Serum Concentrations Research Articles

The clinical potential of 1,5-anhydroglucitol as biomarker in diabetes mellitus.

A crucial measure of diabetes management is to monitor blood glucose, which often requires continuous blood collection, leading to economic burden and discomfort. Blood glucose and glycated hemoglobin A1c serve as traditional indicators of glucose monitoring. But now glycated albumin, fructosamine, and 1,5-anhydroglucitol (1,5-AG) have been gaining more attention. 1,5-AG is a chemically stable monosaccharide that exists in the human body. Its serum concentration remains stable when blood glucose levels are normal. However, it decreases when blood glucose exceeds the renal glucose threshold. Studies have shown that 1.5-AG reflects blood glucose changes in 1 to 2 weeks; therefore, decreased levels of serum 1,5-AG can serve as a clinical indicator of short-term blood glucose disturbances. Recent studies have shown that 1,5-AG can be used not only for the screening and managing of diabetes but also for predicting diabetes-related adverse events and islet β cell function in prediabetic patients. In addition, saliva 1,5-AG demonstrates potential value in the screening and diagnosis of diabetes. This review focuses on the biological characteristics, detection methods, and clinical application of 1,5-AG to promote understanding and applicable research of 1,5-AG in the future.

Impact of Extracorporeal Membrane Oxygenation (ECMO) on Serum Concentrations of Cefepime

ECMO is becoming widely used as a life-saving measure for critically ill patients. However, there is limited data on pharmacokinetics and the dosing of beta-lactam antibiotics in ECMO. In this study, we evaluated the serum concentrations of cefepime in patients on ECMO to determine the impact of ECMO circuitry and to guide therapeutic dosing. Methods: Patients 19 years or older admitted to the ICU, treated with ECMO and beta-lactam antibiotics for presumed or documented infection, were enrolled. Three blood samples (peak, midpoint, trough) were obtained before ECMO (pre-ECMO) and during ECMO (intra-ECMO) at a steady state. Results: Eight patients met inclusion criteria; six received cefepime. All patients were male. Average ± SD age was 45.8 ± 14.7. Four patients received ECMO for severe SARS-CoV-2 infection, and one each for Pneumocystis pneumonia and influenza A infection. Mean ± SD APACHE II and SOFA scores prior to ECMO were 24.6 ± 7.1 and 11.0 ± 3.9, respectively. All but one of the patients received venovenous (VV) ECMO. Cefepime 1 g every 6 h intravenously over 2 min was administered to all patients before and during ECMO. Cefepime concentrations were fit to non-compartment analysis (NCA) and area under the serum concentration–time curve averaged ± SE 211.9 ± 29.6 pre-ECMO and 329.6 ± 32.3 mg*h/L intra-ECMO, p = 0.023. No patients displayed signs of cefepime neurotoxicity. Patients received ECMO for 43.1± 30 days. All patients expired. Cefepime dosed at 1 g every 6 h intravenously appears to achieve therapeutic levels for critically ill patients on ECMO.

The role of candidate pharmacogenetic variants in determining valproic acid efficacy, toxicity and concentrations in patients with epilepsy.

Antiseizure medications (ASM) exhibit considerable interindividual variability in terms of efficacy and adverse events. Genetic variation is thought to contribute to these differences in clinical outcomes. Specifically, the response to valproic acid (VPA), a widely used ASM, is influenced by multiple pharmacogenetic factors. However, and in contrast to other ASMs such as phenytoin and carbamazepine, there is a paucity of data on the association between VPA and various gene variants. The aim of this study was hence to evaluate the influence of candidate pharmacogenetic variants on VPA efficacy, toxicity and serum concentrations in a homogeneous cohort of patients newly diagnosed with genetic generalized epilepsies (GGE). In this prospective cohort study, demographic, clinical and treatment outcomes of GGE patients were retrieved from their medical records. Whole exome sequencing was performed in collaboration with Epi25. Gene variants associated with VPA efficacy, metabolism and toxicities were retrieved from PharmGKB. An analysis was then conducted to explore potential associations between these gene variants and VPA clinical outcomes. Of the 166 patients included, 60 (36.1%) experienced treatment failure while 106 (63.9%) achieved treatment success. After adjusting for VPA maintenance dose, carriers of the rs3892097 (CYP2D6) variant were 2.5 times more likely to experience treatment failure compared to wildtype (p = 0.026). The rs1057910 variant (CYP2C9*3) was associated with increased serum VPA concentrations (p = 0.034). Moreover, the rs1137101 variant (LEPR gene, a metabolism regulator) was significantly associated with a higher risk of weight gain (regression coefficient of 3.430 [0.674; 6.186], p = 0.015) and a higher frequency of hair loss (OR = 3.394 [1.157; 9.956], p = 0.026), while the rs4480 variant (SOD2 gene, encoding for a mitochondrial scavenging enzyme) was correlated with a lower frequency of hair loss (OR = 0.276 [0.089; 0.858], p = 0.026). These findings highlight the role of genetic factors in VPA treatment and underscore the potential for developing therapeutic strategies to enhance patient outcomes and minimize adverse effects.

Cu2+-mediated telomeric dimeric G-quadruplex DNAzyme for highly sensitive colorimetric detection of deferasirox

Deferasirox (DEF) is an important iron chelator for treatment of iron overload–related diseases. Monitoring DEF concentration in human serum will provide some valuable information for clinical diagnosis and therapy of such diseases. In this study, we developed a peroxidase-mimicking colorimetric sensor for the detection of DEF by simple assembly of a telomeric dimeric G-quadruplex DNAzyme with Cu2+. The DNAzyme–catalyzed oxidation of 3,3′,5,5′-tetramethylbenzidine in the presence of H2O2 can generate a quantitative colorimetric signal, and the color change can be discerned by the naked eye. Compared with the reaction rate of the monomeric G-quadruplex–Cu2+ DNAzyme, the reaction rate of the dimeric G-quadruplex–Cu2+ (G2–Cu2+) DNAzyme is significantly accelerated, and the reaction rate gradually increases and then reaches a plateau with increasing number of TTA spacers. Herein, the G2–Cu2+ DNAzyme is chosen for the highly sensitive detection of DEF based on the DEF–Cu2+ complex–induced inhibition of its peroxidase-mimicking activities. The limit of detection (LOD) of DEF is achieved as low as 0.03 μM, and the linear range is from 0.05 to 1.2 μM. The proposed strategy exhibits excellent selectivity in the presence of potential interferents, such as metal ions and small molecules. Importantly, the G2–Cu2+ DNAzyme is further expanded to detect DEF in dispersible tablets and human serum samples. Overall, this G2–Cu2+ DNAzyme provides a simple, low-cost, and rapid platform for DEF detection. This novel strategy is the first example of DEF analysis by utilizing signal amplification technology based on the G-quadruplex DNAzyme and holds great potential for DEF quality control and therapeutic drug monitoring.

Airway epithelium damage in acute respiratory distress syndrome

BackgroundThe airway epithelium (AE) fulfils multiple functions to maintain pulmonary homeostasis, among which ensuring adequate barrier function, cell differentiation and polarization, and actively transporting immunoglobulin A (IgA), the predominant mucosal immunoglobulin in the airway lumen, via the polymeric immunoglobulin receptor (pIgR). Morphological changes of the airways have been reported in ARDS, while their detailed features, impact for mucosal immunity, and causative mechanisms remain unclear. Therefore, this study aimed to assess epithelial alterations in the distal airways of patients with ARDS.MethodsWe retrospectively analyzed lung tissue samples from ARDS patients and controls to investigate and quantify structural and functional changes in the small airways, using multiplex fluorescence immunostaining and computer-assisted quantification on whole tissue sections. Additionally, we measured markers of mucosal immunity, IgA and pIgR, alongside with other epithelial markers, in the serum and the broncho-alveolar lavage fluid (BALF) prospectively collected from ARDS patients and controls.ResultsCompared to controls, airways of ARDS were characterized by increased epithelial denudation (p = 0.0003) and diffuse epithelial infiltration by neutrophils (p = 0.0005). Quantitative evaluation of multiplex fluorescence immunostaining revealed a loss of ciliated cells (p = 0.0317) a trend towards decreased goblet cells (p = 0.056), and no change regarding cell progenitors (basal and club cells), indicating altered mucociliary differentiation. Increased epithelial permeability was also shown in ARDS with a significant decrease of tight (p < 0.0001) and adherens (p = 0.025) junctional proteins. Additionally, we observed a significant decrease of the expression of pIgR, (p < 0.0001), indicating impaired mucosal IgA immunity. Serum concentrations of secretory component (SC) and S-IgA were increased in ARDS (both p < 0.0001), along other lung-derived proteins (CC16, SP-D, sRAGE). However, their BALF concentrations remained unchanged, suggesting a spillover of airway and alveolar proteins through a damaged AE.ConclusionThe airway epithelium from patients with ARDS exhibits multifaceted alterations leading to altered mucociliary differentiation, compromised defense functions and increased permeability with pneumoproteinemia.

First case report of a vertebral osteomyelitis caused by carbapenem-resistant Enterobacter cloacae treated with imipenem/cilastatin/relebactam prolonged infusion then meropenem/vaborbactam in continuous infusion.

Bone and joint infections (BJIs) caused by multidrug-resistant bacteria are becoming more frequent. However, data on the use of novel β-lactam/β-lactamase inhibitors, such as imipenem/cilastatin/relebactam (I-R) and meropenem/vaborbactam (MVB), to treat BJIs is lacking. Furthermore, prolonged infusions of these β-lactams should theoretically optimize pharmacokinetic/pharmacodynamics target in these indications, but there are currently no reports on this type of infusions, especially in the setting of BJI. We report a case of a vertebral osteomyelitis caused by carbapenem-resistant Enterobacter cloacae successfully treated with extended-infusion of I-R (1.25g q6h over 2h), then with continuous infusion of MVB (2g q4h as over 4h). Therapeutic drug monitoring confirmed that extended-infusion of I-R and continuous infusion of MVB achieved serum concentrations up to 12mg/L of imipenem and 19mg/L of meropenem, respectively. The favourable outcome of this patient treated for a vertebral osteomyelitis caused by carbapenem-resistant E. cloacae suggest that extended- and continuous infusions of I-R and MVB, are promising regimens for treatment of BJIs caused by carbapenem-resistant Enterobacterales.

Fast and label-free detection of procalcitonin in human serum for sepsis using a WTex-based extended-gate field-effect transistor biosensor

In this article, we present the first instance of depositing WTex-sensitive films with varying thicknesses (3, 4, and 5 nm) onto flexible polyimide substrates using radio-frequency sputtering. These films were used to create an extended-gate field-effect transistor (EGFET) for pH sensing and detecting procalcitonin (PCT) in the sera of patients with sepsis or bacterial infections. Among the films, the 4 nm WTex film exhibited high sensitivity (59.57 mV/pH), minimal hysteresis (∼0.8 mV), and a low drift rate (0.14 mV/h). Additionally, this WTex-based EGFET sensor retained a pH sensitivity of 59.2 mV/pH even after 180 days of operation and exhibited excellent mechanical flexibility, enduring 500 bending cycles without degradation. Moreover, PCT antibodies, activated using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and N-hydroxysuccinimide, were immobilized on the WTex film functionalized with 3-aminopropyl triethoxysilane. This effective immobilization enabled the specific binding of PCT antigens. The WTex-based EGFET biosensor demonstrated high sensitivity (18.12 mV/pCPCT) across a wide dynamic range (1 fg/mL to 1 μg/mL). Furthermore, the PCT concentrations in patient sera, whether from individuals with or without sepsis or bacterial infections, measured by our biosensor were comparable to results obtained using clinical enzyme-linked immunosorbent assay kits.

Comparison of Serum and Cerebrospinal Fluid Neurofilament Light Chain Concentrations Measured by Ella™ and Lumipulse™ in Patients with Cognitive Impairment.

Neurofilament light chain proteins (NfLs) are considered a promising biomarker of neuroaxonal damage in several neurological diseases. Their measurement in the serum and cerebrospinal fluid (CSF) of patients with dementia may be especially useful. Our aim was to compare the NfL measurement performance of two advanced technologies, specifically the Ella™ microfluidic platform and the Lumipulse™ fully automated system, in patients with cognitive disorders. Thirty subjects with neurodegenerative cognitive disorders (10 with Alzheimer's Disease, 10 with Frontotemporal Dementia, and 10 with non-progressive Mild Cognitive Impairment) seen at the Cognitive Neurology Clinic of Modena University Hospital (Italy) underwent CSF and serum NfL measurement with both the Ella™ microfluidic platform (Bio-Techne, Minneapolis, MN, USA)) and the Lumipulse™ fully automated system for the CLEIA (Fujirebio Inc., Ghent, Belgium). Correlation and regression analyses were applied to assess the association between NfL concentrations obtained with the two assays in CSF and serum. The Passing-Bablok regression method was employed to evaluate the agreement between the assays. There were high correlations between the two assays (r = 0.976, 95% CI. 0.950-0.989 for CSF vs. r = 0.923, 95% CI 0.842-0.964 for serum). A Passing-Bablok regression model was estimated to explain the relationship between the two assays, allowing us to switch from one to the other when only one assay was available. We found a good degree of correlation between the two methods in patients with neurocognitive disorders. We also established a method that will allow comparisons between results obtained with either technique, allowing for meta-analyses and larger sample sizes.

Hydrogen alleviates non-alcoholic fatty liver disease in mice by regulating intestinal flora

Despite being the most common form of chronic liver disease, there are still no approved drugs for thetreatment of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to elucidate the therapeutic effects and possible mechanisms of hydrogen (H2) inhalation in mice with NAFLD. Male C57BL/6 mice (6 weeks old) were fed either a 60% fat diet (high-fat diet [HFD]) or a 10% fat diet (normal diet) for 11 weeks. Then, H2 was administered to random HFD-fed mice for another 11 weeks before they were euthanized. Biochemical analysis of serum samples, histological analysis of liver and ileum samples, 16S rRNA sequencing analysis of stool samples, and analysis of the expression levels of related factors by enzyme-linked immunosorbent assay were conducted to determine the effect of H2 intervention on NAFLD. H2 inhalation alleviated hyperglycemia and impaired glucose tolerance; decreased the serum concentrations of triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, lipopolysaccharide, and tumor necrosis factor-alpha; and ameliorated liver injury by a HFD, although no weight loss was observed. Interestingly, H2 inhalation increased the relative abundance of Akkermansia muciniphila and decreased the Firmicutes-to-Bacteroidia ratio in the intestinal tract of NAFLD mice. These data indicate that H2 alleviated the symptoms of NAFLD by increasing the abundance of A. muciniphila in the intestine. Thus, H2 may be a new potential treatment strategy for patients with NAFLD.

Personalized, disease-stage specific, rapid identification of immunosuppression in sepsis.

Data overlapping of different biological conditions prevents personalized medical decision-making. For example, when the neutrophil percentages of surviving septic patients overlap with those of non-survivors, no individualized assessment is possible. To ameliorate this problem, an immunological method was explored in the context of sepsis. Blood leukocyte counts and relative percentages as well as the serum concentration of several proteins were investigated with 4072 longitudinal samples collected from 331 hospitalized patients classified as septic (n=286), non-septic (n=43), or not assigned (n=2). Two methodological approaches were evaluated: (i) a reductionist alternative, which analyzed variables in isolation; and (ii) a non-reductionist version, which examined interactions among six (leukocyte-, bacterial-, temporal-, personalized-, population-, and outcome-related) dimensions. The reductionist approach did not distinguish outcomes: the leukocyte and serum protein data of survivors and non-survivors overlapped. In contrast, the non-reductionist alternative differentiated several data groups, of which at least one was only composed of survivors (a finding observable since hospitalization day 1). Hence, the non-reductionist approach promoted personalized medical practices: every patient classified within a subset associated with 100% survival subset was likely to survive. The non-reductionist method also revealed five inflammatory or disease-related stages (provisionally named 'early inflammation, early immunocompetence, intermediary immuno-suppression, late immuno-suppression, or other'). Mortality data validated these labels: both 'suppression' subsets revealed 100% mortality, the 'immunocompetence' group exhibited 100% survival, while the remaining sets reported two-digit mortality percentages. While the 'intermediary' suppression expressed an impaired monocyte-related function, the 'late' suppression displayed renal-related dysfunctions, as indicated by high concentrations of urea and creatinine. The data-driven differentiation of five data groups may foster early and non-overlapping biomedical decision-making, both upon admission and throughout their hospitalization. This approach could evaluate therapies, at personalized level, earlier. To ascertain repeatability and investigate the dynamics of the 'other' group, additional studies are recommended.

Deciphering the link: A cutting-edge exploration of the intriguing connection between recurrent pregnancy loss and rare earth elements-Lutetium, praseodymium, samarium, dysprosium, and cerium.

To evaluate the levels of serum rare earth elements (REEs): lutetium [Lu], praseodymium [Pr], samarium [Sm], dysprosium [Dy], and cerium [Ce] in pregnant women with recurrent pregnancy loss (RPL) and evaluate their relationship with total antioxidant capacity (TAC) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA damage. A case-controlled study was conducted on a cohort of 60 female participants, with first-trimester healthy pregnant women as the control group and pregnant women with a history of consecutive abortions as the recurrent pregnancy loss (RPL) group. Following blood collection, serum concentrations of Lu, Pr, Sm, Dy, and Ce were measured using an inductively coupled plasma mass spectrophotometer (ICP-MS). Oxidative stress and DNA damage were evaluated through TAC and DNA damage marker (8-OHdG). Serum levels of Lu, Pr, Sm, Dy, and Ce were higher in women with RPL compared with control (P < 0.001). Intriguingly, a strong significant negative correlation was observed between TAC and REEs (P < 0.05). Lu, Dy, and Ce demonstrated a significant positive correlation with increased DNA damage in the RPL group (P < 0.05). Contrary, there was no evidence of a correlation between 8-OHdG and Pr and Sm. The study highlights a potential association between Lu, Sm, Dy, and Ce and an increased risk of RPL, highlighting REE-induced toxicity as a major risk factor for RPL. The outcome of the study is to advance our understanding of the interplay between rare earth elements and RPL, with potential implications for reproductive medicine, environmental health, and the development of preventive strategies for individuals at risk of RPL.

Comparative Evaluation of Lipid Profile, C-Reactive Protein and Paraoxonase-1 Activity in Dogs with Inflammatory Protein-Losing Enteropathy and Healthy Dogs.

Chronic inflammation alters lipoprotein metabolism and causes changes in the serum concentrations of lipids, C-reactive protein (CRP), and paraoxonase-1 activity (PON-1), an enzyme that may act as a local detoxifier, antioxidant, and immunomodulator in the gastrointestinal tract. Scarce information is available in dogs with protein-losing enteropathy secondary to chronic enteropathy (iPLE). The first aim was to describe and compare the lipid profiles, CRP concentrations and PON-1 activities in healthy dogs and in dogs with iPLE. The second aim was to evaluate correlations among clinicopathological, histologic data and lipid profiles in dogs with iPLE. Serum samples from 51 iPLE and 40 healthy dogs were used to study albumin, total protein, CRP, PON-1 activity, cholesterol, triglycerides and lipoprotein classes. Serum concentrations of albumin, total protein, cholesterol, PON-1 activity, and high-density and very-low-density lipoproteins were lower in iPLE dogs compared to healthy controls, while those of triglycerides, low-density lipoproteins, chylomicrons and CRP were higher. Significant correlations between the lipid profile and the existing chronic enteropathy activity index were not found. High-density and low-density lipoproteins correlated with CRP and PON-1. Triglycerides were significantly higher in dogs with both inflammation and lymphangiectasia. The results need to be confirmed in further studies.

Engineering Supramolecular Nanofiber Depots from a Glucagon-Like Peptide-1 Therapeutic.

Diabetes and obesity have emerged as major global health concerns. Glucagon-like peptide-1 (GLP-1), a natural incretin hormone, stimulates insulin production and suppresses glucagon secretion to stabilize and reduce blood glucose levels and control appetite. The therapeutic use of GLP-1 receptor agonists (e.g., semaglutide) has transformed the standard of care in recent years for treating type 2 diabetes and reversing obesity. The native GLP-1 sequence has a very short half-life, and therapeutic advances have come from molecular engineering to alter the pharmacokinetic profile of synthetic GLP-1 receptor agonists to enable once-weekly administration, reduce the frequency of injection, and improve adherence. Efforts to further extend this profile would offer additional convenience or enable entirely different treatment modalities. Here, an injectable GLP-1 receptor agonist depot is engineered through integration of a prosthetic self-assembling peptide motif to enable supramolecular nanofiber formation and hydrogelation. This supramolecular GLP-1 receptor agonistic (PA-GLP1) offers sustained release in vitro for multiple weeks, supporting long-lasting therapy. Moreover, in a rat model of type 2 diabetes, a single injection of the supramolecular PA-GLP1 formulation achieved sustained serum concentrations for at least 40 days, with an overall reduction in blood glucose levels and reduced weight gain, comparing favorably to daily injections of semaglutide. The general and modular approach is also extensible to other next-generation peptide therapies. Accordingly, the formation of supramolecular nanofiber depots offers a more convenient and long-lasting therapeutic option to manage diabetes and treat metabolic disorders.

Acute hemodynamic effect of oral ketones in patients with acutely decompensated heart failure and low cardiac output syndrome: a prospective randomized study.

Abstract Background Preliminary studies showed positive inotropic effect of mild ketosis in patients with heart failure with reduced ejection fraction (HFrEF). Purpose To evaluate the acute hemodynamic effect of oral administration of beta-hydroxybutyrate (OHB) in patients with HFrEF and low cardiac output syndrome. Methods Patients with acutely decompensated HFrEF treated with inotropic therapy were randomized (1:1) to enteral bolus of OHB (25g of OHB monoester in 65 ml of solution; H.V.M.N Ketone Ester, H.V.M.N, USA) administered three times with 3-hour intervals or to euvolemic placebo. The serum concentration of OHB, biochemical markers, and invasive hemodynamics (Swan-Ganz catheter with continuous thermodilution) were repeatedly measured before and during 24 hours after administration of OHB. The primary endpoint was the maximum change in cardiac index (CI). Results The study included 20 patients with decompensated HFrEF (age: 57 ± 8 years; left ventricular ejection fraction: 21 ± 4%; non-ischemic cardiomyopathy: 16 [80%], median INTERMACS class: 3 [IQR 2 - 4]), who were treated with milrinone (0.5 ± 0.1 ug/kg/min, n=18) or levosimendan (0.1 ug/kg/min up to 25 mg, n=2). Patients in the OHB group (n = 10) did not differ from the placebo group (n = 10) in baseline clinical, biochemical, hemodynamic or echocardiographic characteristics. Baseline OHB concentration was normal (&amp;lt;0.6 mmol/L) in all patients. Administration of OHB increased serum concentration from 0.3 ± 0.2 mmol/L to a maximum of 2.4 ± 0.7 mmol/L (&amp;lt;0.001). Concentrations of OHB peaked at 1.5 ± 0.5 hours after administration of each OHB drink, and the maximum concentration was achieved at 4.1 ± 2.5 hours (Figure 1). No changes in OHB concentration were observed in the placebo group. In both study groups, there was a significant increase of CI at 3 hours compared to baseline, but the increase was significantly greater in the OHB group (OHB: 3.2 ± 0.6 vs. 2.1 ± 0.4 L/min/m2; placebo: 2.3 ± 0.4 vs. 2.0 ± 0.3 L/min/m2; both p&amp;lt;0.001 compared to baseline; p &amp;lt; 0.001 for OHB vs. placebo at 3 hours). The maximum relative increase of CI was 60 ± 24% in the OHB group (p &amp;lt;0.001) and 18 ± 8% in the placebo group (p&amp;lt; 0.01). The change of CI correlated with the change of OHB concentration in the OHB group (r = 0.58, p&amp;lt;0.001) but not in the placebo group (r = 0.1, p = 0.3). The changes in CI were not related to heart rate or concentration of norepinephrine, which did not change significantly throughout the study in both groups. Conclusion Oral administration of OHB leads to a significant temporary increase in myocardial contractility. This novel therapeutic concept might be a promising adjunction to inotropic support in patients with decompensated HFrEF.

SHR-1918, a monoclonal antibody against angiopoietin-like 3, in healthy subjects: a randomized, double-blind, placebo-controlled, phase 1 study

Abstract Background Low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) are important risk factors for atherosclerotic cardiovascular disease. Angiopoietin-like 3 (ANGPTL3) is involved in the regulation of lipid metabolism and can increase serum TG and LDL-C levels by reducing their clearance. SHR-1918 is an ANGPTL3 monoclonal antibody developed to inhibit ANGPTL3 activity, thereby reducing the level of TG and LDL-C. Purpose This phase 1 single ascending dose study aimed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1918 in healthy subjects. Methods Six dose cohorts were planned, including 100, 300, 450, 750, 900 (optional), and 1200 (optional) mg. For each cohort, 12 healthy subjects were enrolled and randomized (9:3) to receive single subcutaneous SHR-1918 or placebo. Subjects were observed for seven days post-dose and followed up to Day 148 for the 100 mg cohort and Day 190 for the other dose cohorts. The primary endpoints were safety and tolerability. Results A total of 72 subjects were enrolled in the six dose cohorts from 100 to 1200 mg (SHR-1918, n = 54; placebo, n = 18). SHR-1918 was well-tolerated at tested doses. Treatment-emergent adverse events (TEAEs) were reported in 49 (90.7%) subjects in the SHR-1918 group and 17 (94.4%) subjects in the placebo group. The most common TEAEs were upper respiratory tract infection (25.9% with SHR-1918 vs. 27.8% with placebo), protein urine present (22.2% vs. 22.2%), and blood uric acid increased (16.7% vs. 16.7%). All TEAEs were mild or moderate in severity. There were no serious adverse events or TEAEs leading to death. Serum concentration of SHR-1918 generally increased with increasing doses. Maximum serum concentration was reached 8.0 to 10.0 days after injection, and mean t½ was 29.4 to 53.3 days across the dose range. SHR-1918 exposure exhibited in a slightly greater-than-dose-proportional manner from 100 to 1200 mg. Serum LDL-C and TG levels markedly and rapidly decreased in all SHR-1918 dose cohorts and remained under the baseline value up to the end of follow-up period for the higher doses, whereas those in the placebo group were above baseline at most follow-up visits (Figure 1 and 2). In the 750 to 1200 mg cohorts, the largest decline in LDL-C from baseline ranged from -46.5% to -49.1%, and the maximum decrease in TG ranged from -67.4% to -82.8%. On Day 85, there remained to be 36.9% to 39.0% reduction in LDL-C and 59.9% to 79.1% reduction in TG for the higher doses. Anti-drug antibody was not detected in SHR-1918-treated subjects. Conclusions SHR-1918 was well-tolerated and showed promising efficacy in healthy subjects. A phase 2 study has initiated to evaluate SHR-1918 in hyperlipidemic patients (NCT06109831).Serum LDL-C after SHR-1918 injectionSerum TG after SHR-1918 injection

The evolution of endothelial dysfunction according to the length of the implanted stent on the background of nebivolol therapy

Abstract Introduction The development of atherosclerosis is the driving cause for arterial interventions using coronary stents. Long-stent implantation can increase the vascular injury thereby contributing to the progression of endothelial dysfunction (ED) by the degradation and reduction bioavailability of the nitric oxide (NO) - thus increasing the risk of major cardiovascular events. Purpose Evaluation the evolution of endothelial dysfunction biomarker depending on the length of the stent implanted on the background of nebivolol therapy. Methods The study included 100 patients with stable angina pectoris II–III functional class (age 59.72±0.59 years) undergoing PCI with stent implantation who started the treatment with nebivolol 5mg per day tangent to the conventional treatment and were exposed to PCI with stent implantation, depending on the stent’s length they were divided in three groups: I group - 14 patients with implanted stent’s length ≤15 mm, II group - 57 subjects with implanted stent’s length =15-30 mm and the III group -29 cases where the implanted stent’s length was ≥30 mm. In all the groups was appreciated in blood the endothelial dysfunction’s marker - NO. This marker was assessed preprocedural, postprocedural (after 24 hours) and at intervals of one month, 3,6,12 months after coronary angioplasty, the NO level being compared between these groups and the reference pattern consisting of 20 healthy people. Results The circulating level of nitric oxide determined in I group -61,28±6,92 μM/L and in the II group -56.6±3.03 μM/L and the III group52.39±3.35 was compromised at the preprocedural stage versus the reference pattern - 78.67±2.72 μM/L. During the post- PCI period (first 24 hours), the biomarker level’s was reduced in I group -52.35±1.66 μM/ L, II group -53.74±2.77 μM/L and III group - 52.98±2.91 μM/L. After one month after the intervention on the backroung of the treatment with nebivolol, was recorded a gaing of the NO value in I group - 64.97±5.35 μM/L, II group -63.15±3.99 μM /L and the III group-59.38±4.46 μM/L. The NO serum concentration during the period 3 and 6 months continued to increase in all groups vs the reference pattern. At the 12-month period, the NO level remained high in all the studied groups versus the baseline: I group 99.2±1.1 μM / L (p&amp;gt;0.05), II group-97.96±2.2 μM/L (p&amp;lt;0.001) and the III group -97.65±1.9 μM/L (p&amp;lt;0.001). Conclusion The stent’s length = 15-30 mm and ≥30 mm reveals the presence of an expanded atherosclerotic process, the substrate of which is constituted by the endothelial dysfunction, this being confirmed by the low preprocedural level of NO. The stent implantation procedure induced the accentuation of endothelial dysfunction, and the 12-month nebivolol treatment favored the increase of NO serum concentraon in all groups by 24.9% vs the reference pattern and by 73.3% vs baseline.

Ginsenoside Rg1 enriches gut microbial indole-3-acetic acid to alleviate depression-like behavior in mice via oxytocin signaling

Background and purposeAlthough a large collection of data has shown that ginsenosides, the major active ingredients from Ginseng, have neuroprotective and anti-depressant effect, the mechanism of action is incompletely understood. This study aims to elucidate the antidepressant mechanism of ginsenoside Rg1 (Rg1), a poorly absorbed ginsenoside, from the perspective of gut microbe to brain signaling. MethodsA mouse model of depression was induced by unpredictable mild stress (UMS). Behavioral and neurochemical tests were conducted to evaluate the effect and mechanism of Rg1 on depressive behavior. Non-target and target metabolomics were performed to identify the signaling metabolites underlying the antidepressant efficacy of Rg1. Gut microbial structure was analyzed by 16S rRNA sequencing and the potential functional strains associated with Rg1 action were investigated by in vitro bacterial culture. Chemical intervention was used to explore the mechanism of Rg1 and signaling metabolite. ResultsRg1 improved UMS-induced despair, anxiety-like and social avoidance behaviors in mice, which were accompanied by increased hypothalamic oxytocin secretion and restored neural proliferation in the hippocampus. Metabolomic analysis of the gut-brain axis revealed that Rg1 increased the concentration of serum and brain indole-3-acetic acid (IAA), a bacterial metabolite that was partially attributed to the enrichment of Lactobacillus murinus in the gut microbiome. Oral supplementation of IAA mimicked the anti-depressant action of Rg1, while oxytocin receptor antagonist abrogated the anti-depressant effects of both Rg1 and IAA. ConclusionOur work provides a new gut-to-brain signaling mechanism for the antidepressant effects of Rg1. In particular, Rg1 enriches the abundance of Lactobacillus murinus, which in turn increases the level of brain IAA and potentiates hypothalamic oxytocin signal. These findings suggest a promising pathway for producing antidepressant effects through gut-brain crosstalk.

Serum Concentrations of Folate Forms Following Supplementation of Multimicronutrients with 400µg or 800µg Mix of (6S)-5-Methyltetrahydrofolate and Folic Acid (1:1) in Women of Childbearing Age.

A mixture of (6S)-5-methyltetrahydrofolate-calcium salt ((6S)-5-MTHF-Ca) and folic acid (FA) from multimicronutrient supplements may show a dose-dependent effect on serum folate concentrations. The study compares fasting concentrations of serum folate spices after 8 weeks of either 400 or 800µgday-1 of 1:1 folate mixture in 172 nonpregnant women. Serum (6S)-5-MTHF concentrations raise from a mean (SD) of 19.1 (13.4) to 73.9 (19.6) nmolL-1 in the 800µg group and from 17.5 (9.4) to 54.5 (21.1) nmolL-1 in the 400µg group (p < 0.001 within-group changes). The raise in serum (6S)-5-MTHF is stronger in the 800µg compared to the 400µg group (p < 0.001 between-group). The prevalence of FA concentrations ≥0.20nmolL-1 increases between baseline and week 8 in both groups, but is not different between the groups (p = 0.116). The mean percentage of (6S)-5-MTHF of total serum folate increases in both intervention groups, but is not different between the groups at 8 weeks (95.5 (4.1)% versus 94.4 (5.7)%, p = 0.309). Supplementation of multimicronutrients with 800µg folate mix for 8 weeks causes higher serum (6S)-5-MTHF concentrations, but not a higher prevalence of detectable FA compares to 400µg folate.

Preclinical Validation of MIN-T: A Novel Controlled-Released Formulation for the Adjunctive Local Application of Minocycline in Periodontitis

Background: Adjunctive treatment of periodontitis lacks solutions which allow for enough time for wound healing in the periodontal pockets by avoiding fast re-colonization. Such a solution might be an antibiotic-containing formulation with a controlled release over a period of weeks. Here, a recently described minocycline-containing approach is qualified for further clinical development by focusing on proof-of-concept, systemic burden, resistance development, and degradation studies. Methods: Animal studies were done in two different (mouse-chamber, rat Porphyromonas gingivalis challenging) models, including effects on inflammation markers, bone loss, and bone structure. Also, serum concentrations of minocycline after local application were determined by HPLC-MS/MS. The resistance status of bacterial clinical isolates against minocycline was investigated and the degradation of the formulation was characterized by laser scanning and scanning electron microscopy. Results: Animal studies clearly demonstrated the applicability of the new formulation in the investigated models. Inflammation markers decreased in a dose-dependent manner and reduced bone loss compared to non-treated group was observed. Therefore, the systemic burden of the antibiotic was neglectable. Minocycline is still effective against oral pathogens; resistance development was not seen. The biodegradable thread was first swollen and subsequently degraded over a period of weeks. Conclusions: The results support the continued clinical development of this new formulation. A phase I clinical trial is planned to further evaluate its safety and efficacy.

Evaluating Biomarkers of Bone Health After an 8-Week Walking Program in Non-Ambulatory Stroke Survivors: A Pilot Study.

Background/Objectives: Stroke survivors have a significantly increased likelihood of developing osteoporosis, a condition characterized by weak and brittle bones as well as an elevated risk of bone fractures. However, previous studies on exercise intervention have mostly been on stroke survivors who are able to walk. The objective of this study was to examine the effect of walking exercise on bone health in non-ambulatory stroke survivors. Methods: This pre- and post-test study enrolled a group of chronic non-ambulatory stroke survivors. They were instructed to complete an 8-week aerobic walking exercise program, three sessions per week. Serum concentrations of osteocalcin (OC) and carboxy-terminal telopeptides of type I collagen (ICTP) were evaluated at baseline and after completing the walking exercise program. In addition, we assessed the ambulation capacity and balance control using the functional ambulation category (FAC) and Berg Balance Scale (BBS), respectively. Results: A total of 9 out of 10 non-ambulatory stroke survivors who were recruited completed the intervention. The serum concentration of OC significantly increased from 8.51 ± 2.28 ng/mL to 9.39 ± 2.97 ng/mL (p < 0.10). The serum concentration of ICTP significantly increased from 4.45 ± 2.58 ng/mL to 5.31 ± 2.92 ng/mL (p < 0.10). Both FAC and BBS scores significantly improved from 1.0 ± 0 to 1.33 ± 0.5 (p < 0.1) and from 7.22 ± 10.02 to 15.78 ± 14.81 (p < 0.01), respectively. Conclusions: The findings of this pilot study suggest that walking exercise may improve bone health by initiating a bone remodeling process in chronic non-ambulatory stroke survivors.