Targeting PAR2-mediated inflammation in osteoarthritis: a comprehensive in vitro evaluation of oleocanthal's potential as a functional food intervention for chondrocyte protection and anti-inflammatory effects.

BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by chronic inflammation and progressive cartilage degradation, ultimately leading to joint dysfunction and disability. Oleocanthal (OC), a bioactive phenolic compound derived from extra virgin olive oil, has garnered significant attention due to its potent anti-inflammatory properties, which are comparable to those of non-steroidal anti-inflammatory drugs (NSAIDs). This study pioneers the investigation into the effects of OC on the Protease-Activated Receptor-2 (PAR-2) mediated inflammatory pathway in OA, aiming to validate its efficacy as a functional food-based therapeutic intervention. METHODS: To simulate cartilage tissue in vitro, human bone marrow-derived mesenchymal stem cells (BMSCs) were differentiated into chondrocytes. An inflammatory OA-like environment was induced in these chondrocytes using lipopolysaccharide (LPS) to mimic the pathological conditions of OA. The therapeutic effects of OC were evaluated by treating these inflamed chondrocytes with various concentrations of OC. The study focused on assessing key inflammatory markers, catabolic enzymes, and mitochondrial function to elucidate the protective mechanisms of OC. Mitochondrial function, specifically mitochondrial membrane potential (ΔΨm), was assessed using Rhodamine 123 staining, a fluorescent dye that selectively accumulates in active mitochondria. The integrity of ΔΨm serves as an indicator of mitochondrial and bioenergetic function. Additionally, Western blotting was employed to analyze protein expression levels, while real-time polymerase chain reaction (RT-PCR) was used to quantify gene expression of inflammatory cytokines and catabolic enzymes. Flow cytometry was utilized to measure cell viability and apoptosis, providing a comprehensive evaluation of OC's therapeutic effects on chondrocytes. RESULTS: The results demonstrated that OC significantly downregulated PAR-2 expression in a dose-dependent manner, leading to a substantial reduction in pro-inflammatory cytokines, including TNF-α, IL-1ß, and MCP-1. Furthermore, OC attenuated the expression of catabolic markers such as SOX4 and ADAMTS5, which are critically involved in cartilage matrix degradation. Importantly, OC was found to preserve mitochondrial membrane potential (ΔΨm) in chondrocytes subjected to inflammatory stress, as evidenced by Rhodamine 123 staining, indicating a protective effect on cellular bioenergetics. Additionally, OC modulated the Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL)/Receptor Activator of Nuclear Factor Kappa-Β (RANK) pathway, suggesting a broader therapeutic action against the multifactorial pathogenesis of OA. CONCLUSIONS: This study is the first to elucidate the modulatory effects of OC on the PAR-2 mediated inflammatory pathway in OA, revealing its potential as a multifaceted therapeutic agent that not only mitigates inflammation but also protects cartilage integrity. The preservation of mitochondrial function and modulation of the RANKL/RANK pathway further underscores OC's comprehensive therapeutic potential in counteracting the complex pathogenesis of OA. These findings position OC as a promising candidate for integration into nutritional interventions aimed at managing OA. However, further research is warranted to fully explore OC's therapeutic potential across different stages of OA and its long-term effects in musculoskeletal disorders.

Beyond Anticoagulation: A Comprehensive Review of Non-Vitamin K Oral Anticoagulants (NOACs) in Inflammation and Protease-Activated Receptor Signaling.

Non-vitamin K oral anticoagulants (NOACs) have revolutionized anticoagulant therapy, offering improved safety and efficacy over traditional agents like warfarin. This review comprehensively examines the dual roles of NOACs-apixaban, rivaroxaban, edoxaban, and dabigatran-not only as anticoagulants, but also as modulators of inflammation via protease-activated receptor (PAR) signaling. We highlight the unique pharmacotherapeutic properties of each NOAC, supported by key clinical trials demonstrating their effectiveness in preventing thromboembolic events. Beyond their established anticoagulant roles, emerging research suggests that NOACs influence inflammation through PAR signaling pathways, implicating factors such as factor Xa (FXa) and thrombin in the modulation of inflammatory responses. This review synthesizes current evidence on the anti-inflammatory potential of NOACs, exploring their impact on inflammatory markers and conditions like atherosclerosis and diabetes. By delineating the mechanisms by which NOACs mediate anti-inflammatory effects, this work aims to expand their therapeutic utility, offering new perspectives for managing inflammatory diseases. Our findings underscore the broader clinical implications of NOACs, advocating for their consideration in therapeutic strategies aimed at addressing inflammation-related pathologies. This comprehensive synthesis not only enhances understanding of NOACs' multifaceted roles, but also paves the way for future research and clinical applications in inflammation and cardiovascular health.

The Relationship between COVID-19 and Hypothalamic-Pituitary-Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess-The CAPISCO International Expert Panel.

Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic-pituitary-adrenal (HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.

Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review.

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including MYH7, MYBPC3, ACTC1, TPM1, MYL2, MYL3, TNNI3, and TNNT23. Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding RNAs (lncRNAs) are a large class of transcripts ≥200 nucleotides in length that do not encode proteins. Compared to coding mRNAs, most lncRNAs are not as well-annotated and their functions are greatly unexplored. Nevertheless, increasing evidence shows that lncRNAs are involved in a variety of biological processes and diseases including HCM. Accumulating evidence has indicated that lncRNAs are dysregulated in HCM, and closely related to sarcomere construction, calcium channeling and homeostasis of mitochondria. In this review, we have summarized the known regulatory and functional roles of lncRNAs in HCM.

Mento's change model in teaching competency-based medical education.

BACKGROUND: Resistance to change is customary and is expected in any organization. However, most of the downsides of change can be avoided if the organization/individual prepares for the change by acknowledging guided strategies. In healthcare, change is the state of nature, which has also translated to medical education (ME). ME in the current era has undergone a shift from a traditional content-based curriculum to a competency-based curriculum. Recently, however, the broader social-accountability movement has accelerated this rate of transformation. One of the key challenges to educators harbingering this transformation to competency-based medical education (CBME) is to redesign the processes of teaching. AIM: Here we define a framework designed using Mento's model of change that will totally agree with introducing positive change in teaching in an institution undergoing transformation from a traditional content-based curriculum to a competency-based curriculum. METHODOLOGY: Using Schein's "unfreezing" as a guide term we critically reflected on the popular change-management models, to home in on Kotter's model of change to transform organizations. However, Kotter's change-model draws from Situational and Contingency Leadership Theories, which may not agree with academic organizations involved in ME. As such organizations adhere to Transactional and Transformational Leadership archetypes, where Leadership is constructively executed by "The Leader Team", we decided to adopt Mento's change-model for our study. Mento's model not only draws from the precepts of Kotter's model, but also incorporates axioms of Jick's and GE's change-models. RESULTS: Using Mento's model a framework was blueprinted to implement active learning (AL) strategies in CBME. Here we have elaborated on the framework using the exemplar of flipped teaching. The development of this framework required the design and execution of a faculty development program, and a step by step guidance plan to chaperon, instruct and implement change in teaching to harbinger CBME. Further, we have also reflected on the change process using Gravin's framework. CONCLUSION: To our knowledge this is the first report of the use of Mento's model of change in medical education. Also, the blueprinted framework is supported by acknowledged leadership theories and can be translated to implement any curricular change in CBME.

A novel 6D-approach to radically transform undergraduate medical education: preliminary reflections from MBRU.

BACKGROUND: Designers of undergraduate medical education (UME) need to address the exponentially expanding volume and variability of scientific knowledge, where by didactic teaching techniques need to be augmented by innovative student-centric pedagogical strategies and implementation of milieus, where information, communication and technology-enabled tools are seamlessly integrated, and lifelong information gathering, assimilation, integration and implementation is the ultimate goal. In UME, the basic sciences provide a solid scaffold allowing students to develop their personal critical decisional framework as well as define the understanding of normal human physiology, pivotal for the identification, categorization and management of pathophysiology. However, most medical schools confine themselves to "stagnant curricula", with the implementation of traditional "teacher centered" pedagogical techniques in the dissemination of the courses pertaining to basic sciences in UME. METHOD: To tackle the above paucity, we present a novel "6D-Approach" for the dissemination of concepts in basic sciences through mentored journal-clubs. The approach is informed by a teaching principle derived from Constructivism. The technique in which the 6D-approach can be implemented in UME, is shown using an example from a first-year course of Molecular Biology and Principles of Genetics at our medical school. A reflection on the impact of 6D-Approach for students as well as instructors is also presented. RESULT: The 6D-approach was positively received by the students and the formal feedback for the course: Molecular Biology and Principles of Genetics, where the approach was repeatedly employed, indicated that students expressed satisfaction with the teaching strategies employed in the course, with ~ 89% of the students in the cohort strongly agreeing with the highest grading score "extremely satisfied". Further, the approach through the use of mentored journal clubs encourages retention of knowledge, critical thinking, metacognition, collaboration and leadership skills in addition to self-evaluation and peer feedback. CONCLUSION: Hence, through the 6D-Approach, our attempt is to initiate, advance and facilitate critical thinking, problem-solving and self-learning in UME, demonstrated by graduating accomplished, competent and safe medical practitioners.

Acylcarnitines are anticoagulants that inhibit factor Xa and are reduced in venous thrombosis, based on metabolomics data.

In many patients with deep vein thrombosis and pulmonary embolism (venous thromboembolism, VTE), biomarkers or genetic risk factors have not been identified. To discover novel plasma metabolites associated with VTE risk, we employed liquid chromatography-mass spectrometry-based untargeted metabolomics, which do not target any specific metabolites. Using the Scripps Venous Thrombosis Registry population for a case-control study, we discovered that 10:1 and 16:1 acylcarnitines were low in plasmas of the VTE patient group compared with matched controls, respectively. Data from targeted metabolomics studies showed that several long-chain acylcarnitines (10:1, 12:0, 12:2, 18:1, and 18:2) were lower in the VTE group. Clotting assays were used to evaluate a causal relationship for low acylcarnitines in patients with VTE. Various acylcarnitines inhibited factor Xa-initiated clotting. Inhibition of factor Xa by acylcarnitines was greater for longer acyl chains. Mechanistic studies showed that 16:0 acylcarnitine had anticoagulant activity in the absence of factor Va or phospholipids. Surface plasmon resonance investigations revealed that 16:0 acylcarnitine was bound to factor Xa and that binding did not require the γ-carboxy glutamic acid domain. In summary, our study identified low plasma levels of acylcarnitines in patients with VTE and showed that acylcarnitines have anticoagulant activity related to an ability to bind and inhibit factor Xa.

Inhibition of thrombin generation in human plasma by phospholipid transfer protein.

BACKGROUND: Plasma phospholipid transfer protein (PLTP) transfers lipids between donors and acceptors (e.g., from HDL to VLDL) and modulates lipoprotein composition, size, and levels. No study has reported an assessment of the effects of PLTP on blood clotting reactions, such as reflected in thrombin generation assays, or on the association of venous thrombosis (VTE) risk with PLTP activity. METHODS: The in vitro effects of PLTP on blood coagulation reactions and the correlations between plasma PLTP activity levels and VTE were studied. RESULTS: Recombinant (r) PLTP concentration-dependently inhibited plasma thrombin generation and factor XII-dependent kallikrein generation when sulfatide was used to stimulate factor XII autoactivation in plasma. However, rPLTP did not inhibit thrombin generation in plasma induced by factor XIa or tissue factor, implicating an effect of PLTP on contact activation reactions. In purified systems, rPLTP inhibited factor XII autoactivation stimulated by sulfatide in the presence of VLDL. In surface plasmon resonance studies, purified factor XII bound to immobilized rPLTP, implying that rPLTP inhibits factor XII-dependent contact activation by binding factor XII in the presence of lipoproteins. Analysis of plasmas from 40 male patients with unprovoked VTE and 40 matched controls indicated that low PLTP lipid transfer activity (≤25th percentile) was associated with an increased risk of VTE after adjustment for body mass index, plasma lipids, and two known thrombophilic genetic risk factors. CONCLUSION: These data imply that PLTP may be an antithrombotic plasma protein by inhibiting generation of prothrombotic factor XIIa in the presence of VLDL. This newly discovered anticoagulant activity of PLTP merits further clinical and biochemical studies.

Progressive muscle relaxation in pandemic times: bolstering medical student resilience through IPRMP and Gagne's model.

Background: Medical education, already demanding, has been further strained by the COVID-19 pandemic's challenges and the shift to distance learning. This context underscores the need for effective stress reduction techniques in competency-based medical curricula (CBMC). Objective: We assessed the feasibility and benefits of integrating a Progressive Muscle Relaxation (PMR) module-a known effective stress-reducing technique-into a time-restricted CBMC, particularly given such modules often find placement as elective rather than mandatory. Methods: Adapting Gagne's nine events of instruction, a 2-h PMR program was designed and implemented during the pandemic. Twenty participants were engaged on a first-come, first-served basis, ensuring adherence to social distancing measures. Feedback was continuously gathered, leading to two post-program focus group sessions. Qualitative data underwent thematic analysis following Braun and Clarke's approach, with study quality maintained by the Standards for Reporting Qualitative Research (SRQR). To gauge adaptability, we aligned the program with various learning outcomes frameworks and explored its fit within CBMC using Bourdieu's Theory of Practice. Results: The pilot PMR program was well-received and effectively incorporated into our CBMC. Our analysis revealed five central themes tied to PMR's impact: Self-control, Self-realization, Liberation, Awareness, and Interpersonal relationships. Feedback indicated the program's capacity to mitigate stress during the pandemic. The SRQR confirmed the study's alignment with qualitative research standards. Further, the PMR program's contents resonated with principal domains of learning outcomes, and its integration into CBMC was supported by Bourdieu's Theory. These observations led us to propose the Integrative Psychological Resilience Model in Medical Practice (IPRMP), a model that captures the intricate interplay between the identified psychological constructs. Conclusion: This research showcases an innovative, theory-guided approach to embed a wellbeing program within CBMC, accentuating PMR's role in fostering resilience among medical students. Our PMR model offers a feasible, cost-effective strategy suitable for global adoption in medical institutions. By instilling resilience and advanced stress-management techniques, PMR ensures that upcoming healthcare professionals are better equipped to manage crises like pandemics efficiently.

New-Onset Diabetes Mellitus in COVID-19: A Scoping Review.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic became superimposed on the pre-existing obesity and diabetes mellitus (DM) pandemics. Since COVID-19 infection alters the metabolic equilibrium, it may induce pathophysiologic mechanisms that potentiate new-onset DM, and we evaluated this issue. METHOD: A systematic review of the literature published from the 1 January 2020 until the 20 July 2023 was performed (PROSPERO registration number CRD42022341638). We included only full-text articles of both human clinical and randomized controlled trials published in English and enrolling adults (age > 18 years old) with ongoing or preceding COVID-19 in whom hyperglycemia was detected. The search was based on the following criteria: "(new-onset diabetes mellitus OR new-onset DM) AND (COVID-19) AND adults". RESULTS: Articles on MEDLINE (n = 70) and the Web of Science database (n = 16) were included and analyzed by two researchers who selected 20 relevant articles. We found evidence of a bidirectional relationship between COVID-19 and DM. CONCLUSIONS: This link operates as a pathophysiological mechanism supported by epidemiological data and also by the clinical and biological findings obtained from the affected individuals. The COVID-19 pandemic raised the incidence of DM through different pathophysiological and psychosocial factors.

Students' Perception of Formative Assessment as an Instructional Tool in Competency-Based Medical Education: Proposal for a Proof-of-Concept Study.

BACKGROUND: In competency-based medical education (CBME), "Assessment for learning" or "Formative Assessment" (FA) plays a key role in augmenting student learning. FAs help students to measure their progress over time, enabling them to proactively improve their performance in summative assessments. FAs also encourage students to learn in a way where they address their knowledge gaps and gaps in their conceptualization of the subject matter. The effectiveness of an FA, as a learning and development instrument, relies on the degree of student involvement in the corresponding educational intervention's design and implementation. The extent of students' engagement in FA can be evaluated by appraising their perception regarding the educational intervention itself. OBJECTIVE: This proof-of-concept study aims to develop a systemic understanding of a Formative Assessment as an Instructional Tool (FAIS) implemented in a biochemistry course in the Basic Medical Sciences component of an undergraduate entry, CBME. METHODS: The educational intervention in question is an FAIS, which is implemented in a biochemistry course in the first semester of a 6-year bachelor of medicine, bachelor of surgery program. When developing the FAIS, each area of knowledge, skills, and attitudes were considered. Assessment formats are developed per Miller's learning pyramid. This multiphase study is meant to rely on a convergent mixed methods design, where qualitative and quantitative data are independently collected and analyzed. Thereafter, the outputs of analyses are systematically merged using joint display analysis process. Qualitative data are collected through a focus group session that captures the students' perception toward the FAIS. Data collection, integral to this focus group session, is exploratory. The inductive qualitative data analysis follows Braun and Clarke's 6-step framework. The quantitative component of this study revolves around investigating the effect of the FAIS on the course's summative assessment. The summative assessment performance of the 71 students, enrolled in the FAIS cohort, will be compared to that of the students in the non-FAIS cohort. The total duration of the proposed multiphase research study is 6 months. RESULTS: This proposed multiphase study is expected to showcase, from a systemic perspective, the effectiveness of the respective educational intervention. It will shed light on the participating students' attitudes in relation to the usefulness of FA in achieving competency goals and in fostering self-directed learning. The proposed study could also uncover the hypothesized association between the FA intervention and enhanced performance in summative assessments. CONCLUSIONS: Our findings will generate evidence regarding the application of FAs, which can be leveraged by other medical educators in contexts similar to those under investigation. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41626.

Efficient Generation of Chondrocytes From Bone Marrow-Derived Mesenchymal Stem Cells in a 3D Culture System: Protocol for a Practical Model for Assessing Anti-Inflammatory Therapies.

BACKGROUND: Chondrocytes are the primary cells responsible for maintaining cartilage integrity and function. Their role in cartilage homeostasis and response to inflammation is crucial for understanding the progression and potential therapeutic interventions for various cartilage-related disorders. Developing an accessible and cost-effective model to generate viable chondrocytes and to assess their response to different bioactive compounds can significantly advance our knowledge of cartilage biology and contribute to the discovery of novel therapeutic approaches. OBJECTIVE: We developed a novel, streamlined protocol for generating chondrocytes from bone marrow-derived mesenchymal stem cells (BMSCs) in a 3D culture system that offers significant implications for the study of cartilage biology and the discovery of potential therapeutic interventions for cartilage-related and associated disorders. METHODS: We developed a streamlined protocol for generating chondrocytes from BMSCs in a 3D culture system using an "in-tube" culture approach. This simple pellet-based 3D culture system allows for cell aggregation and spheroid formation, facilitating cell-cell and cell-extracellular matrix interactions that better mimic the in vivo cellular environment compared with 2D monolayer cultures. A proinflammatory chondrocyte model was created by treating the chondrocytes with lipopolysaccharide and was subsequently used to evaluate the anti-inflammatory effects of vitamin D, curcumin, and resveratrol. RESULTS: The established protocol successfully generated a large quantity of viable chondrocytes, characterized by alcian blue and toluidine blue staining, and demonstrated versatility in assessing the anti-inflammatory effects of various bioactive compounds. The chondrocytes exhibited reduced inflammation, as evidenced by the decreased tumor necrosis factor-α levels, in response to vitamin D, curcumin, and resveratrol treatment. CONCLUSIONS: Our novel protocol offers an accessible and cost-effective approach for generating chondrocytes from BMSCs and for evaluating potential therapeutic leads in the context of inflammatory chondrocyte-related diseases. Although our approach has several advantages, further investigation is required to address its limitations, such as the potential differences between chondrocytes generated using our protocol and those derived from other established methods, and to refine the model for broader applicability and clinical translation.

Evaluating the potential of Vitamin D and curcumin to alleviate inflammation and mitigate the progression of osteoarthritis through their effects on human chondrocytes: A proof-of-concept investigation.

Osteoarthritis (OA) is a chronic degenerative joint disorder primarily affecting the elderly, characterized by a prominent inflammatory component. The long-term side effects associated with current therapeutic approaches necessitate the development of safer and more efficacious alternatives. Nutraceuticals, such as Vitamin D and curcumin, present promising therapeutic potentials due to their safety, efficacy, and cost-effectiveness. In this study, we utilized a proinflammatory human chondrocyte model of OA to assess the anti-inflammatory properties of Vitamin D and curcumin, with a particular focus on the Protease-Activated Receptor-2 (PAR-2) mediated inflammatory pathway. Employing a robust siRNA approach, we effectively modulated the expression of PAR-2 to understand its role in the inflammatory process. Our results reveal that both Vitamin D and curcumin attenuate the expression of PAR-2, leading to a reduction in the downstream proinflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin 6 (IL-6), and Interleukin 8 (IL-8), implicated in the OA pathogenesis. Concurrently, these compounds suppressed the expression of Receptor Activator of Nuclear Factor kappa-Β Ligand (RANKL) and its receptor RANK, which are associated with PAR-2 mediated TNF-α stimulation. Additionally, Vitamin D and curcumin downregulated the expression of Interferon gamma (IFN-γ), known to elevate RANKL levels, underscoring their potential therapeutic implications in OA. This study, for the first time, provides evidence of the mitigating effect of Vitamin D and curcumin on PAR-2 mediated inflammation, employing an siRNA approach in OA. Thus, our findings pave the way for future research and the development of novel, safer, and more effective therapeutic strategies for managing OA.

The role of atherogenic lipoproteins in diabetes: Molecular aspects and clinical significance.

Dyslipidaemia plays a prominent role in the genesis of atherosclerotic plaque and the increased cardiovascular risk in diabetes. Macrophages readily take up atherogenic lipoproteins, transforming into foam cells and amplifying vascular damage in the presence of endothelial dysfunction. We discuss the importance of distinct lipoprotein subclasses in atherogenic diabetic dyslipidaemia as well as the effects of novel anti-diabetic agents on lipoprotein fractions and ultimately on cardiovascular risk prevention. In patients with diabetes, lipid abnormalities should be aggressively identified and treated in conjunction with therapeutical agents used to prevent cardiovascular disease. The use of drugs that improve diabetic dyslipidaemia plays a prominent role in conferring cardiovascular benefit in individuals with diabetes.

Glucometabolic Perturbations in Type 2 Diabetes Mellitus and Coronavirus Disease 2019: Causes, Consequences, and How to Counter Them Using Novel Antidiabetic Drugs - The CAPISCO International Expert Panel.

The growing amount of evidence suggests the existence of a bidirectional relation between coronavirus disease 2019 (COVID-19) and type 2 diabetes mellitus (T2DM), as these two conditions exacerbate each other, causing a significant healthcare and socioeconomic burden. The alterations in innate and adaptive cellular immunity, adipose tissue, alveolar and endothelial dysfunction, hypercoagulation, the propensity to an increased viral load, and chronic diabetic complications are all associated with glucometabolic perturbations of T2DM patients that predispose them to severe forms of COVID-19 and mortality. Severe acute respiratory syndrome coronavirus 2 infection negatively impacts glucose homeostasis due to its effects on insulin sensitivity and ß-cell function, further aggravating the preexisting glucometabolic perturbations in individuals with T2DM. Thus, the most effective ways are urgently needed for countering these glucometabolic disturbances occurring during acute COVID-19 illness in T2DM patients. The novel classes of antidiabetic medications (dipeptidyl peptidase 4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are considered candidate drugs for this purpose. This review article summarizes current knowledge regarding glucometabolic disturbances during acute COVID-19 illness in T2DM patients and the potential ways to tackle them using novel antidiabetic medications. Recent observational data suggest that preadmission use of GLP-1 RAs and SGLT-2is are associated with decreased patient mortality, while DPP-4is is associated with increased in-hospital mortality of T2DM patients with COVID-19. Although these results provide further evidence for the widespread use of these two classes of medications in this COVID-19 era, dedicated randomized controlled trials analyzing the effects of in-hospital use of novel antidiabetic agents in T2DM patients with COVID-19 are needed.

Telemedicine for diabetes management during COVID-19: what we have learnt, what and how to implement.

The past two decades have witnessed telemedicine becoming a crucial part of health care as a method to facilitate doctor-patient interaction. Due to technological developments and the incremental acquisition of experience in its use, telemedicine's advantages and cost-effectiveness has led to it being recognised as specifically relevant to diabetology. However, the pandemic created new challenges for healthcare systems and the rate of development of digital services started to grow exponentially. It was soon discovered that COVID-19-infected patients with diabetes had an increased risk of both mortality and debilitating sequelae. In addition, it was observed that this higher risk could be attenuated primarily by maintaining optimal control of the patient's glucose metabolism. As opportunities for actual physical doctor-patient visits became restricted, telemedicine provided the most convenient opportunity to communicate with patients and maintain delivery of care. The wide range of experiences of health care provision during the pandemic has led to the development of several excellent strategies regarding the applicability of telemedicine across the whole spectrum of diabetes care. The continuation of these strategies is likely to benefit clinical practice even after the pandemic crisis is over.

Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937 cells.

Binding of activated protein C (APC) to cells triggers multiple beneficial cytoprotective activities that suppress apoptosis, inflammation, and endothelial barrier breakdown. One paradigm for APC's signaling emphasizes its binding to endothelial cell protein C receptor (EPCR) and subsequent protease activated receptor (PAR)-1 activation. Here we used human monocytic-like U937 cells to evaluate apolipoprotein E receptor 2 (ApoER2)-dependent signaling by APC and found that APC initiated rapid phosphorylation of Tyr-220 in the adaptor protein disabled-1 (Dab1) and of Ser-473 in Akt. APC also induced phosphorylation of Ser-9 in glycogen synthase kinase 3beta (GSK3beta), which was blocked by the PI3K inhibitor LY294002. Receptor-associated protein (RAP), a general antagonist for binding of ligands to LDL receptor family members, inhibited APC-induced phosphorylation of Dab1 and GSK3beta, whereas anti-EPCR or anti-PAR1 blocking antibodies did not. Knocking down ApoER2 by using siRNA-ablated APC induced Dab1 phosphorylation, suggesting that RAP-sensitive APC-induced signaling requires ApoER2. In surface plasmon resonance equilibrium binding studies, APC bound with high affinity to soluble (s) ApoER2 (apparent K(d), approximately 30 nM) but not to soluble very low density lipoprotein receptor. RAP blocked APC binding to sApoER2 but not to sEPCR. RAP blocked binding of U937 cells to immobilized APC. RAP also blocked APC's ability to inhibit endotoxin-induced tissue factor pro-coagulant activity of U937 cells. Thus, we propose that ligation of ApoER2 by APC signals via Dab1 phosphorylation and subsequent activation of PI3K and Akt and inactivation of GSK3beta, thereby contributing to APC's beneficial effects on cells.

Reconnoitering the Therapeutic Role of Curcumin in Disease Prevention and Treatment: Lessons Learnt and Future Directions.

Turmeric is a plant with a very long history of medicinal use across different cultures. Curcumin is the active part of turmeric, which has exhibited various beneficial physiological and pharmacological effects. This review aims to critically appraise the corpus of literature associated with the above pharmacological properties of curcumin, with a specific focus on antioxidant, anti-inflammatory, anticancer and antimicrobial properties. We have also reviewed the different extraction strategies currently in practice, highlighting the strengths and drawbacks of each technique. Further, our review also summarizes the clinical trials that have been conducted with curcumin, which will allow the reader to get a quick insight into the disease/patient population of interest with the outcome that was investigated. Lastly, we have also highlighted the research areas that need to be further scrutinized to better grasp curcumin's beneficial physiological and medicinal properties, which can then be translated to facilitate the design of better bioactive therapeutic leads.