| 1. |
- Aaseth, Jan O., et al.
(författare)
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Vitamin K and Calcium Chelation in Vascular Health
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:12
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Forskningsöversikt (refereegranskat)abstract
- The observation that the extent of artery calcification correlates with the degree of atherosclerosis was the background for the alternative treatment of cardiovascular disease with chelator ethylenediamine tetraacetate (EDTA). Recent studies have indicated that such chelation treatment has only marginal impact on the course of vascular disease. In contrast, endogenous calcium chelation with removal of calcium from the cardiovascular system paralleled by improved bone mineralization exerted, i.e., by matrix Gla protein (MGP) and osteocalcin, appears to significantly delay the development of cardiovascular diseases. After post-translational vitamin-K-dependent carboxylation of glutamic acid residues, MGP and other vitamin-K-dependent proteins (VKDPs) can chelate calcium through vicinal carboxyl groups. Dietary vitamin K is mainly provided in the form of phylloquinone from green leafy vegetables and as menaquinones from fermented foods. Here, we provide a review of clinical studies, addressing the role of vitamin K in cardiovascular diseases, and an overview of vitamin K kinetics and biological actions, including vitamin-K-dependent carboxylation and calcium chelation, as compared with the action of the exogenous (therapeutic) chelator EDTA. Consumption of vitamin-K-rich foods and/or use of vitamin K supplements appear to be a better preventive strategy than EDTA chelation for maintaining vascular health.
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| 2. |
- Abbasi Aval, Negar, et al.
(författare)
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Assessing the Layer-by-Layer Assembly of Cellulose Nanofibrils and Polyelectrolytes in Pancreatic Tumor Spheroid Formation
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Three-dimensional (3D) tumor spheroids are regarded as promising models for utilization as preclinical assessments of chemo-sensitivity. However, the creation of these tumor spheroids presents challenges, given that not all tumor cell lines are able to form consistent and regular spheroids. In this context, we have developed a novel layer-by-layer coating of cellulose nanofibril–polyelectrolyte bilayers for the generation of spheroids. This technique builds bilayers of cellulose nanofibrils and polyelectrolytes and is used here to coat two distinct 96-well plate types: nontreated/non-sterilized and Nunclon Delta. In this work, we optimized the protocol aimed at generating and characterizing spheroids on difficult-to-grow pancreatic tumor cell lines. Here, diverse parameters were explored, encompassing the bilayer count (five and ten) and multiple cell-seeding concentrations (10, 100, 200, 500, and 1000 cells per well), using four pancreatic tumor cell lines—KPCT, PANC-1, MiaPaCa-2, and CFPAC-I. The evaluation includes the quantification (number of spheroids, size, and morphology) and proliferation of the produced spheroids, as well as an assessment of their viability. Notably, our findings reveal a significant influence from both the number of bilayers and the plate type used on the successful formation of spheroids. The novel and simple layer-by-layer-based coating method has the potential to offer the large-scale production of spheroids across a spectrum of tumor cell lines.
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| 3. |
- Affatato, Oreste, et al.
(författare)
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Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine : A UK Biobank Study
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas.Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions.Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]).Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine.
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| 4. |
- Ahrén, Bo
(författare)
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Contribution of GIP and GLP-1 to the Insulin Response to Oral Administration of Glucose in Female Mice
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- It has previously been shown that the incretin effect accounts for ≈50% of the insulin response to oral glucose in normal mice. Now, I have proceeded and studied the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) to the insulin response to oral glucose in female mice by using receptor antagonists. A specific GIP receptor antagonist (mGIP(3-30); 50 or 500 nmol/kg), a specific GLP-1 receptor antagonist (exendin(9-39); 3 or 30 nmol/kg), the combination of mGIP (500 nmol/kg) and exendin(9-39) (30 nmol/kg), or saline was given intravenously four minutes after administration of glucose (50 mg) through a gastric tube in anesthetized C57/BL6J mice (n = 95) with samples obtained before glucose administration and after 15, 30 and 60 min. The insulinogenic index, determined as the area under the 60 min curve for insulin (AUCinsulin) divided by the AUCglucose, was used to reflect the insulin response. It was found that the insulinogenic index was reduced by 67 ± 4% by mGIP(3-30) (p < 0.001), by 60 ± 14% by exendin(9-39) (p = 0.007) and by 61 ± 14% by the combination of mGIP(3-30) and exendin(9-39) (p = 0.043), both at their highest doses, compared to animals injected with glucose in the same experimental series. It is concluded that both GIP and GLP-1 are required for a normal incretin effect in female mice, that they contribute similarly to the insulin response, and that it is unlikely that there is another incretin hormone in this species.
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| 5. |
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| 6. |
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| 7. |
- Asif, Sana, M.D, PhD student, et al.
(författare)
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Immuno-Modulatory Effects of Dexamethasone in Severe COVID-19 : A Swedish Cohort Study
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Dexamethasone (Dex) has been shown to decrease mortality in severe coronavirus disease 2019 (COVID-19), but the mechanism is not fully elucidated. We aimed to investigate the physiological and immunological effects associated with Dex administration in patients admitted to intensive care with severe COVID-19. A total of 216 adult COVID-19 patients were included-102 (47%) received Dex, 6 mg/day for 10 days, and 114 (53%) did not. Standard laboratory parameters, plasma expression of cytokines, endothelial markers, immunoglobulin (Ig) IgA, IgM, and IgG against SARS-CoV-2 were analyzed post-admission to intensive care. Patients treated with Dex had higher blood glucose but lower blood lactate, plasma cortisol, IgA, IgM, IgG, D-dimer, cytokines, syndecan-1, and E-selectin and received less organ support than those who did not receive Dex (Without-Dex). There was an association between Dex treatment and IL-17A, macrophage inflammatory protein 1 alpha, syndecan-1 as well as E-selectin in predicting 30-day mortality. Among a subgroup of patients who received Dex early, within 14 days of COVID-19 debut, the adjusted mortality risk was 0.4 (95% CI 0.2-0.8), i.e., 40% compared with Without-Dex. Dex administration in a cohort of critically ill COVID-19 patients resulted in altered immunological and physiologic responses, some of which were associated with mortality.
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| 8. |
- Breuer, O, et al.
(författare)
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Intravenous Infusion of High Dose Selenite in End-Stage Cancer Patients: Analysis of Systemic Exposure to Selenite and Seleno-Metabolites
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is one of the main causes of human death globally and novel chemotherapeutics are desperately required. As a simple selenium oxide, selenite is a very promising chemotherapeutic because of pronounced its dose-dependent tumor-specific cytotoxicity. We previously published a first-in-man systematic phase I clinical trial in patients with cancer (from IV to end-stage) (the SECAR trial) showing that selenite is safe and tolerable with an unexpectable high maximum tolerated dose (MTD) and short half-life. In the present study, we analyzed the selenium species in plasma samples, from the patients participating in the SECAR trial and from various time points and dose cohorts using LC-ICP-MS. In conclusion, selenite, selenosugars, and 1–2 unidentified peaks that did not correspond to any standard, herein denoted ui-selenium, were detected in the plasma. However, trimethylated selenium (trimethylselenonoium) was not detected. The unidentified ui-selenium was eluting close to the selenium-containing amino acids (selenomethionine and selenocysteine) but was not part of a protein fraction. Our data demonstrate that the major metabolite detected was selenosugar. Furthermore, the identification of selenite even long after the administration is remarkable and unexpected. The kinetic analysis did not support that dosing per the body surface area would reduce interindividual variability of the systemic exposure in terms of trough concentrations.
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| 9. |
- Bäckryd, Emmanuel, et al.
(författare)
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Cerebrospinal Fluid Metabolomics Identified Ongoing Analgesic Medication in Neuropathic Pain Patients
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cerebrospinal fluid (CSF) can reasonably be hypothesized to mirror central nervous system pathophysiology in chronic pain conditions. Metabolites are small organic molecules with a low molecular weight. They are the downstream products of genes, transcripts and enzyme functions, and their levels can mirror diseased metabolic pathways. The aim of this metabolomic study was to compare the CSF of patients with chronic neuropathic pain (n = 16) to healthy controls (n = 12). Methods: Nuclear magnetic resonance spectroscopy was used for analysis of the CSF metabolome. Multivariate data analysis by projection discriminant analysis (OPLS-DA) was used to separate information from noise and minimize the multiple testing problem. Results: The significant OPLS-DA model identified 26 features out of 215 as important for group separation (R2 = 0.70, Q2 = 0.42, p = 0.017 by CV-ANOVA; 2 components). Twenty-one out of twenty-six features were statistically significant when comparing the two groups by univariate statistics and remained significant at a false discovery rate of 10%. For six out of the top ten metabolite features, the features were absent in all healthy controls. However, these features were related to medication, mainly acetaminophen (=paracetamol), and not to pathophysiological processes. Conclusion: CSF metabolomics was a sensitive method to detect ongoing analgesic medication, especially acetaminophen.
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| 10. |
- Eckerdal, David, et al.
(författare)
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Risk Factors for Long-Term Contracture Recurrence after Collagenase Injection for Dupuytren Disease : A Prospective Cohort Study
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- In Dupuytren disease, little is known about the long-term outcomes of collagenase injection or risk factors for contracture recurrence. In this prospective study, 159 patients (242 fingers) with Dupuytren disease and active extension deficit (AED) ≥20° in a metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joint were treated with collagenase injection during a 14-month period. At 5 years, 18 patients were deceased, 2 could not be contacted, and 13 had undergone fasciectomy. The remaining 126 patients (199 treated fingers) participated in a follow-up evaluation at 52–96 (mean 65) months after injection, with physical examination (114 patients) or telephone interview (12 patients). Recurrence was defined as subsequent treatment (surgery or repeat injection) or ≥20° AED worsening in a treated joint between the 6-week and 5-year measurements. The mean AED at baseline was 42° (SD 24) for MCP joints and 31° (SD 29) for PIP joints and at 5 years 11° (SD 17) and 17° (SD 23), respectively. Recurrence occurred in 17% of MCP joints and 25% of PIP joints. Statistically significant risk factors for PIP joint contracture recurrence were greater baseline AED (odds ratio 1.04, 95% CI 1.02–1.06) and small finger treatment (OR 4.6, 95% CI 1.5–14.3), with no significant risk factors found for MCP contracture recurrence.
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| 11. |
- Fernandez-de-las-Penas, C., et al.
(författare)
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Carpal Tunnel Syndrome: Neuropathic Pain Associated or Not with a Nociplastic Condition
- 2023
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Ingår i: Biomedicines. - 2227-9059. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Carpal tunnel syndrome (CTS) has been traditionally classified as primarily a neuropathic condition with or without pain. Precision medicine refers to an evidence-based method of grouping patients based on their susceptibility to biology, prognosis of a particular disease, or in their response to a specific treatment, and tailoring specific treatments accordingly. In 2021, the International Association for the Study of Pain (IASP) proposed a grading system for classifying patients into nociceptive, neuropathic, or nociplastic phenotypes. This position paper presents data supporting the possibility of subgrouping individuals with specific CTS related-pain into nociceptive, neuropathic, nociplastic or mixed-type phenotypes. Carpal tunnel syndrome is a neuropathic condition but can also be comorbid with a nociplastic pain condition. The presence of extra-median symptoms and the development of facilitated pain processing seem to be signs suggesting that specific CTS cases can be classified as the nociplastic pain phenotype. The clinical responses of therapeutic approaches for the management of CTS are inconclusive. Accordingly, the ability to identify the predominant pain phenotype in patients with CTS could likely be problematic for producing efficient treatment outcomes. In fact, the presence of a nociplastic or mixed-type pain phenotype would explain the lack of clinical effect of treatment interventions targeting the carpal tunnel area selectively. We propose a clinical decision tree by using the 2021 IASP classification criteria for identifying the predominant pain phenotype in people with CTS-related pain, albeit CTS being a priori a neuropathic pain condition. The identification of a nociplastic-associated condition requires a more nuanced multimodal treatment approach to achieve better treatment outcomes.
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| 12. |
- Ghafouri, Bijar, et al.
(författare)
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The Vastus Lateralis Muscle Interstitium Proteome Changes after an Acute Nociception in Patients with Fibromyalgia Compared to Healthy Subjects-A Microdialysis Study
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Fibromyalgia (FM) is a complex disorder and a clinical challenge to diagnose and treat. Microdialysis is a valuable tool that has been used to investigate the interstitial proteins and metabolites of muscle in patients with fibromyalgia. The implantation of the catheter in the muscle causes acute tissue trauma and nociception. The aim of this study was to investigate acute proteome changes in the vastus lateralis muscle in women fibromyalgia patients (FM) and healthy subjects (CON). A further aim was to study if a 15-week resistance exercise program in FM had any influence on how chronic painful muscle responds to acute nociception. Twenty-six women patients with FM and twenty-eight CON were included in this study. A microdialysis catheter (100 kilo Dalton cut off, membrane 30 mm) was inserted in the vastus lateralis muscle, and samples were collected every 20 min. Subjects rated pain before catheter insertion, directly after, and every 20 min of sample collection. Dialysate samples from time points 0-120 were pooled and considered trauma samples due to the catheter insertion. The samples were analyzed with nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS). Advanced multivariate data analysis was used to investigate protein profile changes between the groups. Multivariate data analysis showed significant (CV-ANOVA p = 0.036) discrimination between FM and CON based on changes in 26 proteins. After the 15-week exercise intervention, the expression levels of the 15 proteins involved in muscle contraction, response to stimulus, stress, and immune system were increased to the same expression levels as in CON. In conclusion, this study shows that microdialysis, in combination with proteomics, can provide new insights into the interstitial proteome in the muscle of FM. In response to acute nociception, exercise may alter the innate reactivity in FM. Exercise may also modulate peripheral muscle proteins related to muscle contraction, stress, and immune response in patients with FM.
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| 13. |
- Havelka, Aleksandra, et al.
(författare)
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Analysis of Calprotectin as an Early Marker of Infections Is Economically Advantageous in Intensive Care-Treated Patients
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Calprotectin is released from neutrophil granulocytes upon activation. Several studies have indicated that plasma calprotectin is an early determinant of bacterial infections, which may serve as a diagnostic tool facilitating decision making on antibiotic treatment. The study objective was to explore the health and economic implications of calprotectin as a predictive tool to initiate antimicrobial therapy in a cohort of critically ill patients. Thus, data obtained from a previously published study on calprotectin as a hypothetical early biomarker of bacterial infections in critically ill patients were evaluated regarding the potential cost-effective impact of early analysis of calprotectin on an earlier start of antibiotic treatment. Under the assumption that calprotectin is used predictively and comparators (white blood cells, procalcitonin, and C-reactive protein) are used diagnostically, a cost-effective impact of EUR 11,000-12,000 per patient would be obtained. If calprotectin would be used predictively and comparators would be used predictively for 50% of patients, it is hypothesized that cost-effectiveness would be between EUR 6000 and 7000 per patient, based on reduced stay in the ICU and general ward, respectively. Furthermore, predictive use of calprotectin seems to reduce both mortality and the length of hospital stay. This health economic analysis on the predictive use of plasma calprotectin, which facilitates clinical decision making in cases of suspected sepsis, indicates that such determination has a cost-saving and life-saving impact on the healthcare system.
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| 14. |
- Javeed, Ashir, 1989-, et al.
(författare)
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Early Prediction of Dementia Using Feature Extraction Battery (FEB) and Optimized Support Vector Machine (SVM) for Classification
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Dementia is a cognitive disorder that mainly targets older adults. At present, dementia has no cure or prevention available. Scientists found that dementia symptoms might emerge as early as ten years before the onset of real disease. As a result, machine learning (ML) scientists developed various techniques for the early prediction of dementia using dementia symptoms. However, these methods have fundamental limitations, such as low accuracy and bias in machine learning (ML) models. To resolve the issue of bias in the proposed ML model, we deployed the adaptive synthetic sampling (ADASYN) technique, and to improve accuracy, we have proposed novel feature extraction techniques, namely, feature extraction battery (FEB) and optimized support vector machine (SVM) using radical basis function (rbf) for the classification of the disease. The hyperparameters of SVM are calibrated by employing the grid search approach. It is evident from the experimental results that the newly pr oposed model (FEB-SVM) improves the dementia prediction accuracy of the conventional SVM by 6%. The proposed model (FEB-SVM) obtained 98.28% accuracy on training data and a testing accuracy of 93.92%. Along with accuracy, the proposed model obtained a precision of 91.80%, recall of 86.59, F1-score of 89.12%, and Matthew’s correlation coefficient (MCC) of 0.4987. Moreover, the newly proposed model (FEB-SVM) outperforms the 12 state-of-the-art ML models that the researchers have recently presented for dementia prediction.
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| 15. |
- Karshikoff, Bianka, et al.
(författare)
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Inflammatory Blood Signature Related to Common Psychological Comorbidity in Chronic Pain
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Chronic pain is characterized by high psychological comorbidity, and diagnoses are symptom-based due to a lack of clear pathophysiological factors and valid biomarkers. We investigate if inflammatory blood biomarker signatures are associated with pain intensity and psychological comorbidity in a mixed chronic pain population. Eighty-one patients (72% women) with chronic pain (>6 months) were included. Patient reported outcomes were collected, and blood was analyzed with the Proseek Multiplex Olink Inflammation Panel (Bioscience Uppsala, Uppsala, Sweden), resulting in 77 inflammatory markers included for multivariate data analysis. Three subgroups of chronic pain patients were identified using an unsupervised principal component analysis. No difference between the subgroups was seen in pain intensity, but differences were seen in mental health and inflammatory profiles. Ten inflammatory proteins were significantly associated with anxiety and depression (using the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Patient Health Questionnaire (PHQ-9): STAMBP, SIRT2, AXIN1, CASP-8, ADA, IL-7, CD40, CXCL1, CXCL5, and CD244. No markers were related to pain intensity. Fifteen proteins could differentiate between patients with moderate/high (GAD-7/PHQ-9 > 10) or mild/no (GAD-7/PHQ-9 < 10) psychological comorbidity. This study further contributes to the increasing knowledge of the importance of inflammation in chronic pain conditions and indicates that specific inflammatory proteins may be related to psychological comorbidity.
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| 16. |
- Lagunas-Rangel, Francisco Alejandro, et al.
(författare)
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Drosophila as a Rapid Screening Model to Evaluate the Hypoglycemic Effects of Dipeptidyl Peptidase 4 (DPP4) Inhibitors : High Evolutionary Conservation of DPP4
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, have been an integral part of the treatment of type 2 diabetes mellitus (T2DM) for several years. Despite their remarkable efficacy in lowering glucose levels and their compatibility with other hypoglycemic drugs, recent studies have revealed adverse effects, prompting the search for improved drugs within this category, which has required the use of animal models to verify the hypoglycemic effects of these compounds. Currently, in many countries the use of mammals is being significantly restricted, as well as cost prohibitive, and alternative in vivo approaches have been encouraged. In this sense, Drosophila has emerged as a promising alternative for several compelling reasons: it is cost-effective, offers high experimental throughput, is genetically manipulable, and allows the assessment of multigenerational effects, among other advantages. In this study, we present evidence that diprotin A, a DPP4 inhibitor, effectively reduces glucose levels in Drosophila hemolymph. This discovery underscores the potential of Drosophila as an initial screening tool for novel compounds directed against DPP4 enzymatic activity.
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| 17. |
- Larsson, Anders O., et al.
(författare)
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Biomarkers in Pain
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:9
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 18. |
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| 19. |
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| 20. |
- Martin-Almeida, M, et al.
(författare)
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Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10−8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= −0.015, p = 2.53 × 10−9) and nominally associated in nasal samples (coefficient = −0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes.
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| 21. |
- Mischitelli, Monica, et al.
(författare)
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New Diagnostic and Prognostic Models for the Development of Alcoholic Cirrhosis Based on Genetic Predisposition and Alcohol History
- 2023
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Ingår i: BIOMEDICINES. - 2227-9059. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 cirrhotic patients and 411 non-cirrhotics). At enrollment, the data about lifetime drinking history were collected and all patients were tested for Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, Transmembrane 6 Superfamily 2 (TM6SF2) rs58542926, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 variants. In cross-sectional analyses, models for the diagnosis of cirrhosis were developed using multivariate logistic regression. A predictive score for cirrhosis development over 24 years was built by evaluating time-dependent AUC curves. The best diagnostic accuracy was demonstrated by the model, which also includes daily alcohol consumption, duration of hazardous alcohol use, and genetic variants, with AUCs of 0.951 (95% CI 0.925-0.977) and 0.887 (95% CI 0.925-0.977) for cirrhosis and compensated cirrhosis, respectively. The predictive model for future cirrhosis development (AUC of 0.836 95% CI: 0.769-0.904) accounted for age at onset of at-risk alcohol consumption and the number of PNPLA3 and HSD17B13 variant alleles. We have developed accurate genetic and alcohol consumption models for the diagnosis of alcoholic cirrhosis and the prediction of its future risk.
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| 22. |
- Moulin, Thiago, et al.
(författare)
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Effects of Transient Administration of the NMDA Receptor Antagonist MK-801 in Drosophila melanogaster Activity, Sleep, and Negative Geotaxis
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- MK-801, also called dizocilpine, is an N-methyl-D-aspartate (NMDA) receptor antagonist widely used in animal research to model schizophrenia-like phenotypes. Although its effects in rodents are well characterised, little is known about the outcomes of this drug in other organisms. In this study, we characterise the effects of MK-801 on the locomotion, sleep, and negative geotaxis of the fruit fly Drosophila melanogaster. We observed that acute (24 h) and chronic (7 days) administration of MK-801 enhanced negative geotaxis activity in the forced climbing assay for all tested concentrations (0.15 mM, 0.3 mM, and 0.6 mM). Moreover, acute administration, but not chronic, increased the flies' locomotion in a dose-dependent matter. Finally, average sleep duration was not affected by any concentration or administration protocol. Our results indicate that acute MK-801 could be used to model hyperactivity phenotypes in Drosophila melanogaster. Overall, this study provides further evidence that the NMDA receptor system is functionally conserved in flies, suggesting the usefulness of this model to investigate several phenotypes as a complement and replacement of the rodent models within drug discovery.
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| 23. |
- Muhammad, Taj, et al.
(författare)
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Transforming Cross-Linked Cyclic Dimers of KR-12 into Stable and Potent Antimicrobial Drug Leads
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Is it possible to enhance structural stability and biological activity of KR-12, a truncated antimicrobial peptide derived from the human host defense peptide LL-37? Based on the mapping of essential residues in KR-12, we have designed backbone-cyclized dimers, cross-linked via a disulfide bond to improve peptide stability, while at the same time improving on-target activity. Circular dichroism showed that each of the dimers adopts a primarily alpha-helical conformation (55% helical content) when bound to lyso-phosphatidylglycerol micelles, indicating that the helical propensity of the parent peptide is maintained in the new cross-linked cyclic form. Compared to KR-12, one of the cross-linked dimers showed 16-fold more potent antimicrobial activity against human pathogens Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans and 8-fold increased activity against Escherichia coli. Furthermore, these peptides retained antimicrobial activity at physiologically relevant conditions, including in the presence of salts and in human serum, and with selective Gram-negative antibacterial activity in rich growth media. In addition to giving further insight into the structure-activity relationship of KR-12, the current work demonstrates that by combining peptide stabilization strategies (dimerization, backbone cyclization, and cross-linking via a disulfide bond), KR-12 can be engineered into a potent antimicrobial peptide drug lead with potential utility in a therapeutic context.
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| 24. |
- Myrov, Vladislav O, et al.
(författare)
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Artificial Neural Network (ANN)-Based Pattern Recognition Approach Illustrates a Biphasic Behavioral Effect of Ethanol in Zebrafish : A High-Throughput Method for Animal Locomotor Analysis
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Variations in stress responses between individuals are linked to factors ranging from stress coping styles to the sensitivity of neurotransmitter systems. Many anxiolytic compounds can increase stressor engagement through the modulation of neurotransmitter systems and are used to investigate stress response mechanisms. The effect of such modulation may vary in time depending on concentration or environment, but those effects are hard to dissect because of the slow transition. We investigated the temporal effect of ethanol and found that ethanol-treated individual zebrafish larvae showed altered behavior that is different between drug concentrations and decreases with time. We used an artificial neural network approach with a time-dependent method for analyzing long (90 min) experiments on zebrafish larvae and found that individuals from the 0.5% group begin to show locomotor activity corresponding to the control group starting from the 60th minute. The locomotor activity of individuals from the 2% group after the 80th minute is classified as the activity of individuals from the 1.5% group. Our method shows three clusters of different concentrations in comparison with two clusters, which were obtained with the usage of a statistical approach for analyzing just the speed of fish movements. In addition, we show that such changes are not explained by basic behavior statistics such as speed and are caused by shifts in locomotion patterns.
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| 25. |
- Persson, Sofia, et al.
(författare)
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Hyperandrogenic symptoms are a persistent suffering in midlife women with pcos; a prospective cohort study in sweden
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women, and the majority suffers from hyperandrogenism. Hyperandrogenism causes psychological morbidity and impaired quality of life in women with PCOS during the reproductive years, but data on prevalence and impact during midlife are lacking. Thus, this study aimed to address whether hyperandrogenism persists into midlife and, if so, what impact it has on quality of life. In order to answer this question, we performed a multicenter prospective cohort study, where we included women already diagnosed with PCOS who had reached the age of 45 years or more and age-matched controls. All participants underwent a physical exam, structured medical interview, biochemical testing and filled out self-assessment questionnaires. More than 40% of the women with PCOS and 82% of those who presented with the hyperandrogenic phenotype at the diagnostic work-up still suffered from hirsutism. Circulating testosterone levels were similar between women with PCOS and controls while free androgen index was higher in women with PCOS, independent of weight. Women with hyperandrogenic PCOS expressed persisting concerns regarding hirsutism at the follow-up assessment. In conclusion, women with PCOS who present with hyperandrogenic symptoms at the time they are diagnosed with PCOS have a higher risk of persistent androgenic symptoms and impaired quality of life in midlife.
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| 26. |
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| 27. |
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| 28. |
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| 29. |
- Sereti, Evangelia, et al.
(författare)
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Pancreatic Cancer Organoids : An Emerging Platform for Precision Medicine?
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:3
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Forskningsöversikt (refereegranskat)abstract
- Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with remarkable resistance to treatment, poor prognosis, and poor clinical outcome. More efficient therapeutic approaches are urgently needed to improve patients’ survival. Recently, the development of organoid culture systems has gained substantial attention as an emerging preclinical research model. PDAC organoids have been developed to study pancreatic cancer biology, progression, and treatment response, filling the translational gap between in vitro and in vivo models. Here, we review the rapidly evolving field of PDAC organoids and their potential as powerful preclinical tools that could pave the way towards precision medicine for pancreatic cancer.
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| 30. |
- Wirestam, Lina, et al.
(författare)
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Plasma Osteopontin Reflects Tissue Damage in Acute Pancreatitis
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Several scoring systems for clinical prediction of the severity of acute pancreatitis (AP) have been proposed. Yet, there is still a need for an easy-to-measure biomarker. Osteopontin (OPN) may be released to the circulation early during tissue injury, but the significance of OPN in AP has not yet been established. We aimed to evaluate plasma levels of OPN in relation to the severity of AP. In 39 individuals with confirmed AP, plasma was collected on the day of admission and consecutively for three days thereafter. Sex- and age-matched healthy blood donors (n = 39) served as controls. Plasma OPN was measured by a commercial enzyme-linked immunosorbent assay. At admission, patients with AP displayed higher OPN, 156.4 ng/mL (IQR 111.8-196.2) compared to controls, 37.4 ng/mL (IQR 11.7-65.7) (p < 0.0001). However, OPN levels on admission could not discriminate between mild and moderate-to-severe disease (132.6 ng/mL vs. 163.4 ng/mL). Nevertheless, the changes in OPN within 24 h of admission and Day 2/3 were higher among patients with moderate/severe AP (33.7%) compared to mild AP (-8.1%) (p = 0.01). This indicates that OPN is a relevant biomarker reflecting tissue injury in AP. The increase in OPN over time suggests that serial OPN measurements could contribute to the early detection of at-risk patients. Prospective studies assessing OPN in relation to outcome in AP are warranted.
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| 31. |
- Zhao, KX, et al.
(författare)
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In Vivo CaV3 Channel Inhibition Promotes Maturation of Glucose-Dependent Ca2+ Signaling in Human iPSC-Islets
- 2023
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- CaV3 channels are ontogenetically downregulated with the maturation of certain electrically excitable cells, including pancreatic β cells. Abnormally exaggerated CaV3 channels drive the dedifferentiation of mature β cells. This led us to question whether excessive CaV3 channels, retained mistakenly in engineered human-induced pluripotent stem cell-derived islet (hiPSC-islet) cells, act as an obstacle to hiPSC-islet maturation. We addressed this question by using the anterior chamber of the eye (ACE) of immunodeficient mice as a site for recapitulation of in vivo hiPSC-islet maturation in combination with intravitreal drug infusion, intravital microimaging, measurements of cytoplasmic-free Ca2+ concentration ([Ca2+]i) and patch clamp analysis. We observed that the ACE is well suited for recapitulation, observation and intervention of hiPSC-islet maturation. Intriguingly, intraocular hiPSC-islet grafts, retrieved intact following intravitreal infusion of the CaV3 channel blocker NNC55-0396, exhibited decreased basal [Ca2+]i levels and increased glucose-stimulated [Ca2+]i responses. Insulin-expressing cells of these islet grafts indeed expressed the NNC55-0396 target CaV3 channels. Intraocular hiPSC-islets underwent satisfactory engraftment, vascularization and light scattering without being influenced by the intravitreally infused NNC55-0396. These data demonstrate that inhibiting CaV3 channels facilitates the maturation of glucose-activated Ca2+ signaling in hiPSC-islets, supporting the notion that excessive CaV3 channels as a developmental error impede the maturation of engineered hiPSC-islet insulin-expressing cells.
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