A carrier-free nanovaccine combined with cancer immunotherapy overcomes gemcitabine resistance.

Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.

Emerging Therapies for Non-Alcoholic Steatohepatitis (NASH): A Comprehensive Review of Pharmacological and Non-Pharmacological Approaches.

Non-alcoholic steatohepatitis (NASH) has emerged as a significant global health concern, closely linked to the obesity epidemic and metabolic syndrome. This review explores emerging therapies for NASH that go beyond traditional lifestyle modifications. The complex pathophysiology of NASH, involving insulin resistance, lipotoxicity, oxidative stress, and chronic inflammation, offers multiple targets for therapeutic intervention. While lifestyle changes remain fundamental, their limitations in achieving sustained improvements highlight the need for effective pharmacological and interventional therapies. This review discusses novel pharmacological approaches, including farnesoid X receptor (FXR) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, and agents addressing metabolic dysfunction, inflammation, and fibrosis. Promising candidates such as obeticholic acid, lanifibranor, and semaglutide are highlighted, along with combination therapies targeting multiple pathways simultaneously. Non-pharmacological interventions, including bariatric surgery, endoscopic bariatric and metabolic therapies, and innovative exercise regimens, are also examined for their potential in NASH management. Despite significant advancements, NASH drug development faces challenges due to the disease's complexity, patient heterogeneity, and stringent regulatory requirements. This review also addresses these limitations and explores future directions, including personalized medicine approaches, non-invasive diagnostic tools, and the potential of microbiome modulation and regenerative therapies. The evolving landscape of NASH research emphasizes the need for multidisciplinary approaches integrating advances in diagnostics, therapeutics, and digital health technologies. As the field progresses, the focus remains on developing more effective, personalized, and accessible strategies for preventing, diagnosing, and treating NASH, with the ultimate goal of improving outcomes for patients affected by this increasingly prevalent liver disease.

Effects of glucagon-like peptide-1 receptor agonists on endoscopy outcomes: A systematic review & meta-analysis.

BACKGROUND AND AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are known to cause delayed gastric emptying, however the effect on clinical outcomes during upper endoscopy/colonoscopy remains unclear. We conducted a meta-analysis to reconcile the data. METHODS: Online databases were searched for studies evaluating GLP-1RAs vs control group (no GLP-1RAs) in patients undergoing endoscopy. The outcomes of interest were rate of retained gastric contents (RGC), aborted procedures, aspiration events and subjective bowel preparation quality. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a random-effects model. RESULTS: A total of 23 studies with 77,271 patients (4,449 in the GLP-1 RA arm and 72,703 in the control arm) were included. The mean age ranged from 47.6 to 72 years and 58.4% were females. As compared to the control group, the GLP-1 RA group had higher odds of RGC (OR 15.39, 95% CI 4.65-50.99, p < 0.01) and aborted procedures (OR 13.86, 95% CI 4.42-43.43, p < 0.01). No significant differences were observed between the two groups in terms of aspiration events (OR 21.06, 95% CI 0.13-3379.01, p=0.24) and subjective bowel preparation quality (OR 0.94, 95% CI 0.67-1.31, p=0.83). CONCLUSION: While statistical significance was reached in terms of visible RGC and early termination of endoscopies in patients on GLP-1RAs, these events were overall rare. GLP-1RAs do not appear to pose significant risk, as the odds of developing aspiration were comparable in the two groups.

GLP-1 Receptor Agonists in Overweight and Obese Individuals With Type 1 Diabetes Using an Automated Insulin Delivery Device: A Real-World Study.

INTRODUCTION: Automated insulin delivery (AID) systems have improved glycemic control in individuals with type 1 diabetes (T1D) but overweight and increased cardiovascular risk remain a challenge. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with improved cardiometabolic profile but are currently not approved for the treatment of T1D. MATERIAL AND METHODS: Individuals with T1D at Steno Diabetes Center Copenhagen, Denmark, treated with AID and off-label GLP-1 RA for at least six months between January 2017 and May 2024 were included in a retrospective chart review study. RESULTS: Nineteen individuals with (median [range]) age 42 (24-60) years were included. At GLP-1 RA initiation, hemoglobin A1c (HbA1c) was 7.3% (6.1%-8.7%), HbA1c 56 (43-72) mmol/mol, body weight 91.5 (78.0-115.0) kg, and body mass index 35.4 (27.0-42.0) kg/m2. Time in range was 74% (29%-82%), time above range 25% (18%-71%) while time below range was 1% (0%-5%). After six months of treatment, body weight changed -11% (-22% to -3%; P = .001) and total daily insulin dose changed -15.1 (-32.5 to -8.2) IU (P = .004). There were no significant changes in HbA1c or other glucose measures. One person developed ketoacidosis caused by infusion set failure, but none reported severe hypoglycemia. CONCLUSION: Glucagon-like peptide-1 receptor agonist as add-on therapy for six months in individuals with obesity and AID-treated T1D led to considerable weight loss and a reduction in insulin dose.

Challenges in the care and treatment of patients with extreme obesity.

Obesity is a prevalent chronic disease. The management of extreme obesity - i.e., body mass index (BMI) ≥ 50 kg/m2 or obesity class IV and V - is still far from ideal. Individuals with extreme obesity have a high risk of surgical complications, mortality, comorbidities, and reduced weight loss following bariatric surgery. Although lifestyle changes and anti-obesity medications are recommended for all patients with extreme obesity as adjuvants to weight loss, these measures are less effective than bariatric surgery. As a first step, sleeve gastrectomy or an inpatient very-low-calorie diet should be incentivized to enhance weight loss before definitive surgery. Although malabsorptive procedures lead to greater weight loss, they are associated with an increased risk of early complications and malnutrition. Nonstandard techniques employed in clinical trial protocols, such as transit bipartition, may be performed as they maintain a weight loss potency comparable to that of the classic duodenal switch but with fewer nutritional problems. Anatomical causes should be investigated in patients with postoperative suboptimal clinical response or recurrent weight gain. In these cases, the initiation of anti-obesity drugs, endoscopic therapies, or a conversion procedure might be recommended. More studies are needed to address the specific population of patients with extreme obesity, as their outcomes are expected to be distinct from those of patients with lower BMI.

Therapeutic potential of agents targeting cannabinoid type 2 receptors in organ fibrosis.

The endocannabinoid system has garnered attention as a potential therapeutic target in a range of pathological disorders. Cannabinoid receptors type 2 (CB2) are a class of G protein-coupled receptors responsible for transmitting intracellular signals triggered by both endogenous and exogenous cannabinoids, including those derived from plants (phytocannabinoids) or manufactured synthetically (synthetic cannabinoids). Recent recognition of the role of CB2 receptors in fibrosis has fueled interest in therapeutic targeting of CB2 receptors in fibrosis. Fibrosis is characterized by the alteration of the typical cellular composition within the tissue parenchyma, resulting from exposure to diverse etiological factors. The pivotal function of CB2 agonists has been widely recognized in the regulation of inflammation, fibrogenesis, and various other biological pathologies. The modulation of CB2 receptors, whether by enhancing their expression or activating their function, has the potential to provide benefits in numerous conditions, particularly by avoiding any associated adverse effects on the central nervous system. The sufficient activation of CB2 receptors resulted in the complete suppression of gene expression related to transforming growth factor ß1 and its subsequent fibrogenic response. Multiple reports have also indicated the diverse functions that CB2 agonists possess in mitigating chronic inflammation and subsequent fibrosis development in various types of tissues. While currently in the preclinical stage, the advancement of CB2 compounds has garnered significant attention within the realm of drug discovery. This review presents a comprehensive synthesis of various independent experimental studies elucidating the pivotal role of identified natural and synthetic CB2 agonists in the pathophysiology of organ fibrosis, specifically in the cardiac, hepatic, and renal systems.

Exposure to GLP-1 Receptor Agonist and Bariatric Surgery Use on Obesity Policy Support.

BACKGROUND: Glucagon-like-peptide-1 receptor agonists (GLP-1s) are a newer class of obesity medications that have garnered significant attention by the public and media. Media reports suggest that medical interventions such as GLP-1s are often perceived as weight loss "shortcuts." PURPOSE: The present experimental research tested the effect of exposure to medical weight loss interventions on GLP-1 policy support, dependent on body mass index. METHODS: A sample of 440 participants (Mage  = 37, SD = 12.6) were randomly assigned to read about a woman who lost 15% of her body weight either with a GLP-1, bariatric surgery, or diet/exercise. Participants reported on beliefs that the woman took a weight loss "shortcut" and support for three policies expanding GLP-1 coverage. RESULTS: Exposure to a woman who lost weight with GLP-1 or bariatric surgery (vs. diet/exercise) led to higher GLP-1 policy support. However, such exposure was also indirectly associated with lower policy support, partially mediated by weight loss "shortcut" beliefs. CONCLUSIONS: This study provides evidence that exposure to medical weight loss interventions leads to higher GLP-1 policy support. Exposure may also, indirectly, lead to lower policy support due to beliefs that such interventions are shortcuts. Findings have implications for policymakers who are interested in how perceptions of medical weight loss interventions influence support for obesity treatments and related health policies.

Media reports suggest that medical interventions to treat obesity, such as GLP-1 agonists, are often perceived as weight loss "shortcuts" or "taking the easy way out." This experimental study tested the effect of exposure to medical weight loss interventions on support for GLP-1 policies, dependent on participant body mass index. A sample of 440 participants were randomly assigned to read about a woman who lost 15% of her body weight either with a GLP-1, bariatric surgery, or diet/exercise. Then participants reported on beliefs that the woman took a weight loss "shortcut" and support for three policies expanding GLP-1 coverage. Results showed that exposure to a woman who lost weight with GLP-1 or bariatric surgery, compared to diet/exercise, led to higher GLP-1 policy support. However, such exposure was also indirectly associated with lower GLP-1 policy support due to higher weight loss "shortcut" beliefs. Findings have implications for policymakers who are interested in how perceptions of medical weight loss interventions influence support for obesity treatments and related health policies.

Semaglutide and smoking cessation in individuals with type 2 diabetes mellitus: there is no smoke without fire!

Tobacco use represents the leading preventable risk factor for premature deaths worldwide. A meta-analysis of 74 epidemiological studies, including 3.2 million individuals with type 2 diabetes mellitus (T2DM) from 33 countries, reported a pooled prevalence of smoking of 20.8% among individuals with T2DM. Cigarette smoking further aggravates existing deleterious vascular effects of T2DM. Namely, chronic hyperglycemia and exposure to cigarette smoke cause additive injurious effect on the endothelium, leading to an acceleration of vascular complications seen in persons with T2DM and tobacco use disorders (TUD). In a recent study, Wang and colleagues found that semaglutide use was associated with a significantly lower risk for medical encounters for TUD, when compared to other antidiabetic drug classes; indeed, this effect was strongest compared with insulins and weakest compared with other glucagon-like peptide-1 receptor agonists. Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed irrespective of the presence of obesity. Therefore, semaglutide use might be useful in terms of smoking cessation among individuals with T2DM, thus offering an additional benefit for this constantly growing population. However, those interesting findings should be confirmed through dedicated, large-scale randomized controlled trials.

Non-alcoholic fatty liver disease risk with GLP-1 receptor agonists and SGLT-2 inhibitors in type 2 diabetes: a nationwide nested case-control study.

BACKGROUND: Non-alcoholic fatty liver diseases (NAFLDs)/non-alcoholic steatohepatitis (NASH) are the most common liver disorders among patients with type 2 diabetes. Newer classes of glucose-lowering agents (GLAs), such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), have been shown to improve liver-related biomarkers. However, their effects on the development of NAFLD/NASH remain inconclusive. METHODS: A nested case-control study was conducted using Taiwan's National Health Insurance Research Database for 2011-2018. Patients aged ≥ 40 years, diagnosed with type 2 diabetes, having stable non-insulin GLA use, and without NAFLD/NASH history were included. Patients with incident NAFLD/NASH were matched up to 10 randomly sampled controls based on individual's age, gender, cohort entry date, type 2 diabetes diagnosis date, and disease risk score. Conditional logistic regression analyses were employed to estimate the association between liver risk and treatment exposure. Dose-response analysis was also performed. RESULTS: There were 621,438 study patients included for analysis. During 1.8 years of median follow-up, the incidence of NAFLD/NASH was 2.7 per 1000 person-years. After matching, 5,730 incident NAFLD cases (mean age: 57.6 years, male: 53.2%) and 45,070 controls (57.7 years, 52.7%) were identified. Using GLP-1RAs or SGLT2is was associated with an insignificantly lower NAFLD/NASH risk (i.e., odds ratios [95% CIs]: 0.84 [0.46-1.52] and 0.85 [0.63-1.14], respectively) and increased cumulative SGLT2i doses were significantly associated with a reduced NAFLD/NASH risk (0.61 [0.38-0.97]). CONCLUSION: GLP-1RA and SGLT2i therapies in type 2 diabetes patients might prevent NAFLD/NASH development, with a significantly lower risk related to greater treatment exposure.

Antidiabetic Treatment and Prevention of Ischemic Stroke: A Systematic Review.

Background: Diabetes mellitus (DM) is a prevalent disease in the general population and also a well-established risk factor for the development of ischemic stroke. Patients who have been diagnosed with diabetes have a 20% higher risk for developing ischemic stroke in comparison to non-diabetic individuals. The aim of the current systematic review is to provide the latest evidence regarding the association between antidiabetic treatment and the prevention of ischemic stroke. Methods: A comprehensive search in scientific literature databases PUBMED, COCHRANE, and SCOPUS was conducted. The studies that were deemed as eligible for this review were those that examined the clinical benefits of therapeutic strategies in terms of preventing ischemic strokes. Results: A total of 32 studies met the established selection criteria. The included studies showed that pioglitazone treatment significantly reduced the risk for recurrent stroke in patients with DM. Furthermore, in the context of primary prevention, the improvement in glycemic control after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RA) semaglutide and dulaglutide was associated with a reduction in the risk of ischemic stroke in diabetic subjects. Metformin monotherapy may reduce stroke risk, while dipeptidyl peptidase 4 inhibitors, sodium-glucose co-transporter 2 inhibitors, and insulin do not seem to affect the incidence of stroke. Conclusions: The findings of the present systematic review suggest that pioglitazone and GLP-1RA may decrease the risk of stroke. Further studies are needed to provide additional data regarding the preventive effect of novel antidiabetic drugs, such as dual glucose-dependent insulinotropic polypeptide/GLP-1RA agents, on stroke.

Great Expectations: Semaglutide as Antidiabetic Weight Management in a Psychiatric Hospital.

This report explores the potential role of glucagon-like peptide 1 (GLP-1) receptor agonists in minimizing the metabolic side effects of psychotropic medications in patients with underlying type 2 diabetes (T2D) in inpatient psychiatric settings. The introduction of novel antidiabetic medications such as GLP-1 receptor agonists has broadened the options for managing metabolic disorders, particularly T2D. These medications not only offer effective glycemic control but also provide cardiovascular and renal benefits and help with weight management. Given the tendency of psychotropic medications to cause weight gain and metabolic complications, this report presents 2 cases where weekly doses of semaglutide improved blood glucose levels and prevented weight gain in patients receiving chronic psychotropic medications. Integrating GLP-1 receptor agonists into inpatient psychiatric care can help mitigate the metabolic adverse effects of psychotropic medications. However, considerations such as cost, accessibility, and institutional formulary restrictions are essential to ensure comprehensive patient care.

GLP-1 Receptor Agonists Confer No Increased Rates of IBD Exacerbation Among Patients With IBD.

BACKGROUND: In patients with inflammatory bowel disease (IBD), multimorbidity with obesity and type 2 diabetes is common and increasing. Glucagon-like peptide 1 (GLP-1) receptor agonists are increasingly being prescribed for patients with IBD, yet their impact on patients with IBD is largely unknown. We aimed to assess the impact of GLP-1 receptor agonists on the course of IBD. METHODS: We identified all IBD patients prescribed GLP-1 receptor agonists at a large academic healthcare network between 2009 and 2023. We analyzed demographics and IBD characteristics in the year pre- and post-GLP-1 receptor agonist prescription and matched them to non-IBD controls. Our primary outcome was IBD exacerbation in the year following GLP-1 receptor agonist initiation, measured as a composite of IBD-related hospitalization, corticosteroid prescription, medication escalation or changes, or IBD-related surgery. Secondary outcomes included change in metabolic risk factors. RESULTS: Overall, 224 patients met inclusion criteria. At GLP-1 receptor agonist initiation, the median age was 54 years, 63% were female, 77% were White, and median BMI was 33.2 kg/m2. Compared to the 12-month period prior to GLP-1 receptor agonist initiation, in the 12 months post-GLP-1 receptor agonist initiation, there was no change in rates of IBD exacerbation, IBD-related hospitalization, steroids prescription, medication escalation or changes, or IBD-related surgery. There was a significant decrease in BMI in the year following GLP-1 receptor agonist initiation (median BMI 33.5 vs 31.6 kg/m2, P < .01), with rates of decrease comparable to non-IBD matched controls. CONCLUSIONS: In patients with IBD, GLP-1 receptor agonists are effective for weight loss and associated with few episodes of disease exacerbation.

We demonstrated that GLP-1 receptor agonist initiation confers no increased rates of IBD exacerbations among diabetic and nondiabetic patients with IBD. Additionally, compared to non-IBD matched controls, GLP-1 receptor agonists are similarly effective for weight loss.

The Potential Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists as a Type of Conservative Treatment of Endometrial Cancer in Women of Reproductive Age: A Review of the Literature and a Call for Study.

Endometrial cancer (EC) is among the most common gynecological malignancies in developed countries and its occurrence has been increasing dramatically in the past few years. An in-depth knowledge of the causes of endometrial cancer, such as unopposed estrogen, insulin resistance, and chronic inflammation, has resulted in the suggestion of numerous interventions to decrease the occurrence of this cancer. Recent research has established a connection between obesity and type 2 diabetes mellitus (T2DM) with a higher chance of developing endometrial cancer, suggesting that insulin resistance is a key factor in its onset. Moreover, evidence from both epidemiological and clinical studies indicates that metformin, a drug used to treat diabetes, could possibly help in the prevention of specific types of cancer such as endometrial cancer. The aim of this study is to explore the possible impact of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) in the non-surgical management of endometrial cancer. GLP-1 has various functions and is produced when nutrients are consumed. Besides promoting the release of insulin, GLP-1 also suppresses the secretion of glucagon and reduces appetite. Moreover, the fact that GLP-1 receptors are found in different organs and tissues such as the brain, lung, pancreas, stomach, heart, and endometrium indicates that GLP-1RAs have multiple functions. Prior research has shown that it triggers apoptosis in endometrial cancer cells. Nevertheless, the precise physiological function of GLP-1 receptors in endometrial cancer still needs to be fully understood.

SGLT2i and GLP1-RA exert additive cardiorenal protection with a RAS blocker in uninephrectomized db/db mice.

Introduction: Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease in the developed world. The current treatment of the DKD with renin-angiotensin system (RAS) blockade does not totally halt the progression to end stage kidney disease. Currently, several drugs have shown to delay DKD progression such as sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA). We hypothesized that by combining several drugs that prevent DKD progression on top of RAS blockade a synergistic effect would be achieved in terms of cardiorenal protection. In the present study, we analysed if the combination of a RAS blocker (ramipril) with a SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide) in a type 2 diabetic mouse model could have add-on effects in kidney and heart protection. Methods: Male and female uninephrectomized type 2 diabetic db/db mice were treated with empagliflozin and/or semaglutide on top of ramipril during 8 weeks. During the study body weight, water and food intake were weekly monitored, glycaemia biweekly and albuminuria and glomerular filtration rate (GFR) before and after the treatment. At the end of the experiment, kidney and heart were isolated for histological and gene expression studies as well as for intrarenal RAS state assessment. Results: Semaglutide combined with ramipril and/or empagliflozin significantly decreased albuminuria but only when combined with both compounds, semaglutide further decreased blood glucose, glomerular hyperfiltration in male mice and glomerular mesangial matrix expansion. In kidney, only the triple treatment with empagliflozin, semaglutide and ramipril reduced the expression of the proinflammatory and profibrotic genes ccl2 and TGFß1. In addition, the combination of empagliflozin and semaglutide on top of RAS blockade was superior in decreasing cardiomyocyte hypertrophy and heart fibrosis in db/db mice. Discussion: Our results suggest that the combination of SGLT2i with GLP-1RA is superior in cardiorenal protection in DKD than the drugs administered alone on top of RAS blockade.

[Thrombopoietin-mediated regulation of hematopoietic stem cells].

Sustaining lifelong hematopoiesis requires maintenance, proliferation, and differentiation of hematopoietic stem cells. Thrombopoietin is a cytokine essential for regulation of hematopoietic stem cells as well as differentiation and maturation of megakaryocytes required for platelet production. Due to these properties, thrombopoietin agonists have been used to treat bone marrow failure syndromes such as aplastic anemia. Through analysis of thrombopoietin gene-deficient mice, my colleagues and I have demonstrated the mechanism of action of thrombopoietin receptor agonists in hematopoietic stem cell maintenance and differentiation. This review focuses on governance of homeostasis in the hematopoietic system by thrombopoietin signaling.

Left ventricular systolic function after inhalation of beta-2 agonists in healthy athletes.

Inhaled beta-2 adrenoceptor agonists (iß2A) are routinely used as bronchodilators in the treatment of asthma. However, their cardiac effects in athletes are scarcely examined. Thus, the aim of this study was to evaluate the effects of iß2A on left ventricular (LV) systolic function (SF) by echocardiography in healthy, non-asthmatic female and male endurance athletes. A randomized, double-blinded, placebo-controlled, balanced, 4-way complete block cross-over study was conducted. Twenty-four healthy athletes (12f/12m: 22.9 ± 2.7/24.4 ± 4.6 years) randomly completed 4 study arms (placebo; salbutamol; formoterol; formoterol + salbutamol). After inhalation of the study medication, the participants performed a 10-min time trial (TT) on a bicycle ergometer. After each TT an echocardiography was performed to determine LVSF. Blood samples were collected pre, post, 3 h and 24 h post TT. In females, total serum concentrations for salbutamol and formoterol were higher. LV ejection fraction (LVEF) and LV global longitudinal strain (LVendoGLS) showed a treatment effect for the whole study group (p < 0.0001) and a sex effect on LVEF (p = 0.0085). In women, there was a significant treatment effect for all medication arms (at least p ≤ 0.01) both on LVEF and LVendoGLS. In men only formoterol and formoterol + salbutamol displayed a treatment effect on LVEF (p = 0.0427, p = 0.0330; respectively), whereas on LVendoGLS only formoterol + salbutamol was significant (p = 0.0473). The iß2A significantly influenced LVSF after an acute bout of exercise in healthy endurance athletes. These effects were even more pronounced when combining both iß2A that supports a dose-dependent effect on cardiac function. Moreover, female athletes had higher serum concentrations of ß2 agonists and stronger effects on LVSF compared to male athletes. This is mainly explained by differences in body weight and related plasma volume and may indicate a potential risk when increasing dose above the tested concentrations. Trial registration: At the European Union Drug Regulating Authorities Clinical Trials (Eudra CT) with the number 201,500,559,819 (registered prospectively on 09/12/2015) and at the German register for clinical studies (DRKS number 00010574 registered retrospectively on 16/11/2021).

Flow cytometry-assisted analysis of phenotypic maturation markers on an immortalized dendritic cell line.

Dendritic cells (DCs), and especially so conventional type I DCs (cDC1s), are fundamental regulators of anticancer immunity, largely reflecting their superior ability to engulf tumor-derived material and process it for cross-presentation on MHC Class I molecules to CD8+ cytotoxic T lymphocytes (CTLs). Thus, investigating key DC functions including (but not limited to) phagocytic capacity, expression of CTL-activating ligands on the cell surface, and cross-presentation efficacy is an important component of multiple immuno-oncology studies. Unfortunately, DCs are terminally differentiated cells, implying that they cannot be propagated indefinitely in vitro and hence must be generated ad hoc from circulating or bone marrow-derived precursors, which presents several limitations. Here, we propose a simple, cytofluorometric method to quantify phenotypic activation markers including CD80, CD86 and MHC class II molecules on the surface of a conditionally immortalized immature DC line that can be indefinitely propagated in vitro but also driven into maturation at will with a simple change in culture conditions. Upon appropriate scaling and automatization, this approach is compatible with high-throughput screening programs for the discovery of novel DC activators that do not suffer from batch variability and other limitations associated with the generation of fresh DCs.

Exploiting the triple quadrupole mass analyzer for the open detection and tentative identification of synthetic cannabinoid receptor agonists based on common fragmentation pathways.

BACKGROUND: The use of new psychoactive substances (NPS) has emerged as a significant public health concern globally, due to their unknown and unpredictable effects on both physical and mental health. Among them, synthetic cannabinoids receptor agonists (SCRAs) currently stand as the most widely consumed NPS family in Europe. Since the detection of JWH-018 in 2008, the structures of these compounds have evolved to circumvent legislation and/or enhance their effects, consequently increasing the number of reported SCRAs to be monitored. Therefore, new strategies are needed to identify these compounds, whether in seized products or in biological samples. RESULTS: This study presents the development of an open method for detecting SCRAs employing a "pseudo-target" screening approach, a strategy previously developed and used in our laboratory for synthetic cathinones identification. The methodology involves monitoring the main product ions and neutral losses derived from 179 SCRAs of the third and fourth generations, based on their fragmentation pathways. This approach allows for the tentative identification of the SCRAs, supported also by the created database. The versatility of the developed methodology is highlighted, extending its utility beyond seizure products or 'legal highs', to biological samples. In this sense, it has been successfully applied not only to the detection of SCRAs in research chemicals but also in authentic urine from an anonymous SCRAs consumer, through the identification of a metabolite. SIGNIFICANCE: This strategy will be particularly useful for the rapid detection of SCRAs in forensic and toxicological laboratories equipped with low-resolution MS/MS instrumentation. This is a valuable tool for the identification and monitoring of SCRAs across various contexts, significantly contributing to public health and forensic security efforts. It is especially beneficial for healthcare providers, enabling them to make informed treatment decisions.

Discovery of novel and potent sulfonamide derivatives as orally available drug for psoriasis.

The retinoid-related orphan receptor gamma-t (RORγt), a member of the nuclear receptor superfamily, functions as a ligand-dependent transcription factor. As a pivotal modulator in the development and functionality of T-helper 17 (Th17) cells, RORγt plays a crucial role in immune response regulation. Inverse agonists targeting RORγt demonstrate significant potential in modulating Th17 cell activity, offering a promising avenue for the development of therapeutics aimed at treating autoimmune diseases associated with Th17 dysregulation. GSK2981278 is a potent RORγt inverse agonist, but a drawback of GSK2981278 is its low pharmacokinetic profile, leading to a clinical failure. We have explored detailed structure-activity relationship of GSK2981278 trying to improve metabolic stability while maintaining RORγt activity. As a result, a novel series of sulfonamide derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. b14 had greatly improved In Vitro metabolic stability (T1/2 = 36.2 min) compared to GSK2981278 (T1/2 = 0.8 min). Oral dosing of compound b14 resulted in a dose-dependent suppression of IL-17A cytokine levels within a murine model of imiquimod-induced skin inflammation, underscoring its potential as a therapeutic intervention.