bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Cathepsin B in the Degradation of Aβ and in the Production of Aβ Peptides Starting With Ala2 in Cultured Astrocytes
Authors: Oberstein Timo Jan , Utz Janine , Spitzer Philipp , Klafki Hans Wolfgang , Wiltfang Jens , Lewczuk Piotr , Kornhuber Johannes , Maler Juan Manuel
Published: January 2021

Astrocytes may not only be involved in the clearance of Amyloid beta peptides (Aβ) in Alzheimer's disease (AD), but appear to produce N-terminally truncated Aβ (Aβn−x) independently of BACE1, which generates the N-Terminus of Aβ starting with Asp1 (Aβ1−x). A candidate protease for the generation of Aβn−x is cathepsin B (CatB), especially since CatB has also been reported to degrade Aβ, which could explain the opposite roles of astrocytes in AD. In this study, we investigated the influence of CatB inhibitors and the deletion of the gene encoding CatB (CTSB) using CRISPR/Cas9 technology on Aβ2−x and Aβ1−x levels in cell culture supernatants by one- and two-dimensional Urea-SDS-PAGE followed by immunoblot. While the cell-permeant inhibitors E64d and CA-074 Me did not significantly affect the Aβ1−x levels in supernatants of cultured chicken and human astrocytes, they did reduce the Aβ2−x levels. In the glioma-derived cell line H4, the Aβ2−x levels were likewise decreased in supernatants by treatment with the more specific, but cell-impermeant CatB-inhibitor CA-074, by CA-074 Me treatment, and by CTSB gene deletion. Additionally, a more than 2-fold increase in secreted Aβ1−x was observed under the latter two conditions. The CA-074 Me-mediated increase of Aβ1−x, but not the decrease of Aβ2−x, was influenced by concomitant treatment with the vacuolar H+-ATPase inhibitor Bafilomycin A1. This indicated that non-lysosomal CatB mediated the production of Aβ2−x in astrocytes, while the degradation of Aβ1−x seemed to be dependent on lysosomal CatB in H4 cells, but not in primary astrocytes. These findings highlight the importance of considering organelle targeting in drug development to promote Aβ degradation.
Ramadan Fasting During the COVID-19 Pandemic; Observance of Health, Nutrition and Exercise Criteria for Improving the Immune System
Authors: Moghadam Majid Taati , Taati Behzad , Paydar Ardakani Seyed Mojtaba , Suzuki Katsuhiko
Published: January 2021

Fasting is one of the religious rituals of Muslims worldwide who refrain from eating foods and liquids every year during Ramadan. This year (2020), Ramadan is very different from previous years due to the outbreak of a terrible microscopic giant called coronavirus disease 2019 (COVID-19). The pandemic COVID-19 has made Ramadan very important this year because the virus has infected millions of people around the world and killed thousands, especially people with immunodeficiency. In dealing with COVID-19, maintaining good hygiene and supporting the immune system are effective, preventive approaches. Moderate exercise training and proper nutrition are the most important factors to support immune function. Lack of facilities, poor health and many traditions that lead to public community gatherings have made many Islamic countries susceptible to this dangerous virus. In such an unprecedented situation, there are many Muslims who doubt whether they can fast or not. Therefore, the proposal of usable exercise programs and effective nutritional strategies is imperative. In this study, we will look at the proposed health effects of fasting and its impact on the immune system, the effects of Ramadan intermittent fasting on resting values and responses of immunological/antioxidant biomarkers in elite and recreational athletes, together with the important health, nutrition, and exercise advice that fasting people need to follow in the event of a COVID-19 outbreak.
Types of Transnasal Endoscopic Nasopharyngectomy for Recurrent Nasopharyngeal Carcinoma: Shanghai EENT Hospital Experience
Authors: Liu Quan , Sun Xicai , Li Han , Zhou Jiaying , Gu Yurong , Zhao Weidong , Li Houyong , Yu Hongmeng , Wang Dehui
Published: January 2021

Background

Transnasal endoscopic nasopharyngectomy (TEN) has become increasingly used for recurrent nasopharyngeal carcinoma (rNPC); however, there is no report on the definitive resectable contour for TEN according to the latest staging system for nasopharyngeal carcinoma. The aim of this study was to establish the types of TEN for rNPC.

Materials and Methods

A total of 101 rNPC patients underwent TEN from January 2016 to April 2019 at the authors’ institution. TEN was categorized into four types, which included type I (n=40) with resection of the nasopharynx and sinuses; type II (n=10) with lateral extension to the parapharyngeal space; type III (n=40) with lateral extension to the floor of the middle cranial fossa and the infratemporal fossa and superior extension to the orbital apex and the cavernous sinus back to the prevertebral region; and type IV (n=11) with the resection of the involved internal carotid artery following type III. The 2-year overall survival rate (OS) and local recurrence-free survival rate (LRFS) were assessed.

Results

The median time of follow-up was 20 months. Twenty-five patients reoccurred. Nineteen patients died. Independent predictors of outcome on multivariate analysis were recurrent T stage (P = 0.039), types of TEN (P = 0.002) and surgical margin (P = 0.003). The 2-year OS and LRFS was 76.2% and 53.6%, respectively.

Conclusions

The result of TEN in the treatment of rNPC is promising. The types of TEN will provide effective guideline for surgical treatment of rNPC.
Hormonal Receptor Immunochemistry Heterogeneity and 18F-FDG Metabolic Heterogeneity: Preliminary Results of Their Relationship and Prognostic Value in Luminal Non-Metastatic Breast Cancers
Authors: Aide Nicolas , Elie Nicolas , Blanc-Fournier Cécile , Levy Christelle , Salomon Thibault , Lasnon Charline
Published: January 2021

Introduction

We aimed to investigate whether 18F-FDG PET metabolic heterogeneity reflects the heterogeneity of estrogen receptor (ER) and progesterone receptor (PR) expressions within luminal non-metastatic breast tumors and if it could help in identifying patients with worst event-free survival (EFS).

Materials and methods

On 38 PET high-resolution breast bed positions, a single physician drew volumes of interest encompassing the breast tumors to extract SUVmax, histogram parameters and textural features. High-resolution immunochemistry (IHC) scans were analyzed to extract Haralick parameters and descriptors of the distribution shape. Correlation between IHC and PET parameters were explored using Spearman tests. Variables of interest to predict the EFS status at 8 years (EFS-8y) were sought by means of a random forest classification. EFS-8y analyses were then performed using univariable Kaplan-Meier analyses and Cox regression analysis. When appropriate, Mann-Whitney tests and Spearman correlations were used to explore the relationship between clinical data and tumoral PET heterogeneity variables.

Results

For ER expression, correlations were mainly observed with 18F-FDG histogram parameters, whereas for PR expression correlations were mainly observed with gray-level co-occurrence matrix (GLCM) parameters. The strongest correlations were observed between skewness_ER and uniformity_HISTO (ρ = −0.386, p = 0.017) and correlation_PR and entropy_GLCM (ρ = 0.540, p = 0.001), respectively. The median follow-up was 6.5 years and the 8y-EFS was 71.0%. Random forest classification found age, clinical stage, SUVmax, skewness_ER, kurtosis_ER, entropy_HISTO, and uniformity_HISTO to be variables of importance to predict the 8y-EFS. Univariable Kaplan-Meier survival analyses showed that skewness_ER was a predictor of 8y-EFS (66.7 ± 27.2 versus 19.1 ± 15.2, p = 0.018 with a cut-off value set to 0.163) whereas other IHC and PET parameters were not. On multivariable analysis including age, clinical stage and skewness_ER, none of the parameters were independent predictors. Indeed, skewness_ER was significantly higher in youngest patients (ρ = −0.351, p = 0.031) and in clinical stage III tumors (p = 0.023).

Conclusion

A heterogeneous distribution of ER within the tumor in IHC appeared as an EFS-8y prognosticator in luminal non-metastatic breast cancers. Interestingly, it appeared to be correlated with PET histogram parameters which could therefore become potential non-invasive prognosticator tools, provided these results are confirmed by further larger and prospective studies.
Progression-Mediated Changes in Mitochondrial Morphology Promotes Adaptation to Hypoxic Peritoneal Conditions in Serous Ovarian Cancer
Authors: Grieco Joseph P. , Allen Mitchell E. , Perry Justin B. , Wang Yao , Song Yipei , Rohani Ali , Compton Stephanie L. E. , Smyth James W. , Swami Nathan S. , Brown David A. , Schmelz Eva M.
Published: January 2021

Ovarian cancer is the deadliest gynecological cancer in women, with a survival rate of less than 30% when the cancer has spread throughout the peritoneal cavity. Aggregation of cancer cells increases their viability and metastatic potential; however, there are limited studies that correlate these functional changes to specific phenotypic alterations. In this study, we investigated changes in mitochondrial morphology and dynamics during malignant transition using our MOSE cell model for progressive serous ovarian cancer. Mitochondrial morphology was changed with increasing malignancy from a filamentous network to single, enlarged organelles due to an imbalance of mitochondrial dynamic proteins (fusion: MFN1/OPA1, fission: DRP1/FIS1). These phenotypic alterations aided the adaptation to hypoxia through the promotion of autophagy and were accompanied by changes in the mitochondrial ultrastructure, mitochondrial membrane potential, and the regulation of reactive oxygen species (ROS) levels. The tumor-initiating cells increased mitochondrial fragmentation after aggregation and exposure to hypoxia that correlated well with our previously observed reduced growth and respiration in spheroids, suggesting that these alterations promote viability in non-permissive conditions. Our identification of such mitochondrial phenotypic changes in malignancy provides a model in which to identify targets for interventions aimed at suppressing metastases.
Relevance of Neonatal Behavior Assessment Scale for Infants With Somatic Disorders: Comparison on One Matched Group of Control
Authors: Belot Rose-Angélique , Bouteloup Margaux , Mariage André , Candilis-huisman Drina , Mottet Nicolas , Mellier Denis
Published: January 2021

Objective:To compare the Neonatal Behavior Assessment Scale results in two groups of infants with or without somatic disorder (N= 26).

Method:The Neonatal Behavior Assessment Scale was administered to two groups (clinical and control) of 13 infants each, aged from 5 to 18 weeks, matched 2 by 2 according to sex, age, rank among siblings, and parental socio-professional category. The first group includes infants with somatic disorder (clinical) and is matched with a second group of “healthy infants” (control).

Results:Results indicate that the mean score of the control group is significantly higher than that of the clinical group. Most of the items are affected by the presence of a somatic disorder. Indeed, five out of the six categories present a statistically significant difference in favor of the control group, more specifically for the items “state regulation,” “motor system,” and “orientation/interaction.”

Conclusion:This exploratory research enables a precise description of infants' difficulty in regulating excitations and the impact of somatic disorders on their development. This innovative knowledge will assist pediatricians and health professionals in the understanding of infants' characteristics to develop an adapted-care.
Spinal Cord Involvement in Pediatric-Onset Metabolic Disorders With Mendelian and Mitochondrial Inheritance
Authors: Tabarki Brahim , Hakami Wejdan , Alkhuraish Nader , Tlili-Graies Kalthoum , Alfadhel Majid
Published: January 2021

Previous reviews have described the features of brain involvement in pediatric-onset metabolic disorders with Mendelian and mitochondrial inheritance, but only a few have focused on spinal cord abnormalities. An increasing number of metabolic disorders with Mendelian and mitochondrial inheritance in children with predominant spinal cord involvement has been recognized. Spinal cord involvement may be isolated or may occur more frequently with brain involvement. Timely diagnosis and occasional genetic counseling are needed for timely therapy. Therefore, clinicians must be aware of the clinical, laboratory, and radiographic features of these disorders. In this review, we describe pediatric-onset metabolic disorders with Mendelian and mitochondrial inheritance and predominant spinal cord involvement. Furthermore, we provide an overview of these conditions, including background information and examples that require rapid identification, focusing on treatable conditions; that would be catastrophic if they are not recognized.
Adolescents With ADHD Do Not Take Longer to Recover From Concussion
Authors: Cook Nathan E. , Iverson Grant L. , Maxwell Bruce , Zafonte Ross , Berkner Paul D.
Published: January 2021

The objective of this study was to determine whether adolescents with attention-deficit/hyperactivity disorder (ADHD) have prolonged return to school and sports following concussion compared to those without ADHD and whether medication status or concussion history is associated with recovery time. We hypothesized that having ADHD would not be associated with longer recovery time. This prospective observational cohort study, conducted between 2014 and 2019, examined concussion recovery among school sponsored athletics throughout Maine, USA. The sample included 623 adolescents, aged 14–19 years (mean = 16.3, standard deviation = 1.3 years), 43.8% girls, and 90 (14.4%) reported having ADHD. Concussions were identified by certified athletic trainers. We computed days to return to school (full time without accommodations) and days to return to sports (completed return to play protocol) following concussion. Adolescents with ADHD [median days = 7, interquartile range (IQR) = 3–13, range = 0–45] did not take longer than those without ADHD (median days = 7, IQR = 3–13, range = 0–231) to return to school (U = 22,642.0, p = 0.81, r = 0.01; log rank: χ12 = 0.059, p = 0.81). Adolescents with ADHD (median days = 14, IQR = 10–20, range = 2–80) did not take longer than those without ADHD (median days = 15, IQR = 10–21, range = 1–210) to return to sports (U = 20,295.0, p = 0.38, r = 0.04; log rank: χ12 = 0.511, p = 0.48). Medication status and concussion history were not associated with longer recovery times. Adolescents with ADHD did not take longer to functionally recover following concussion. Recovery times did not differ based on whether adolescents with ADHD reported taking medication to treat their ADHD or whether they reported a prior history of concussion.
Case Report: Pediatric Recurrent Acute Liver Failure Caused by Neuroblastoma Amplified Sequence (NBAS) Gene Mutations
Authors: Jiang Bingxin , Xiao Fangfei , Li Xiaolu , Xiao Yongmei , Wang Yizhong , Zhang Ting
Published: January 2021

Acute liver failure (ALF) in childhood is a rapidly progressive, potentially life-threatening condition that occurs in previously healthy children of all ages. However, the etiology of ~50% of cases with pediatric ALF remains unknown. We herein report a 4-year-old Chinese girl with recurrent ALF (RALF) due to a mutation in the neuroblastoma amplified sequence (NBAS) gene. The patient had suffered from multiple episodes of fever-related ALF since early childhood. She had also suffered from acute kidney injury, hypertension, mild pulmonary hypertension, pleural effusion, and hypothyroidism. A novel compound heterozygote mutation, c.3596G> A (p.C1199Y)/ex.9del (p.216-248del), in the NBAS gene was identified by whole-exome sequencing (WES). The missense mutation c.3596G> A (p. C1199Y) was inherited from her father, and ex.9del (p.216-248del) was inherited from her mother. The patient was managed with intensive treatments, such as renal replacement therapy (CRRT), intravenous antibiotics, and glucose infusion, and was discharged after full recovery. We identified a novel compound heterozygote mutation in the NBAS gene that caused fever-related RALF in a Chinese child, which further expands the mutational spectrum of NBAS.
Pediatric Liver Disease Patients and Secondary Glycosylation Abnormalities
Authors: Bogdańska Anna , Lipiński Patryk , Szymańska-Rożek Paulina , Jankowska Irena , Socha Piotr , Tylki-Szymańska Anna
Published: January 2021

Background: Isoelectric focusing (IEF) of serum transferrin (Tf) is still the method of choice for diagnosis of congenital disorders of glycosylation (CDG). An abnormal glycosylation is also a known phenomenon in adult liver disease patients. The aim of this study was to characterize glycosylation disturbances in pediatric patients with primary liver disease. However, there are no reports of this phenomenon in children.

Materials and Methods: Between 1995 and 2019, circa 2,000 serum Tf isoform analyses have been performed in children with primary liver diseases; some of them underwent subsequent analyses. We enrolled in this study 19 patients who developed an acute liver injury (ALI)/failure (ALF) or exhibited a chronic liver disease (CLD) and were evaluated and listed for liver transplantation (LTx) or had just undergone this procedure, and secondary abnormal serum Tf isoform profile.

Results: Among 12 patients with ALI/ALF, 10 had an increased percentage of asialo-, monosialo-, and disialo-Tf isoforms. All patients with CLD had an increased percentage of asialo- and monosialo-Tf isoform. Two patients diagnosed with recurrent ALF had very specific serum Tf profile with a huge increase in the asialo- and monosialo-Tf isoform. On follow-up analyses (available in some patients), serum Tf IEF profile normalized in parallel to normalization of liver function tests, spontaneously or during treatment, including glucocorticosteroids in AIH, LTx in CLD.

Conclusions: All pediatric patients with primary liver disease had increased asialo-Tf as well as monosialo-Tf isoforms. None of them had elevated percentage of trisialo-Tf isoform.
Artificial Intelligence in Pharmacoepidemiology: A Systematic Review. Part 2–Comparison of the Performance of Artificial Intelligence and Traditional Pharmacoepidemiological Techniques
Authors: Sessa Maurizio , Liang David , Khan Abdul Rauf , Kulahci Murat , Andersen Morten
Published: January 2021

Aim: To summarize the evidence on the performance of artificial intelligence vs. traditional pharmacoepidemiological techniques.

Methods: Ovid MEDLINE (01/1950 to 05/2019) was searched to identify observational studies, meta-analyses, and clinical trials using artificial intelligence techniques having a drug as the exposure or the outcome of the study. Only studies with an available full text in the English language were evaluated.

Results: In all, 72 original articles and five reviews were identified via Ovid MEDLINE of which 19 (26.4%) compared the performance of artificial intelligence techniques with traditional pharmacoepidemiological methods. In total, 44 comparisons have been performed in articles that aimed at 1) predicting the needed dosage given the patient’s characteristics (31.8%), 2) predicting the clinical response following a pharmacological treatment (29.5%), 3) predicting the occurrence/severity of adverse drug reactions (20.5%), 4) predicting the propensity score (9.1%), 5) identifying subpopulation more at risk of drug inefficacy (4.5%), 6) predicting drug consumption (2.3%), and 7) predicting drug-induced lengths of stay in hospital (2.3%). In 22 out of 44 (50.0%) comparisons, artificial intelligence performed better than traditional pharmacoepidemiological techniques. Random forest (seven out of 11 comparisons; 63.6%) and artificial neural network (six out of 10 comparisons; 60.0%) were the techniques that in most of the comparisons outperformed traditional pharmacoepidemiological methods.

Conclusion: Only a small fraction of articles compared the performance of artificial intelligence techniques with traditional pharmacoepidemiological methods and not all artificial intelligence techniques have been compared in a Pharmacoepidemiological setting. However, in 50% of comparisons, artificial intelligence performed better than pharmacoepidemiological techniques.
Kanglexin protects against cardiac fibrosis and dysfunction in mice by TGF-β1/ERK1/2 noncanonical pathway
Authors: Liu Xue , Han Weina , An Na , Cao Na , Wu Tingting , Yang Shuang , Ding Lili , Chen Xiaoli , Chen Chao , Aruhan  , Zhang Yannan , Wang Kexin , Suo Lianhuan , Huang Jian , Wang Jinhui , Zhao Xin , Zhu Jiuxin , Zhang Yan , Yang Baofeng
Published: January 2021

Cardiac fibrosis is a common pathological manifestation accompanied by various heart diseases, and antifibrotic therapy is an effective strategy to prevent diverse pathological processes of the cardiovascular system. We currently report the pharmacological evaluation of a novel anthraquinone compound (1,8-dihydroxy-6-methyl-9,10-anthraquinone-3-oxy ethyl succinate) named Kanglexin (KLX), as a potent cardioprotective agent with antifibrosis activity. Our results demonstrated that the administration of KLX by intragastric gavage alleviated cardiac dysfunction, hypertrophy, and fibrosis induced by transverse aortic constriction (TAC) surgical operation. Meanwhile, KLX administration relieved endothelial to mesenchymal transition of TAC mice. In TGF β1-treated primary cultured adult mouse cardiac fibroblasts (CFs) and human umbilical vein endothelial cells (HUVECs), KLX inhibited cell proliferation and collagen secretion. Also, KLX suppressed the transformation of fibroblasts to myofibroblasts in CFs. Further studies revealed that KLX-mediated cardiac protection was due to the inhibitory role of TGF-β1/ERK1/2 noncanonical pathway. In summary, our study indicates that KLX attenuated cardiac fibrosis and dysfunction of TAC mice, providing a potentially effective therapeutic strategy for heart pathological remodeling.
MYH9 Inhibition Suppresses TGF-β1-Stimulated Lung Fibroblast-to-Myofibroblast Differentiation
Authors: Sun Xionghua , Zhu Mei , Chen Xihua , Jiang Xiaogang
Published: January 2021

Previous cDNA microarray results showed that MYH9 gene expression levels are increased in TGF-β1-stimulated lung fibroblast. Recently, our proteomic results revealed that the expression levels of MYH9 protein are notably upregulated in lung tissues of bleomycin-treated rats. However, whether MYH9 plays a critical role in the differentiation of fibroblast remains unclear. Herein, we demonstrated that TGF-β1 increased MYH9 expression, and siRNA-mediated knockdown of MYH9 and pharmacological inhibition of MYH9 ATPase activity remarkably repressed TGF-β1-induced lung fibroblast-to-myofibroblast differentiation. TGF-β1-stimulated MYH9 induction might be via ALK5/Smad2/3 pathway but not through noncanonical pathways, including p38 mitogen-activated kinase, and Akt pathways in lung fibroblasts. Our results showed that MYH9 inhibition suppressed TGF-β1-induced lung fibroblast-to-myofibroblast differentiation, which provides valuable information for illuminating the pathological mechanisms of lung fibroblast differentiation, and gives clues for finding new potential target for pulmonary fibrosis treatment.
Regulating T Cell Population Alleviates SLE by Inhibiting mTORC1/C2 in MRL/lpr Mice
Authors: Zhang Dongya , Wang Meiling , Shi Guoping , Pan Peng , Ji Jianjian , Li Pengfei
Published: January 2021

It’s well known that the mammalian target of rapamycin (mTOR) exerts a critical role in the regulator of immune cells and is associated with T cells dysfunction in patients with systemic lupus erythematosus (SLE). Antigen-induced T-cell proliferation via mTORC1 suppressed by Rapamycin has been used to improve SLE primarily. Previously it has showed that INK128, a highly potent, specific orally inhibitor of mTORC1 and mTORC2, significantly attenuates SLE in pristine-induced lupus mice. Herein we compared the cure effects of INK128 and rapamycin on lupus mice. We treated MRL/lpr mice with INK128 or rapamycin at 12 weeks-age. The effect of the two inhibitors on the lupus mice was determined by immunohistochemistry. The effect of the two inhibitors on T cell populations was investigated by flow cytometry. The mTOR signaling was measured by Western Blot. INK128 remarkably alleviated SLE by reducing splenomegaly, renal inflammation and damage, and resuming T-cell dysfunction. The more effective of INK128 on SLE than rapamycin. INK128 effectively suppressed mTORC1 and mTORC2 activity in T cells, but rapamycin just suppressed mTORC1 activity. Thus, our results show that INK128 is can effectively alleviate SLE and be used as one of the potential clinical therapeutic candidates for SLE.
Tissue Distribution of ACE2 Protein in Syrian Golden Hamster (Mesocricetus auratus) and Its Possible Implications in SARS-CoV-2 Related Studies
Authors: Suresh Voddu , Parida Deepti , Minz Aliva P. , Sethi Manisha , Sahoo Bhabani S. , Senapati Shantibhusan
Published: January 2021

The Syrian golden hamster (Mesocricetus auratus) has recently been demonstrated as a clinically relevant animal model for SARS-CoV-2 infection. However, lack of knowledge about the tissue-specific expression pattern of various proteins in these animals and the unavailability of reagents like antibodies against this species hampers these models’ optimal use. The major objective of our current study was to analyze the tissue-specific expression pattern of angiotensin-converting enzyme 2, a proven functional receptor for SARS-CoV-2 in different organs of the hamster. Using two different antibodies (MA5-32307 and AF933), we have conducted immunoblotting, immunohistochemistry, and immunofluorescence analysis to evaluate the ACE2 expression in different tissues of the hamster. Further, at the mRNA level, the expression of Ace2 in tissues was evaluated through RT-qPCR analysis. Both the antibodies detected expression of ACE2 in kidney, small intestine, tongue, and liver. Epithelium of proximal tubules of kidney and surface epithelium of ileum expresses a very high amount of this protein. Surprisingly, analysis of stained tissue sections showed no detectable expression of ACE2 in the lung or tracheal epithelial cells. Similarly, all parts of the large intestine were negative for ACE2 expression. Analysis of tissues from different age groups and sex didn’t show any obvious difference in ACE2 expression pattern or level. Together, our findings corroborate some of the earlier reports related to ACE2 expression patterns in human tissues and contradict others. We believe that this study’s findings have provided evidence that demands further investigation to understand the predominant respiratory pathology of SARS-CoV-2 infection and disease.
Open Innovation in Medical and Pharmaceutical Research: A Literature Landscape Analysis
Authors: Yeung Andy Wai Kan , Atanasov Atanas G. , Sheridan Helen , Klager Elisabeth , Eibensteiner Fabian , Völkl-Kernsock Sabine , Kletecka-Pulker Maria , Willschke Harald , Schaden Eva
Published: January 2021

Open innovation in medical and pharmaceutical research has grown steadily over the last decade. However, the performance of the published literature in terms of the scientific impact and gaining social media attention remains largely unexplored. The scientific literature of open innovation was examined by means of bibliometric analyses to identify the most prolific authors, organizations, countries, journals, research areas, and recurring terms. By accessing the Web of Science Core Collection and Altmetric electronic databases, citation-related and Altmetric data were evaluated. Public-private partnerships and a selection of newly introduced potential novel drugs in the analyzed publications were identified. North America and Europe were the major literature contributors. Research outputs were mainly published in journals focused on business and economics, pharmacology and pharmacy, and engineering. Many pharmaceutical and biotechnological companies contributed to the analyzed publications, with higher mean citation counts and social media attention (Altmetric score) than nonindustry articles. Public-private partnerships fostered financial support, sharing of expertise and intellectual property, and research collaborations. In summary, open innovation might serve as a powerful strategy to both benefit the involved industry entities and accelerate the development of solutions and products for the betterment of human health.
Methylene Blue Inhibits the SARS-CoV-2 Spike–ACE2 Protein-Protein Interaction–a Mechanism that can Contribute to its Antiviral Activity Against COVID-19
Authors: Bojadzic Damir , Alcazar Oscar , Buchwald Peter
Published: January 2021

Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, which is the first critical step initiating the viral attachment and entry of this coronavirus responsible for the ongoing COVID-19 pandemic. As part of this, we found that methylene blue, a tricyclic phenothiazine compound approved by the FDA for the treatment of methemoglobinemia and used for other medical applications (including the inactivation of viruses in blood products prior to transfusion when activated by light), inhibits this interaction. We confirmed that it does so in a concentration-dependent manner with a low micromolar half-maximal inhibitory concentration (IC50 = 3 μM) in our protein-based ELISA-type setup, while chloroquine, siramesine, and suramin showed no inhibitory activity in this assay. Erythrosine B, which we have shown before to be a promiscuous SMI of PPIs, also inhibited this interaction. Methylene blue inhibited the entry of a SARS-CoV-2 spike bearing pseudovirus into ACE2-expressing cells with similar IC50 (3.5 μM). Hence, this PPI inhibitory activity could contribute to its antiviral activity against SARS-CoV-2 even in the absence of light by blocking its attachment to ACE2-expressing cells and making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.
Dissecting Efficacy and Metabolic Characteristic Mechanism of Taxifolin on Renal Fibrosis by Multivariate Approach and Ultra-Performance Liquid Chromatography Coupled With Mass Spectrometry-Based Metabolomics Strategy
Authors: Ren Lei , Guo Hao-Nan , Yang Jun , Guo Xiao-Ying , Wei Ye-Sheng , Yang Zhao
Published: January 2021

Taxifolin (TFN) is an important natural compound with antifibrotic activity; however, its pharmacological mechanism is not clear. In this study, our aim is to gain insight into the effects of TFN and its potential mechanisms in unilateral ureteral obstruction (UUO) animal model using metabolomics approach to identify the metabolic biomarkers and perturbed pathways. Serum metabolomics analysis by UPLC-Q-TOF/MS was carried out to discover the changes in the metabolic profile. It showed that TFN has a significant protective effect on UUO-induced renal fibrosis and a total of 32 potential biomarkers were identified and related to RF progression. Of note, 27 biomarkers were regulated by TFN treatment, which participate in eight metabolic pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, and phenylalanine metabolism. It also showed that metabolomics was a promising strategy to better dissect metabolic characteristics and pharmacological mechanisms of natural compounds by multivariate approach and ultra-performance liquid chromatography coupled with mass spectrometry.
Clinical Practice Guideline for Tripterygium Glycosides/Tripterygium wilfordii Tablets in the Treatment of Rheumatoid Arthritis
Authors: Lin Na , Zhang Yan-Qiong , Jiang Quan , Liu Wei , Liu Jian , Huang Qing-Chun , Wu Kuan-Yu , Tu Sheng-Hao , Zhou Zu-Shan , Chen Wei-Heng , Li Xiao-Xia , Ding Ying , Fang Yong-Fei , Liu Jian-Ping , Li Zhen-Bin , He Dong-Yi , Chen Yao-Long , Lou Yu-Qian , Tao Qing-Wen , Wang Qing-Wen , Jin Ying-Hui , Liao Xing , Li Tai-Xian , Wang Xiao-Yue
Published: January 2021

Tripterygiumwilfordii Hook F (TwHF) is one of the most commonly used and effective traditional Chinese herbal medicines against rheumatoid arthritis (RA). Both Tripterygium Glycoside Tablets (TGT) and Tripterygium wilfordii Tablets (TWT) are the representative TwHF-based agents enrolled into the 2019 edition of Medicine Catalog for National Basic Medical Insurance, Injury Insurance, and Maternity Insurance. However, individual differences in TGT/TWT response across patients usually exist in the process of treating RA, implying that the clinical application of the two agents may not be standardized leading to the ineffective treatment and the risk of side effects. Growing evidence show that the bioactive constituents of TwHF may often have toxicity, the package insert of TGT and TWT may not be described in detail, and the therapeutic windows of the two agents are narrow. Thus, it is an urgent task to develop a standardized clinical practice guideline for TGT and TWT in the treatment of RA. In the current study, a group of clinical experts of traditional Chinese medicine and Western medicine in the research field of rheumatism diseases, pharmacists, and methodologists of evidence-based medicine were invited to select the clinical questions, to determine the levels of the evidence and the strength of the recommendations, and to develop the recommendations and good practice points. The guideline is formed based on the combination of clinical research evidence and expert experience (evidence-based, consensus, supplemented by experience). The clinical problems which are supported by clinical evidence may form recommendations, and the clinical problems without clinical evidence may form experts’ suggestions. Both recommendations and experts' suggestions in this guideline summarized the clinical indications, usage, dosage, combined medication, and safety of TGT and TWT against RA systematically and comprehensively, which may offer a professional guidance in the context of the clinical application of the two TwHF-based agents.
Allopregnanolone Decreases Evoked Dopamine Release Differently in Rats by Sex and Estrous Stage
Authors: Dornellas Ana Paula S. , Macedo Giovana C. , McFarland Minna H. , Gómez-A Alexander , O’Buckley Todd K. , Da Cunha Claudio , Morrow A. Leslie , Robinson Donita L.
Published: January 2021

Mesolimbic dopamine transmission is dysregulated in multiple psychiatric disorders, including addiction. Previous studies found that the endogenous GABAergic steroid (3α,5α)-3-hydroxy-5-pregnan-20-one (allopregnanolone) modulates dopamine levels in the nucleus accumbens and prefrontal cortex. As allopregnanolone is a potent positive allosteric modulator of GABAA receptors, and GABAA receptors can regulate dopamine release, we hypothesized that allopregnanolone would reduce phasic fluctuations in mesolimbic dopamine release that are important in learning and reward processing. We used fast-scan cyclic voltammetry in anesthetized female and male rats to measure dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area, before and after administration of allopregnanolone. Allopregnanolone (7.5–25 mg/kg, IP) reduced evoked dopamine release in both male and female rats, compared to β-cyclodextrin vehicle. In males, all doses of allopregnanolone decreased dopamine transmission, with stronger effects at 15 and 25 mg/kg allopregnanolone. In females, 15 and 25 mg/kg allopregnanolone reduced dopamine release, while 7.5 mg/kg allopregnanolone was no different from vehicle. Since allopregnanolone is derived from progesterone, we hypothesized that high endogenous progesterone levels would result in lower sensitivity to allopregnanolone. Consistent with this, females in proestrus (high progesterone levels) were less responsive to allopregnanolone than females in other estrous cycle stages. Furthermore, 30 mg/kg progesterone reduced evoked dopamine release in males, similar to allopregnanolone. Our findings confirm that allopregnanolone reduces evoked dopamine release in both male and female rats. Moreover, sex and the estrous cycle modulated this effect of allopregnanolone. These results extend our knowledge about the pharmacological effects of neurosteroids on dopamine transmission, which may contribute to their therapeutic effects.
Montelukast Use Decreases Cardiovascular Events in Asthmatics
Authors: Hoxha Malvina , Tedesco Calogero C. , Quaglin Silvana , Malaj Visar , Pustina Linda , Capra Valerie , Evans Jilly F. , Sala Angelo , Rovati G. Enrico
Published: January 2021

Cysteinyl leukotrienes are proinflammatory mediators with a clinically established role in asthma and a human genetic and preclinical role in cardiovascular pathology. Given that cardiovascular disease has a critical inflammatory component, the aim of this work was to conduct an observational study to verify whether the use of a cysteinyl leukotriene antagonist, namely, montelukast, may protect asthmatic patients from a major cardiovascular event and, therefore, represent an innovative adjunct therapy to target an inflammatory component in cardiovascular disease. We performed an observational retrospective 3-year study on eight hundred adult asthmatic patients 18 years or older in Albania, equally distributed into two cohorts, exposed or nonexposed to montelukast usage, matched by age and gender according to information reported in the data collection. Patients with a previous history of myocardial infarction or ischemic stroke were excluded. In summary, 37 (4.6%) of the asthmatic patients, 32 nonexposed, and five exposed to montelukast suffered a major cardiovascular event during the 3-year observation period. All the cardiovascular events, in either group, occurred among patients with an increased cardiovascular risk. Our analyses demonstrate that, independent from gender, exposure to montelukast remained a significant protective factor for incident ischemic events (78% or 76% risk reduction depending on type of analysis). The event-free Kaplan–Meier survival curves confirmed the lower cardiovascular event incidence in patients exposed to montelukast. Our data suggest that there is a potential preventative role of montelukast for incident cardiac ischemic events in the older asthmatic population, indicating a comorbidity benefit of montelukast usage in asthmatics by targeting cysteinyl leukotriene-driven cardiac disease inflammation.
ABT-263 Reduces Hypertrophic Scars by Targeting Apoptosis of Myofibroblasts
Authors: Yang Xiaolan , Xiao Yongqiang , Zhong Chenjian , Shu Futing , Xiao Shichu , Zheng Yongjun , Xia Zhaofan
Published: January 2021

Background:Inhibiting proliferation and inducing apoptosis of myofibroblasts is becoming one of the promising and effective ways to treat hypertrophic scar. ABT-263, as an orally bioavailable BCL-2 family inhibitor, has showed great antitumor characteristics by targeting tumor cell apoptosis. The objective of this study was to explore whether ABT-263 could target apoptosis of overactivated myofibroblasts in hypertrophic scar.

Methods:In vivo, we used ABT-263 to treat scars in a rabbit ear scar model. Photographs and ultrasound examination were taken weekly, and scars were harvested on day 42 for further Masson trichrome staining.In vitro, the expression levels of BCL-2 family members, including prosurvival proteins, activators, and effectors, were detected systematically in hypertrophic scar tissues and adjacent normal skin tissues, as well as in human hypertrophic scar fibroblasts (HSFs) and human normal dermal fibroblasts (HFBs). The roles of ABT-263 in apoptosis and proliferation of HSFs and HFBs were determined by annexin V/PI assay, CCK-8 kit, and cell cycle analysis. Mitochondrial membrane potential was evaluated by JC-1 staining and the expression of type I/III collagen and α-SMA was measured by PCR, western blotting, and immunofluorescence staining. Furthermore, immunoprecipitation was performed to explore the potential mechanism.

Results:In vivo, ABT-263 could significantly improve the scar appearance and collagen arrangement, decrease scar elevation index (SEI), and induce cell apoptosis.In vitro, the expression levels of BCL-2, BCL-XL, and BIM were significantly higher in scar tissues and HSFs than those in normal skin tissues and HFBs. ABT-263 selectively induced HSFs apoptosis by releasing BIM from binding with prosurvival proteins. Moreover, ABT-263 inhibited HSFs proliferation and reduced the expression of α-SMA and type I/III collagen in a concentration- and time- dependent manner.

Conclusion:HSFs showed increased mitochondrial priming with higher level of proapoptotic activator BIM and were primed to death. ABT-263 showed great therapeutic ability in the treatment of hypertrophic scar by targeting HSFs.
Thymoquinone Prevents Dopaminergic Neurodegeneration by Attenuating Oxidative Stress Via the Nrf2/ARE Pathway
Authors: Dong Jianjian , Zhang Xiaoming , Wang Shijing , Xu Chenchen , Gao Manli , Liu Songyang , Li Xiaoxiao , Cheng Nan , Han Yongsheng , Wang Xun , Han Yongzhu
Published: January 2021

Studies have indicated that oxidative stress plays a crucial role in the development of Parkinson’s disease (PD) and other neurodegenerative conditions. Research has also revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) triggers the expression of antioxidant genes via a series of antioxidant response elements (AREs), thus preventing oxidative stress. Thymoquinone (TQ) is the bioactive component of Nigella sativa, a medicinal plant that exhibits antioxidant and neuroprotective effects. In the present study we examined whether TQ alleviates in vivo and in vitro neurodegeneration induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by acting as an activator of the Nrf2/ARE cascade. We showed that TQ significantly reduced MPP+-mediated cell death and apoptosis. Moreover, TQ significantly elevated the nuclear translocation of Nrf2 and significantly increased the subsequent expression of antioxidative genes such as Heme oxygenase 1 (HO-1), quinone oxidoreductase (NQO1) and Glutathione-S-Transferase (GST). The application of siRNA to silence Nrf2 led to an abolishment in the protective effects of TQ. We also found that the intraperitoneal injection of TQ into a rodent model of PD ameliorated oxidative stress and effectively mitigated nigrostriatal dopaminergic degeneration by activating the Nrf2-ARE pathway. However, these effects were inhibited by the injection of a lentivirus wrapped Nrf2 siRNA (siNrf2). Collectively, these findings suggest that TQ alleviates progressive dopaminergic neuropathology by activating the Nrf2/ARE signaling cascade and by attenuating oxidative stress, thus demonstrating that TQ is a potential novel drug candidate for the treatment of PD.
Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells
Authors: Wu Zhuo-Xun , Yang Yuqi , Wang Jing-Quan , Zhou Wen-Min , Chen Junyu , Fu Yi-Ge , Patel Ketankumar , Chen Zhe-Sheng , Zhang Jian-Ye
Published: January 2021

The emergence of multidrug resistance (MDR) has been a major issue for effective cancer chemotherapy as well as targeted therapy. One prominent factor that causes MDR is the overexpression of ABCB1 transporter. In the present study, we revealed that the Aurora kinase inhibitor GSK-1070916 is a substrate of ABCB1. GSK-1070916 is a newly developed inhibitor that is currently under clinical investigation. The cytotoxicity assay showed that overexpression of ABCB1 significantly hindered the anticancer effect of GSK-1070916 and the drug resistance can be abolished by the addition of an ABCB1 inhibitor. GSK-1070916 concentration-dependently stimulated ABCB1 ATPase activity. The HPLC drug accumulation assay suggested that the ABCB1-overexpressing cells had lower levels of intracellular GSK-1070916 compared with the parental cells. GSK-1070916 also showed high binding affinity to ABCB1 substrate-binding site in the computational docking analysis. In conclusion, our study provides strong evidence that ABCB1 can confer resistance to GSK-1070916, which should be taken into consideration in clinical setting.
The Role of Oxidative Stress and Natural Antioxidants in Ovarian Aging
Authors: Yang Liuqing , Chen Yun , Liu Yan , Xing Yu , Miao Chenyun , Zhao Ying , Chang Xiangwei , Zhang Qin
Published: January 2021

The ovarian system comprises vital organs in females and is of great significance for the maintenance of reproductive potential and endocrine stability. Although complex pathogenesis undoubtedly contributes to ovarian aging, increasing attention is being paid to the extensive influence of oxidative stress. However, the role of oxidative stress in ovarian aging is yet to be fully elucidated. Exploring oxidative stress-related processes might be a promising strategy against ovarian aging. In this review, compelling evidence is shown that oxidative stress plays a role in the etiology of ovarian aging and promotes the development of other ovarian aging-related etiologies, including telomere shortening, mitochondrial dysfunction, apoptosis, and inflammation. In addition, some natural antioxidants such as quercetin, resveratrol, and curcumin have a protective role in the ovaries through multiple mechanisms. These findings raise the prospect of oxidative stress modulator-natural antioxidants as therapeutic interventions for delaying ovarian aging.
Ischemic and Bleeding Events of Ticagrelor Monotherapy in Korean Patients With and Without Diabetes Mellitus: Insights From the TICO Trial
Authors: Yun Kyeong Ho , Cho Jae Young , Lee Seung Yul , Rhee Sang Jae , Kim Byeong Keuk , Hong Myeong Ki , Jang Yangsoo , Oh Seok Kyu ,   the TICO Investigators
Published: January 2021

Background: Ticagrelor monotherapy after 3 months dual antiplatelet therapy (DAPT) with aspirin and ticagrelor can reduce bleeding without increasing ischemic events after percutaneous coronary intervention (PCI). However, the impact of this approach among the patient with diabetes remains unknown.

Methods: This was a sub-analysis of the Ticagrelor Monotherapy after 3 months in the Patients Treated with New Generation Sirolimus Eluting Stent for Acute Coronary Syndrome (TICO) trial. After successful PCI, the patients were randomly assigned to ticagrelor monotherapy after 3-months DPAT or to ticagrelor-based 12-months DAPT. We compared ischemic events and bleeding events between the patients with diabetes and without diabetes for 12 months. Ischemic events were defined as death, myocardial infarction, ischemic stroke, transient ischemic attack, stent thrombosis, and any revascularizations. Bleeding events were defined according to the Thrombolysis in Myocardial Infarction (TIMI) criteria and Bleeding Academic Research Consortium (BARC) definition.

Results: Between August 2015 and October 2018, 3,056 patients were enrolled in the TICO trial, of which 835 (27.3%) had diabetes mellitus. Diabetes mellitus was associated with all evaluated ischemic and bleeding events. No significant differences in any ischemic events were observed in patients with diabetes between ticagrelor monotherapy after 3-months DAPT and ticagrelor-based 12-months DAPT (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.45–1.52, p = 0.540). In patients with diabetes, the overall incidence of bleeding complications during the 12-months follow-up period did not differ between the two treatment groups (HR 0.83, 95% CI 1.48–1.43, p = 0.505). However, ticagrelor monotherapy was significantly reduced both any TIMI bleeding and BARC three or five bleeding events in diabetes patients in the 3-months landmark analysis, after 3-months DAPT period (HR 0.20, 95% CI 0.07–0.59, p = 0.003).

Conclusion: In diabetic patients, ticagrelor monotherapy showed a lower incidence of bleeding complications after 3-months DAPT period, without increasing ischemic complications, compared with ticagrelor-based 12-months DAPT (ClinicalTrials.gov Identifier: NCT02494895).