Development of cordycepin formulations for preclinical and clinical studies

There is extensive literature on in vivo studies with cordycepin but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is a promising drug candidate in multiple therapeutic areas and there is a growing interest in studies aimed at assessing the pharmacological activity of this compound in relevant animal disease models. It is likely that many reported in vivo studies used formulations in which cordycepin was incompletely soluble. This can potentially confound the interpretation of pharmacokinetics and efficacy results. Furthermore, the presence of particles in intravenously administered suspension can cause adverse effects and should be avoided. Here we present the results from our development of simple and readily applicable formulations of cordycepin based on quantitative solubility assessment. Homogeneous solutions of cordycepin were prepared in phosphate-buffered saline (PBS) at different pH levels, suitable as formulations for both intravenously and oral administration. For the purpose of high-dose oral administration we also developed propylene glycol (PPG)-based vehicles in which cordycepin is completely soluble. The stability of the newly developed formulations was also assessed, as well the feasibility of their sterilisation by filtration. Additionally, an HPLC-UV method for the determination of cordycepin in the formulations, which may also be useful for other purposes, was developed and validated. Our study could provide useful information for improvement of future preclinical and clinical studies involving cordycepin

Performance Analysis of Single-Step Localization Method Based on Matrix Eigen-Perturbation Theory with System Errors

Direct position determination (DPD) is a novel technique in passive localization field recently, receiving superior localization performance compared with the conventional two-step method. The DPD estimator using Doppler shifts is first proposed by Weiss, but it is not suitable for antenna arrays. Additionally, the performance analysis of this method with system errors is absent. This study discusses the single-step localization problem based on moving arrays and exhibits the performance analysis via matrix eigen-perturbation theory with system errors. First, the DPD method using angle of arrival and Doppler shifts is introduced. Then, by adding the eigenvalue perturbations to the estimated Hermitian matrix, the asymptotic linear formulation of localization errors is derived. Consequently, the mean square error of the DPD method is available. Finally, Cramér⁻Rao bound without system errors is presented, providing a benchmark for the best localization precision and revealing the influence of system errors on the localization precision. Simulation results demonstrate the theoretical analysis in this study

A Fast ML-Based Single-Step Localization Method Using EM Algorithm Based on Time Delay and Doppler Shift for a Far-Field Scenario

This study discusses the localization problem based on time delay and Doppler shift for a far-field scenario. The conventional location methods employ two steps that first extract intermediate parameters from the received signals and then determine the source position from the measured parameters. As opposed to the traditional two-step methods, the direct position determination (DPD) methods accomplish the localization in a single step without computing intermediate parameters. However, the DPD cost function often remains non-convex, thereby it will cost a high amount of computational resources to find the estimated position through traversal search. Weiss proposed a DPD estimator to mitigate the computational complexity via eigenvalue decomposition. Unfortunately, when the computational resources are rather limited, Weiss’s method fails to satisfy the timeliness. To solve this problem, this paper develops a DPD estimator using expectation maximization (EM) algorithm based on time delay and Doppler shift. The proposed method starts from choosing the transmitter-receiver range vector as the hidden variable. Then, the cost function is separated and simplified via the hidden variable, accomplishing the transformation from the high dimensional nonlinear search problem into a few one dimensional search subproblems. Finally, the expressions of EM repetition are obtained through Laplace approximation. In addition, we derive the Cramér–Rao bound to evaluate the best localization performance in this paper. Simulation results confirm that, on the basis of guaranteeing high accuracy, the proposed algorithm makes a good compromise in localization performance and computational complexity

Systematic observations of enhanced oil recovery and associated changes at carbonate-brine and carbonate-petroleum interfaces

Abstract Enhanced oil recovery (EOR) from carbonates is obtained by injection of controlled ionic strength brines containing “active ions” (e.g., SO4 2−, Mg2+, Ca2+). It is generally believed that this occurs through the interaction of the active ions at the carbonate-brine interface (e.g., within a thin brine layer separating the petroleum and the carbonate phases). Here, in-situ observations show how one active ion, SO4 2−, alters behavior at the carbonate-petroleum interface. Displacement of petroleum from initially oil-wet carbonate rocks using brines with variable SO4 concentrations systematically changes oil recovery, in situ contact angles, and connectivity of the oil phase, confirming that the active ion alters interactions at the oil/brine/carbonate interface, as expected. Measurements of model calcite-fluid interfaces show that there is no measurable sorption of SO4 to carbonate-brine interfaces but reveals that the carbonate-petroleum interface is altered by previous exposure to SO4-containing brines. These results suggest that EOR in carbonates is controlled indirectly by active ions. We propose that this may be due to a reduced oleophilicity of the carbonate caused by chemical complexation between the active ion and petroleum’s acidic and basic functional groups. This mechanism explains how both anions and cations act as active ions for EOR in carbonates

Exploring the interactions between metabolic dysfunction-associated fatty liver disease and micronutrients: from molecular mechanisms to clinical applications

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) has emerged as a significant global health concern, representing a major cause of liver disease worldwide. This condition spans a spectrum of histopathologic stages, beginning with simple fatty liver (MAFL), characterized by over 5% fat accumulation, and advancing to metabolic (dysfunction)-associated steatohepatitis, potentially leading to hepatocellular carcinoma. Despite extensive research, there remains a substantial gap in effective therapeutic interventions. This condition’s progression is closely tied to micronutrient levels, crucial for biological functions like antioxidant activities and immune efficiency. The levels of these micronutrients exhibit considerable variability among individuals with MAFLD. Moreover, the extent of deficiency in these nutrients can vary significantly throughout the different stages of MAFLD, with disease progression potentially exacerbating these deficiencies. This review focuses on the role of micronutrients, particularly vitamins A, D, E, and minerals like iron, copper, selenium, and zinc, in MAFLD’s pathophysiology. It highlights how alterations in the homeostasis of these micronutrients are intricately linked to the pathophysiological processes of MAFLD. Concurrently, this review endeavors to harness the existing evidence to propose novel therapeutic strategies targeting these vitamins and minerals in MAFLD management and offers new insights into disease mechanisms and treatment opportunities in MAFLD

Biological activities, Molecular mechanisms, and Clinical application of Naringin in Metabolic syndrome

Metabolic syndrome has become major health problems in recent decades, and natural compounds receive considerable attention in the management of metabolic syndrome. Among them, naringin is abundant in citrus fruits and tomatoes. Many studies have investigated the therapeutic effects of naringin in metabolic syndrome. This review discusses in vitro and in vivo studies on naringin and implications for clinical trials on metabolic syndrome such as diabetes mellitus, obesity, nonalcoholic fatty liver disease, dyslipidemia, and hypertension over the past decades, overviews the molecular mechanisms by which naringin targets metabolic syndrome, and analyzes possible correlations between the different mechanisms. This review provides a theoretical basis for the further application of naringin in the treatment of metabolic syndrome

Serum Levels of IL-1β, IL-6, TGF-β, and MMP-9 in Patients Undergoing Carotid Artery Stenting and Regulation of MMP-9 in a New In Vitro Model of THP-1 Cells Activated by Stenting

Inflammation plays an important role in the pathophysiological process after carotid artery stenting (CAS). Monocyte is a significant source of inflammatory cytokines in vascular remodeling. Telmisartan could reduce inflammation. In our study, we first found that, after CAS, the serum IL-1β, IL-6, TGF-β, and MMP-9 levels were significantly increased, but only MMP-9 level was elevated no less than 3 months. Second, we established a new in vitro model, where THP-1 monocytes were treated with the supernatants of human umbilical vein endothelial cells (HUVECs) that were scratched by pipette tips, which mimics monocytes activated by mechanical injury of stenting. The treatment enhanced THP-1 cell adhesion, migration and invasion ability, and the phosphorylation of ERK1/2 and Elk-1 and MMP-9 expression were significantly increased. THP-1 cells pretreated with PD98095 (ERK1/2 inhibitor) attenuated the phosphorylation of ERK1/2 and Elk-1 and upregulation of MMP-9, while pretreatment with telmisartan merely decreased the phosphorylation of Elk-1 and MMP-9 expression. These results suggested that IL-1β, IL-6, TGF-β, and MMP-9 participate in the pathophysiological process after CAS. Our new in vitro model mimics monocytes activated by stenting. MMP-9 expression could be regulated through ERK1/2/Elk-1 pathway, and the protective effects of telmisartan after stenting are partly attributed to its MMP-9 inhibition effects via suppression of Elk-1

Systematic Review of Clinical Practice Guidelines Related to Multiple Sclerosis

<div><p>Background</p><p>High quality clinical practice guidelines (CPGs) can provide clinicians with explicit recommendations on how to manage health conditions and bridge the gap between research and clinical practice. Unfortunately, the quality of CPGs for multiple sclerosis (MS) has not been evaluated.</p><p>Objective</p><p>To evaluate the methodological quality of CPGs on MS using the AGREE II instrument.</p><p>Methods</p><p>According to the inclusion and exclusion criteria, we searched four databases and two websites related to CPGs, including the Cochrane library, PubMed, EMBASE, DynaMed, the National Guideline Clearinghouse (NGC), and Chinese Biomedical Literature database (CBM). The searches were performed on September 20th 2013. All CPGs on MS were evaluated by the AGREE II instrument. The software used for analysis was SPSS 17.0.</p><p>Results</p><p>A total of 27 CPGs on MS met inclusion criteria. The overall agreement among reviews was good or substantial (ICC was above 0.70). The mean scores for each of all six domains were presented as follows: scope and purpose (mean ± SD: 59.05±16.13), stakeholder involvement (mean ± SD: 29.53±17.67), rigor of development (mean ± SD: 31.52±21.50), clarity of presentation (mean ± SD: 60.39±13.73), applicability (mean ± SD: 27.08±17.66), editorial independence (mean ± SD: 28.70±22.03).</p><p>Conclusions</p><p>The methodological quality of CPGs for MS was acceptable for scope, purpose and clarity of presentation. The developers of CPGs need to pay more attention to editorial independence, applicability, rigor of development and stakeholder involvement during the development process. The AGREE II instrument should be adopted by guideline developers.</p></div

Searching and selecting guidelines flowchart.

<p>Searching and selecting guidelines flowchart.</p