. To facilitate its application in the clinic, we developed a nomogram and demonstrated that it predicts the prognosis of glioma patients with good accuracy and reliability using multiple datasets. We examined the function of necroptosis in the tumor microenvironment (TME) and the prognosis of gliomas, which may be useful for guiding individualized treatment plans for gliomas targeting necroptosis.
Contrast Agents for Hepatocellular Carcinoma Imaging: Value and Progression
Authors: Zhang Ying , Numata Kazushi , Du Yuewu , Maeda Shin
Published: June 2022

Hepatocellular carcinoma (HCC) has the third-highest incidence in cancers and has become one of the leading threats to cancer death. With the research on the etiological reasons for cirrhosis and HCC, early diagnosis has been placed great hope to form a favorable prognosis. Non-invasive medical imaging, including the associated contrast media (CM)-based enhancement scan, is taking charge of early diagnosis as mainstream. Meanwhile, it is notable that various CM with different advantages are playing an important role in the different imaging modalities, or even combined modalities. For both physicians and radiologists, it is necessary to know more about the proper imaging approach, along with the characteristic CM, for HCC diagnosis and treatment. Therefore, a summarized navigating map of CM commonly used in the clinic, along with ongoing work of agent research and potential seeded agents in the future, could be a needed practicable aid for HCC diagnosis and prognosis.
Meconium Peritonitis, Intestinal Atresia Combined With Biliary Atresia: A Case Report
Authors: Han Yijiang , Hu Shuqi , Chen Baohai , Huang Shoujiang , Qin Qi , Tou Jinfa
Published: June 2022

Meconium peritonitis (MP) combined with intestinal atresia (IA) is a rare neonatal condition, and it is even rarer in combination with biliary atresia (BA). We describe a case of an infant who developed short bowel syndrome after partial intestinal resection due to MP and IA, along with a Santullienterostomy. During continuous enteral and parenteral nutrition, the stool color became paler. BA was identified by elevated direct bilirubin (DBIL), gamma-glutamyltransferase (GGT), serum matrix metalloproteinase-7 (MMP-7), and hepatobiliary ultrasound; then, Kasai portoenterostomy (KPE) was performed promptly. The Roux-en-Y limb was adjusted intraoperatively to preserve the maximum length of the small intestine while closing the enterostomy. After the operation, the infant gradually adapted to enteral nutrition, his bilirubin level returned to normal, and his weight gradually caught up to the normal range. Although rare, BA should be suspected when MP is combined with IA and when the stool becomes paler in color in the enterostomy state.
The Effect of Serine Protease Inhibitors on Visceral Pain in Different Rodent Models With an Intestinal Insult
Authors: Ceuleers Hannah , Hanning Nikita , De bruyn Michelle , De Man Joris G , De Schepper Heiko U , Li Qian , Liu Liansheng , Abrams Steven , Smet Annemieke , Joossens Jurgen , Augustyns Koen , De Meester Ingrid , Pasricha Pankaj J , De Winter Benedicte Y
Published: June 2022

Background: Serine proteases are believed to play a key role in the origin of abdominal pain in IBD and IBS. We previously demonstrated a reduction of visceral pain in a post-inflammatory IBS rat model after a single intraperitoneal or intracolonic administration of a serine protease inhibitor. The aim of this study was to investigate the efficacy of serine protease inhibition on visceral pain in two different animal models involving a colonic insult based either on acute inflammation or on neonatal irritation. Moreover, protease profiling was explored in the acute colitis model.

Methods: An acute 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis rat model and a chronic neonatal acetic acid mouse model were used in this study. Visceral sensitivity was quantified by visceromotor responses (VMRs) to colorectal distension, 30 min after intraperitoneal administration of the serine protease inhibitors nafamostat, UAMC-00050 or their vehicles. Colonic samples from acute colitis rats were used to quantify the mRNA expression of a panel of serine proteases and mast cell tryptase by immunohistochemistry. Finally, proteolytic activities in colonic and fecal samples were characterized using fluorogenic substrates.

Key Results: We showed a significant and pressure-dependent increase in visceral hypersensitivity in acute colitis and neonatal acetic acid models. UAMC-00050 and nafamostat significantly reduced VMRs in both animal models. In acute colitis rats, the administration of a serine protease inhibitor did not affect the inflammatory parameters. Protease profiling of these acute colitis animals revealed an increased tryptase immunoreactivity and a downregulation of matriptase at the mRNA level after inflammation. The administration of UAMC-00050 resulted in a decreased elastase-like activity in the colon associated with a significantly increased elastase-like activity in fecal samples of acute colitis animals.

Conclusion: In conclusion, our results suggest that serine proteases play an important role in visceral hypersensitivity in an acute TNBS colitis model in rats and a neonatal acetic acid model in mice. Moreover, we hypothesize a potential mechanism of action of UAMC-00050 via the alteration of elastase-like proteolytic activity in acute inflammation. Taken together, we provided fundamental evidence for serine protease inhibitors as a promising new therapeutic strategy for abdominal pain in gastrointestinal diseases.
Molecular Mechanism of Anti-Colorectal Cancer Effect of Hedyotis diffusa Willd and Its Extracts
Authors: Wu Zihong , Yin Bei , You Fengming
Published: June 2022

With the sharp change in our diet and lifestyle, the incidence of colorectal cancer (CRC) is increasing among young people and has become the second most common malignant tumor worldwide. Although the current treatment of CRC is getting updated rapidly, recurrence and metastasis are still inevitable. Therefore, new anticancer drugs are needed to break existing limitations. In recent years, Hedyotis diffusa Willd (HDW) extracts have been proved to demonstrate excellent anti-colorectal cancer effects and have been widely used in clinical practices. In this review, we aim to explore the advantages, potential signaling pathways, and representative active ingredients of HDW in the treatment of CRC from the perspective of molecular mechanism, in order to provide new ideas for the future treatment of CRC.
Models and Techniques to Study Aortic Valve Calcification in Vitro, ex Vivo and in Vivo. An Overview
Authors: Bogdanova Maria , Zabirnyk Arsenii , Malashicheva Anna , Semenova Daria , Kvitting John-Peder Escobar , Kaljusto Mari-Liis , Perez Maria del Mar , Kostareva Anna , Stensløkken Kåre-Olav , Sullivan Gareth J , Rutkovskiy Arkady , Vaage Jarle
Published: June 2022

Aortic valve stenosis secondary to aortic valve calcification is the most common valve disease in the Western world. Calcification is a result of pathological proliferation and osteogenic differentiation of resident valve interstitial cells. To develop non-surgical treatments, the molecular and cellular mechanisms of pathological calcification must be revealed. In the current overview, we present methods for evaluation of calcification in different ex vivo, in vitro and in vivo situations including imaging in patients. The latter include echocardiography, scanning with computed tomography and magnetic resonance imaging. Particular emphasis is on translational studies of calcific aortic valve stenosis with a special focus on cell culture using human primary cell cultures. Such models are widely used and suitable for screening of drugs against calcification. Animal models are presented, but there is no animal model that faithfully mimics human calcific aortic valve disease. A model of experimentally induced calcification in whole porcine aortic valve leaflets ex vivo is also included. Finally, miscellaneous methods and aspects of aortic valve calcification, such as, for instance, biomarkers are presented.
Interactions Between Natural Products and Tamoxifen in Breast Cancer: A Comprehensive Literature Review
Authors: Yen Christine , Zhao Fan , Yu Zhichao , Zhu Xiaoshu , Li Chun Guang
Published: June 2022

Introduction: Tamoxifen (TAM) is the most commonly used hormone therapeutic drug for the treatment of estrogen receptor-positive (ER+) breast cancer. 30%–70% of clinical breast cancer patients use natural products, which may increase the likelihood of drug interactions.

Objective: To evaluate the evidence for the interactions between natural products and TAM in breast cancer.

Methods: Electronic databases, including PubMed, CINAHL Plus (via EbscoHost), European PMC, Medline, and Google Scholar, were searched for relevant publications. The search terms include complementary and alternative medicine, natural products, plant products, herbs, interactions, tamoxifen, breast cancer, and their combinations.

Results: Various in vitro and in vivo studies demonstrated that the combined use of natural products with TAM produced synergistic anti-cancer effects, including improved inhibition of tumor cell growth and TAM sensitivity and reduced side effects or toxicity of TAM. In contrast, some natural products, including Angelica sinensis (Oliv.) Diels [Apiaceae], Paeonia lactiflora Pall., Rehmannia glutinosa (Gaertn.) DC., Astragalus mongholicus Bunge, and Glycyrrhiza glabra L. [Fabaceae], showed estrogen-like activity, which may reduce the anti-cancer effect of TAM. Some natural products, including morin, silybin, epigallocatechin gallate (EGCG), myricetin, baicalein, curcumin, kaempferol, or quercetin, were found to increase the bioavailability of TAM and its metabolites in vivo. However, three are limited clinical studies on the combination of natural products and TAM.

Conclusion: There is evidence for potential interactions of various natural products with TAM in pre-clinical studies, although the relevant clinical evidence is still lacking. Further studies are warranted to evaluate the potential interactions of natural products with TAM in clinical settings.
Shenkang Injection for Treating Renal Fibrosis-Metabonomics and Regulation of E3 Ubiquitin Ligase Smurfs on TGF-β/Smads Signal Transduction
Authors: Zou Junju , Zhou Xiaotao , Chen Xian , Ma Yuerong , Yu Rong
Published: June 2022

At present, TGF-β is the most critical fibrogenic factor known. Smad ubiquitin ligase Smurfs play an important role in the regulation of the TGF-/Smads signaling pathway, which is linked to metabolite changes in renal fibrosis. Previous studies have shown that Shenkang injection can prevent and treat chronic kidney disease through multiple channels of action. However, the precise relationship between Shenkang injection and the regulation of the TGF-/Smads signaling pathway in the treatment of chronic kidney disease is unknown. Here, we evaluated the pharmacological effects of Shenkang injection on ubiquitination and metabolic changes of the TGF-β/Smads signaling pathway in UUO mice using pathology-related indicators, immunoprecipitation, subcellular co-location, and metabonomics analysis. Our findings indicate that Shenkang injection can promote nuclear translocation of Smurf1 and Smurf2 to TGF- membrane receptors TR-I and Smad2 and ubiquitinated degradation of these proteins. Furthermore, the formation of TβR-I/TβR-II, TβR-I/Smad2, and TβR-I/Smad3 complexes was inhibited to negatively regulate the TGF-β/Smad signaling pathway induced renal tubular epithelial transdifferentiation (EMT). The EMT process is not very relevant in vivo, although it is clear that TGF-β induces EMT in cultured cells, which has been demonstrated by numerous teams around the world. However, this is not the case with the in vivo models of kidney fibrosis, especially UUO. In addition, Shenkang injection can improve amino acid metabolism, purine metabolism, and fatty acid metabolism disorders.
Deciphering the Active Compounds and Mechanisms of HSBDF for Treating ALI via Integrating Chemical Bioinformatics Analysis
Authors: Wang Yanru , Jin Xiaojie , Fan Qin , Li Chenghao , Zhang Min , Wang Yongfeng , Wu Qingfeng , Li Jiawei , Liu Xiuzhu , Wang Siyu , Wang Yu , Li Ling , Ling Jia , Li Chaoxin , Wang Qianqian , Liu Yongqi
Published: June 2022

The Huashi Baidu Formula (HSBDF), a key Chinese medical drug, has a remarkable clinical efficacy in treating acute lung injury (ALI), and it has been officially approved by the National Medical Products Administration of China for drug clinical trials. Nevertheless, the regulated mechanisms of HSBDF and its active compounds in plasma against ALI were rarely studied. Based on these considerations, the key anti-inflammatory compounds of HSBDF were screened by molecular docking and binding free energy. The key compounds were further identified in plasma by LC/MS. Network pharmacology was employed to identify the potential regulatory mechanism of the key compounds in plasma. Next, the network pharmacological prediction was validated by a series of experimental assays, including CCK-8, EdU staining, test of TNF-α, IL-6, MDA, and T-SOD, and flow cytometry, to identify active compounds. Molecular dynamic simulation and binding interaction patterns were used to evaluate the stability and affinity between active compounds and target. Finally, the active compounds were subjected to predict pharmacokinetic properties. Molecular docking revealed that HSBDF had potential effects of inhibiting inflammation by acting on IL-6R and TNF-α. Piceatannol, emodin, aloe-emodin, rhein, physcion, luteolin, and quercetin were key compounds that may ameliorate ALI, and among which, there were five compounds (emodin, aloe-emodin, rhein, luteolin, and quercetin) in plasma. Network pharmacology results suggested that five key compounds in plasma likely inhibited ALI by regulating inflammation and oxidative damage. Test performed in vitro suggested that HSBDF (0.03125 mg/ml), quercetin (1.5625 μM), emodin (3.125 μM), and rhein (1.5625 μM) have anti-inflammatory function against oxidative damage and decrease apoptosis in an inflammatory environment by LPS-stimulation. In addition, active compounds (quercetin, emodin, and rhein) had good development prospects, fine affinity, and stable conformations with the target protein. In summary, this study suggested that HSBDF and its key active components in plasma (quercetin, emodin, and rhein) can decrease levels of pro-inflammatory factors (IL-6 and TNF-α), decrease expression of MDA, increase expression of T-SOD, and decrease cell apoptosis in an inflammatory environment. These data suggest that HSBDF has significant effect on anti-inflammation and anti-oxidative stress and also can decrease cell apoptosis in treating ALI. These findings provided an important strategy for developing new agents and facilitated clinical use of HSBDF against ALI.
Bafetinib Suppresses the Transcription of PD-L1 Through c-Myc in Lung Cancer
Authors: Chen Xi , Du Qianqian , Guo Hongjie , He Qiaojun , Yang Bo , Ding Ling
Published: June 2022

Given the limitations of the existing antibody-based therapies, including immune-related adverse events, poor response rates, and intravenous route of dosing, small molecules inhibitors targeting PD-L1 are highly desirable. By cell-based screening, we found that tyrosine kinase inhibitor Bafetinib dramatically suppresses PD-L1 protein expression in a dose-dependent manner. In parallel, cell membrane PD-L1 is also reduced by Bafetinib. We confirm that Bafetinib doesn’t affect the protein half-life of PD-L1 but significantly inhibits the transcription of PD-L1. Among the transcription factors that regulate PD-L1 expression, c-Myc is downregulated by Bafetinib. Bafetinib caused PD-L1 inhibition is abolished when c-Myc is knocked-down. Further, we identified that Bafetinib reduced c-Myc expression because of transcription inhibition. By using the CT26 tumor model, we further confirm that Bafetinib suppressed PD-L1 expression in vivo. In conclusion, our study shows that Bafetinib inhibits the transcription of PD-L1 through transcription factor c-Myc, suggesting that Bafetinib might be a small molecule drug targeting PD-L1.
Promoting Angiogenesis Effect and Molecular Mechanism of Isopropyl Caffeate (KYZ), a Novel Metabolism-Derived Candidate Drug, Based on Integrated Network Pharmacology and Transgenic Zebrafish Models
Authors: Kong Haotian , Wang Songsong , Zhang Yougang , Zhang Yangtengjiao , He Qiuxia , Dong Rong , Zheng Xiaohui , Liu Kechun , Han Liwen
Published: June 2022

Aim of the study: Ischemic diseases have a huge impact on people’s health, which can cause blood supply blockage or restriction in specific tissues. Researchers must develop novel drugs with great efficacy and low toxicity for the prevention and treatment of such diseases. Isopropyl caffeic acid (KYZ) was one of the metabolites of caffeic acid in vivo. This study is to explore the protective effect and mechanism of KYZ on ischemic disease from the perspective of angiogenesis in vivo and in vitro, providing support for the treatment of ischemic diseases and the discovery of a new candidate drug. Methods: The network pharmacology and molecular docking were used to predict the targets of KYZ. In addition, the effects of KYZ on damaged and normal blood vessels were evaluated using the Tg (fli1: EGFP) transgenic zebrafish. The HUVECs model was used to study the effects of KYZ on proliferation, migration, and tube formation. The same dosage of caffeic acid (CA) was also administered in vitro and in vivo at the same time to assess the pharmacodynamic difference between the two compounds. Western Blot and ELISA methods were used to detect the expression of related target proteins. Results: The result from the network pharmacology indicated that the targets of KYZ were related to angiogenesis. It was also found that KYZ could repair the vascular damage induced by the PTK787 and promote the growth of subintestinal vessels in normal zebrafish. The result also indicated that KYZ’s angiogenic ability is better than the precursor compound CA. In HUVECs, KYZ could promote cell proliferation, migration, and tube formation. Further mechanistic study suggested that the KYZ could induce the release of VEGF factor in HUVECs, up-regulate the expression of VEGFR2, and activate the PI3K/AKT and MEK/ERK signaling pathways. Conclusions: These data show that KYZ may promote angiogenesis through VEGF, PI3K/AKT, and MEK/ERK signaling pathways, suggesting that KYZ exhibited great potential in the treatment of ischemic cardio-cerebrovascular diseases.
The Efficacy and Safety of Remimazolam Tosilate Versus Dexmedetomidine in Outpatients Undergoing Flexible Bronchoscopy: A Prospective, Randomized, Blind, Non-Inferiority Trial
Authors: Chen Xingfang , Xin Deqian , Xu Guangjun , Zhao Jing , Lv Qing
Published: June 2022

Purpose: This study aimed to compare the efficacy and safety of remimazolam tosilate-remifentanil (RT-RF) vs dexmedetomidine-remifentanil (Dex-RF) for outpatients undergoing fiberoptic bronchoscopy (FB).

Patients and methods: We conducted a double-blind, randomized, prospective study involving a total of 146 outpatients undergoing FB divided into two groups. The RT-RF (RR) group (n = 73) received an initial dose of 12 mg/kg/h of RT for 10 min followed by a maintenance dose of 1–2 mg/kg/h, while the Dex-RF (DR) group (n = 73) received an initial dose of 0.5 μg/kg of Dex for 10 min followed by a maintenance dose of 0.2–0.7 μg/kg/h. All outpatients also received 0.05–0.2 μg/kg/min RF to maintain the Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scale <3. The primary outcome was rate of successful FB completed. Secondary outcomes were time metrics, hemodynamics, intubating conditions, oxygen saturation, coughing severity, number of remedies, total dose of fentanyl, RF, RT, and Dex, incidence of dreaming, patient and bronchoscopist satisfaction, willingness to repeat bronchoscopy, and adverse events.

Results: The FB successful completion rate was 94.52% (95% CI: 89.20–99.90) in the RR group and 91.78% (95% CI: 85.30–98.20) in the DR group. Compared with patients in the DR group, the onset time, time to fully alert, and hospital discharge were all significantly shorter in the RR group (p < 0.01), and hemodynamics were more stable in the RR group. Intubating conditions, clinically acceptable intubating conditions, lowest oxygen saturation, coughing severity, consumption of fentanyl and RF, number of remedies, and patient and bronchoscopist satisfaction were similar between the groups (p > 0.05), as were demographic characteristics, incidence of dreaming, willingness to repeat bronchoscopy, and adverse events (p > 0.05).

Conclusion: RT-RF has non-inferior efficacy, better time metrics and hemodynamic stability for outpatients undergoing FB than Dex-RF.

Systematic Review Registration: [http://www.chictr.org.cn/showproj.aspx?proj=66673], identifier [ChiCTR2000041524].
Qiliqiangxin Modulates the Gut Microbiota and NLRP3 Inflammasome to Protect Against Ventricular Remodeling in Heart Failure
Authors: Lu Yingdong , Xiang Mi , Xin Laiyun , Zhang Yang , Wang Yuling , Shen Zihuan , Li Li , Cui Xiangning
Published: June 2022

Aims: Pathological left ventricular (LV) remodeling induced by multiple causes often triggers fatal cardiac dysfunction, heart failure (HF), and even cardiac death. This study is aimed to investigate whether qiliqiangxin (QL) could improve LV remodeling and protect against HF via modulating gut microbiota and inhibiting nod-like receptor pyrin domain 3 (NLRP3) inflammasome activation.

Methods: Rats were respectively treated with QL (100 mg/kg/day) or valsartan (1.6 mg/kg/day) by oral gavage after transverse aortic constriction or sham surgery for 13 weeks. Cardiac functions and myocardial fibrosis were assessed. In addition, gut microbial composition was assessed by 16S rDNA sequencing. Furthermore, rats’ hearts were harvested for histopathological and molecular analyses including immunohistochemistry, immunofluorescence, terminal-deoxynucleotidyl transferase-mediated 2’-deoxyuridine 5’-triphosphated nick end labeling, and Western blot.

Key findings: QL treatment preserved cardiac functions including LV ejection fractions and fractional shortening and markedly improved the LV remodeling. Moreover, HF was related to the gut microbial community reorganization like a reduction in Lactobacillus, while QL reversed it. Additionally, the protein expression levels like IL-1β, TNF-α, NF-κB, and NLRP3 were decreased in the QL treatment group compared to the model one.

Conclusion: QL ameliorates ventricular remodeling to some extent in rats with HF by modulating the gut microbiota and NLRP3 inflammasome, which indicates the potential therapeutic effects of QL on those who suffer from HF.
Protective Effects and Mechanisms of Yinchen Linggui Zhugan Decoction in HFD-Induced Nonalcoholic Fatty Liver Disease Rats Based on Network Pharmacology and Experimental Verification
Authors: Jiang Hui , Mao Tangyou , Liu Yuyue , Tan Xiang , Sun Zhongmei , Cheng Yuan , Han Xiao , Zhang Yang , Wang Jiali , Shi Lei , Guo Yi , Li Junxiang , Han Haixiao
Published: June 2022

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease, characterized by excessive accumulation of hepatocyte fat. However, there is no exact and effective pharmacotherapy for NAFLD. Yinchen linggui zhugan decoction (YLZD) has been widely used to treat NAFLD. Nevertheless, its pharmacological and molecular mechanisms have not been clearly elucidated. This study was carried out to investigate the active components of YLZD and explore its potential mechanisms for treating NAFLD by network pharmacology and experimental verification. The results showed that a total of 120 active components of YLZD and 365 targets were retrieved through databases, and the main active ingredients of YLZD consisted of chlorogenic acid, emodin, aloe-emodin, rhein, and geniposide. KEGG enrichment analysis revealed fundamental roles of TNF, PI3K/AKT, HIF-1α, and insulin resistance signaling pathways in the treatment of NAFLD by YLZD. Moreover, our experimental verification results showed that YLZD improved the liver pathological and cholesterol level, and reduced the expressions of TNF-α, IL-1β, IL-6, NF-κB, CCL2, and CXCL10 in NAFLD rats, which all belonged to TNF signaling pathway. The molecular docking confirmed the correlation between the four core components (chlorogenic acid, emodin, rhein, and geniposide) and key factors (TNF-α, IL-6, and NF-κB) in TNF signaling pathway. In conclusion, the present study systematically clarified the protective mechanisms of YLZD against NAFLD through targeting the TNF signaling pathway, and provided new ideas for the drug research of this disease.