bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin Affects Gut Microbiota Composition and Diversity Associated with Amelioration of Dextran Sulfate Sodium-Induced Colitis in Mice
Authors: Liu Zhiyi , Liao Wangdi , Zhang Zihan , Sun Ruipu , Luo Yunfei , Chen Qiongfeng , Li Xin , Lu Ruiling , Ying Ying 
Published: May 2021

Background: Inflammatory bowel disease (IBD) is an increasingly common and globally emergent immune-mediated disorder. The etiology of IBD is complex, involving multiple factors such as immune dysregulation, environmental factors, genetic mutations, and microbiota dysbiosis, exacerbated by a lack of effective clinical therapies. Recently, studies hypothesized that dysbiosis of intestinal flora might participate in the onset of IBD. Metformin is widely used to treat type 2 diabetes and has shown beneficial effects in mouse models of IBD, although its underlying mechanisms remain poorly understood. Accumulating studies found that metformin shows beneficial effects for diabetes by affecting microbiota composition. This study explores possible regulatory effects of metformin on intestinal microecology during treatment for IBD.Methods: Inflammation was induced using 3% Dextran Sulfate Sodium (DSS) solution to generate mice models of IBD. Metformin treatments were assayed by measuring body weights and colon lengths of mice and H&amp;E staining to observe histological effects on colon tissue structures. Changes in bacterial community composition and diversity-related to IBD and metformin treatment were assessed by high-throughput metagenomic sequencing analysis.Results: Metformin administration significantly ameliorated body weight loss, inhibited colon shrinking, and contributed to preserving the integrity of colon histological structures. The gut microbiota profiles revealed that the biodiversity of intestinal flora lost during inflammation was restored under metformin treatment. Metformin administration was also associated with decreased pathogenic Escherichia shigella and increased abundance of Lactobacillus and Akkermansia.Conclusion: Metformin appears to induce anti-inflammatory effects, thus ameliorating colitis symptoms, concurrent with enrichment for beneficial taxa and restored microbial diversity, suggesting a viable strategy against IBD.
MicroRNA-33b is a Potential Non-Invasive Biomarker for Response to Atorvastatin Treatment in Chilean Subjects With Hypercholesterolemia: A Pilot Study
Authors: Ubilla Carmen Gloria , Prado Yalena , Angulo Jeremy , Obreque Ignacio , Paez Isis , Saavedra Nicolás , Saavedra Kathleen , Zambrano Tomás , Salazar Luis A. 
Published: May 2021

Evidence accumulated so far indicates that circulating levels of microRNAs (miRNAs) are associated with several pathologies. Therefore, differential expression of extracellular miRNAs exhibits promising potential for screening and diagnosis purposes. We evaluated plasma miRNAs in response to the lipid-lowering drug atorvastatin in patients with hypercholesterolemia (HC) and controls. Methods: We selected miRNAs based on previous data reported by our group and also by employing bioinformatics tools to identify 10 miRNAs related to cholesterol metabolism and statin response genes. Following miRNA identification, we determined plasma levels of miRNA-17-5p, miRNA-30c-5p, miRNA-24-3p, miRNA-33a-5p, miRNA-33b-5p, miRNA-29a-3p, miRNA-29b-3p, miRNA-454-3p, miRNA-590-3p and miRNA-27a-3p in 20 HC patients before and after 1 month of 20 mg/day atorvastatin treatment, evaluating the same miRNA set in a group of 20 healthy subjects, and employing qRT-PCR to determine differential miRNAs expression. Results: HC individuals showed significant overexpression of miRNA-30c-5p and miRNA-29b-3p vs. NL (p = 0.0008 and p = 0.0001, respectively). Once cholesterol-lowering treatment was concluded, HC individuals showed a substantial increase of three extracellular miRNAs (miRNA-24-3p, miRNA-590, and miRNA-33b-5p), the latter elevated more than 37-fold (p = 0.0082). Conclusion: Data suggest that circulating miRNA-30c-5p and miRNA-29b-3p are associated with hypercholesterolemia. Also, atorvastatin induces a strong elevation of miRNA-33b-5p levels in HC individuals, which could indicate an important function that this miRNA may exert upon atorvastatin therapy. Additional studies are needed to clarify the role of this particular miRNA in statin treatment.
Identification of Docetaxel as a Potential Drug to Promote HDL Biogenesis
Authors: Choi Hong Y. , Ruel Isabelle , Genest Jacques 
Published: May 2021

Objective: Our recent studies showed that desmocollin 1 (DSC1) binds to apoA-I in order to inhibit apoA-I-mediated high density lipoprotein (HDL) biogenesis in atherosclerotic plaques. To promote HDL biogenesis in the plaque, here we search for small molecules that block apoA-I-DSC1 interactions.Approach and Results: We combined mutational and computational mapping methods to show that amino acid residues 442–539 in the mature DSC1 protein form an apoA-I binding site (AIBS). Using a crystal structure of the AIBS, we carried out virtual screening of 10 million small molecules to estimate their binding affinities to the AIBS, followed by the selection of 51 high-affinity binding molecules as potential inhibitors of apoA-I-DSC1 interactions. Among the 51, the chemotherapy drug docetaxel showed the highest potency in promoting apoA-I-mediated HDL biogenesis in primary human skin fibroblasts with the half-maximal effective concentration of 0.72 nM. In silico docking studies suggest that the taxane ring in docetaxel binds to the AIBS and that the carbon-13 sidechain of the taxane tightens/stabilizes the binding. The HDL biogenic effect of docetaxel was also observed in two predominant cell types in atherosclerosis, macrophages and smooth muscle cells. Importantly, docetaxel promoted HDL biogenesis at concentrations much lower than those required for inducing cytotoxicity.Conclusion: Determination of the AIBS in DSC1 and AIBS structure-based virtual screening allowed us to identify docetaxel as a strong HDL biogenic agent. With the remarkable potency in promoting HDL biogenesis, a chemotherapy drug docetaxel may be repurposed to enhance atheroprotective HDL functions.
Pharmacodynamic Evaluation of Dosing, Bacterial Kill, and Resistance Suppression for Zoliflodacin Against Neisseria gonorrhoeae in a Dynamic Hollow Fiber Infection Model
Authors: Jacobsson Susanne , Golparian Daniel , Oxelbark Joakim , Alirol Emilie , Franceschi Francois , Gustafsson Tomas N. , Brown David , Louie Arnold , Drusano George , Unemo Magnus 
Published: May 2021

Antimicrobial resistance in Neisseria gonorrhoeae is threatening the treatment and control of gonorrhea globally, and new treatment options are imperative. Utilizing our dynamic in vitro hollow fiber infection model (HFIM), we examined the pharmacodynamics of the first-in-class spiropyrimidinetrione (DNA gyrase B inhibitors), zoliflodacin, against the N. gonorrhoeae reference strains World Health Organization F (susceptible to all relevant antimicrobials) and WHO X (extensively drug resistant, including resistance to ceftriaxone) over 7 days. Dose-range experiments with both strains, simulating zoliflodacin single oral dose regimens of 0.5–8 g, and dose-fractionation experiments with WHO X, simulating zoliflodacin oral dose therapy with 1–4 g administered as q12 h and q8 h for 24 h, were performed. A kill-rate constant that reflected a rapid bacterial kill during the first 6.5 h for both strains and all zoliflodacin doses was identified. In the dose-range experiments, the zoliflodacin 2–8 g single-dose treatments successfully eradicated both WHO strains, and resistance to zoliflodacin was not observed. However, zoliflodacin as a single 0.5 g dose failed to eradicate both WHO strains, and a 1 g single dose failed to eradicate WHO X in one of two experiments. The zoliflodacin 1 g/day regimen also failed to eradicate WHO X when administered as two and three divided doses given at q12 h and q8 h in the dose-fractionation studies, respectively. All failed regimens selected for zoliflodacin-resistant mutants. In conclusion, these data demonstrate that zoliflodacin should be administered at &gt;2 g as a single oral dose to provide effective killing and resistance suppression of N. gonorrhoeae. Future studies providing pharmacokinetic data for zoliflodacin (and other gonorrhea therapeutic antimicrobials) in urogenital and extragenital infection sites, particularly in the pharynx, and evaluation of gonococcal strains with different gyrB mutations would be important.
Effects of Genetic Polymorphism in CYP2D6, CYP2C19, and the Organic Cation Transporter OCT1 on Amitriptyline Pharmacokinetics in Healthy Volunteers and Depressive Disorder Patients
Authors: Matthaei Johannes , Brockmöller Jürgen , Steimer Werner , Pischa Konstanze , Leucht Stefan , Kullmann Maria , Jensen Ole , Ouethy Typhaine , Tzvetkov Mladen Vassilev , Rafehi Muhammad 
Published: May 2021

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms.
Identification of Tumor Necrosis Factor-Alpha (TNF-α) Inhibitor in Rheumatoid Arthritis Using Network Pharmacology and Molecular Docking
Authors: Bai Liang Liang , Chen Hao , Zhou Peng , Yu Jun 
Published: May 2021

Background: This study aimed to investigate the molecular mechanism of Radix Paeoniae Alba (white peony, WP) in treating immune inflammatory diseases of rheumatoid arthritis (RA) and tumor necrosis factor-alpha (TNF-α) inhibitors (TNFis) by using network pharmacology and molecular docking.Methods: In this study, the ingredient of WP and the potential inflammatory targets of RA were obtained from the Traditional Chinese Medicine Systematic Pharmacology Database, GeneCard, and OMIM databases, respectively. The establishment of the RA–WP-potential inflammatory target gene interaction network was accomplished using the STRING database. Network maps of the WP–RA-potential inflammatory target gene network were constructed using Cytoscape software. Gene ontology (GO) and the biological pathway (KEGG) enrichment analyses were used to further explore the RA mechanism and therapeutic effects of WP. Molecular docking technology was used to analyze the optimal effective components from WP for docking with TNF-α.Results: Thirteen active ingredients and 71 target genes were screened from WP, and 49 of the target genes intersected with RA target inflammatory genes and were considered potential therapeutic targets. Network pharmacological analysis showed that the WP active ingredients such as mairin, DPHCD, (+)-catechin, beta-sitosterol, paeoniflorin, sitosterol, and kaempferol showed better correlation with RA inflammatory target genes such as PGR, PTGS1, PTGS2, NR3C2, TNFSF15, and CHRM2, respectively. The immune-inflammatory signaling pathways of the active ingredients for the treatment of RA are the TNF-α signaling pathway, Toll-like receptor signaling pathway, cell apoptosis, interleukin-17 signaling pathway, C-type lectin receptor signaling pathway, mitogen-associated protein kinase, etc. Molecular docking results suggested that mairin was the most appropriate natural TNFis.Conclusion: Our findings provide an essential role and basis for further immune-inflammatory studies into the molecular mechanisms of WP and TNFis development in RA.
Impact of Morphine Dependence and Withdrawal on the Reinforcing Effectiveness of Fentanyl, Cocaine, and Methamphetamine in Rats
Authors: Seaman Jr Robert W. , Collins Gregory T. 
Published: May 2021

Recent estimates suggest increased popularity of the concurrent use of opioids and stimulants, with over 50% of treatment-seeking opioid users reporting regular stimulant use. The goal of the current study was to determine how opioid dependence and withdrawal affect the reinforcing effects of fentanyl, cocaine, and methamphetamine. Male Sprague-Dawley rats were allowed to self-administer fentanyl under a progressive ratio (PR) schedule of reinforcement. Baseline evaluations of reinforcing effectiveness of fentanyl, cocaine, and methamphetamine were determined. Opioid dependence was then established by administering escalating doses of morphine (10–40 mg/kg) twice-daily for four days and subsequently maintained by once-daily injections of 40 mg/kg morphine. To evaluate the impact of opioid dependence and withdrawal on the self-administration of fentanyl, cocaine, and methamphetamine, sessions occurred either 12 or 20 h after the morphine, respectively. During opioid withdrawal, the fentanyl dose-response curve was shifted rightward with an increase in maximal effectiveness, whereas it was shifted rightward with a reduction in maximal effectiveness when evaluated in rats currently dependent on opioids, relative to baseline. The reinforcing effects of cocaine and methamphetamine were unchanged by either condition. The current studies provide direct evidence that the reinforcing effects of fentanyl are increased in opioid-withdrawn rats and reduced in opioid-dependent rats, relative to rats that are not physically dependent on opioids. These findings suggest that motivations to use opioids are dependent on the state of the individual whereas stimulants retain their reinforcing effects regardless of whether the individual is in an opioid-dependent or withdrawn state.
Cancer and Relationship Dissolution: Perspective of Partners of Cancer Patients
Authors: Nalbant Bahar , Karger André , Zimmermann Tanja 
Published: May 2021

PurposeCancer can be a burden on the relationship and even lead to relationship dissolution. Previous studies about the impact of cancer on close relationships almost exclusively involve cancer patients. So far, little is known about the views of spouses. Therefore, this study focuses on partners or ex-partners of cancer patients.MethodsIn this cross-sectional study, N = 265 partners or ex-partners of cancer patients are examined regarding a possible separation, the reasons for separation and the influence of the cancer on the relationship. In addition, predictors of separation and the positive or negative perception of the impact of cancer on the relationship were investigated.ResultsThe separation rate (23.4%) was marginally lower than in the general population in Germany (35.79%). The most frequent reason for separation was the death of the cancer patient (59.6%), followed by relationship problems (26.9%), and the cancer disease itself (9.6%). Among those who were separated, 57.4% reported that cancer contributed to the separation. On average, the influence of cancer on relationship dissolution is indicated with 82.9%. Also, for those who stayed together, 83.7% reported an impact of the cancer on the relationship, of which 55.9% reported a negative impact. Logistic regressions indicated that higher levels of depression were associated with greater odds of a more negative perception of the influence of cancer on the relationship, whereas a more satisfied relationship tended to be associated with a more positive perception. Those who had no psychological treatment in the past, lower anxiety levels and lower relationship satisfaction had an increased risk of separation. Overall, relationship satisfaction was significantly lower than in the general population in Germany.ConclusionIn particular, psychological factors such as depression and anxiety as well as relationship satisfaction appear to be factors influencing separation and the perception of the influence of cancer on the relationship as positive or negative. Therefore, it seems to be reasonable to consider these aspects in the psychosocial support and also to include the partners in order to achieve a stable and satisfied relationship which has a positive effect on health and psychological well-being.
How Having a Clear Why Can Help Us Cope With Almost Anything: Meaningful Well-Being and the COVID-19 Pandemic in México
Authors: Quiroga-Garza Angelica , Cepeda-Lopez Ana C. , Villarreal Zambrano Sofía , Villalobos-Daniel Victor E. , Carreno David F. , Eisenbeck Nikolett 
Published: May 2021

Background: Coronavirus disease 2019 (COVID-19) has resulted in an increase in known risk factors for mental health problems. Mexico adopted lockdown and physical distancing as a containment strategy with potential consequences on day to day life, such as social isolation, loss of income and loneliness that can have important consequences in terms of mental health.Objective: We aimed to examine the effect of the initial phases of the COVID-19 pandemic on psychological distress, well-being and perceived physical health among Mexican-base respondents and to examine whether coping strategies would play a potential intermediating role in relation to these variables. Under the Existential Positive Psychology perspective, an emphasis was made on meaning-centered coping.Methods: A cross-sectional study was conducted between April 30 and June 16th 2020 among 604 Mexicans-base respondents of which 471 were women and 132 men. Data was collected by using online questionnaires. Psychological distress was measured using the Depression, Anxiety, and Stress Scale (DASS-21). The Brief COPE Inventory was used to assess problem-focused and emotion-focused coping strategies. We also used the Meaning-Centered Coping Scale (MCCS). PERMA-Profiler was used to assess well-being, perceived physical health, and loneliness. Profiler and Descriptive analyses and bivariate linear regression were performed to examine the association of variables.Results: 45.9% of the participants reported moderate to extremely severe psychological distress. Our results demonstrate that problem-focused and emotion-focused coping were positively related to psychological distress, whereas meaning-centered coping was negatively associated with distress. Furthermore, psychological distress played a potential negative role in the perceived physical health, while meaning-centered coping and well-being buffered the negative influence of psychological distress on perceived physical health (completely standardized indirect effect = –0.01, SE: 0.012, 95% CI [−0.065; −0.017].Conclusion: Meaning-centered coping was found to suppress the negative influence of psychological distress on sensation of decreased physical health corroborating the critical role of meaning in life in promoting well-being. Future studies can further examine the value of the critical role of meaning in life in promoting well-being as a protective factor against severe distress during traumatic events. Findings of this study can be used to orient policies and interventions aimed to alleviate suffering in the midst of the COVID-19 pandemic.
Getting to Know the Inner Self. Exploratory Study of Identity Oriented Psychotrauma Therapy—Experiences and Value From Multiple Perspectives
Authors: Stjernswärd Sigrid 
Published: May 2021

Early trauma and failures in attachment attunement can affect future relational patterns, health and well-being. The processing of trauma, especially complex trauma, through adequate interventions may help integrate traumatic experiences, enhance health and quality of life. Despite years of clinical practice with Identity oriented psychotrauma therapy (IoPT), there is a lack of scientific research on the subject.Objective: The study's aim was to explore the experiences and value of IoPT for persons with experiences of IoPT, whether as a therapist, client, representative and/or observer.Methods: The study has an explorative, qualitative design. Data collection through individual in-depth interviews and focus groups with 20 participants and data analysis were inspired by grounded theory.Results: The results showed an exploratory process of self-discovery and self-development, Getting to know the inner self, to which all categories were interrelated through their contribution to the process. The findings shed light on the experiences and tangible value of IoPT for the participants from the perspectives of client, therapist, representative and observer. These perspectives were intertwined and illuminated in terms of their contribution to the process.Conclusion: IoPT seems to have transformative potential in terms of a self-exploratory journey from multiple perspectives. The need for effective treatments to enhance health and prevent further ill health in persons affected by complex trauma motivates the exploration of novel treatment approaches and formats to support clients toward health enhancing strategies. Further quantitative and qualitative research is motivated to enhance our understanding of the workings and value of IoPT for self-development, health and quality of life.