Molecular Weight Research Articles

Antidiabetic Advancements In Silico: Pioneering Novel Heterocyclic Derivatives through Computational Design

Background:: Deficiency of insulin signaling in type 2 diabetes results from insulin resistance or defective insulin secretion and induced hyperglycemia. By reducing glycated hemoglobin, SGLT2 inhibitors improve hyperuricemia, blood lipids, and weight loss without increasing the risk of hypoglycemia. By targeting this pathway, SGLT2 inhibitors can become a prominent target in the management of type 2 diabetes. Objective:: This study aimed to carry out the molecular docking and ADMET prediction of novel imidazo(2,1-b)-1,3,4 thiadiazole derivatives as SGLT2 inhibitors. Methods:: The chemical structures of 108 molecules were drawn by using ChemDraw Professional 15.0. Further, their energy minimization was also carried out by using Chem Bio Draw three-dimensional (3D) Ultra 12.0. Molecular docking was also carried out using a Molegro Virtual Docker to identify the best-fitting molecules and to identify the potential leads on the basis of dock score. The predicted parameters of drug-likeness according to Lipinski’s rule of five, such as molecular weight, log P, hydrogen bond acceptor, hydrogen bond donors, and number of rotatable bonds of the selected compounds, were predicted using pKCSM software. Results:: About 108 molecules were designed by employing different substitutions on imidazothiadiazole nucleus as SGLT2 inhibitors. Out of these, 10 compounds were found to have better interactions with the active site of SGLT2 protein and the highest dock scores compared to canagliflozin. Compounds 39a and 39b demonstrated good interactions and the highest docking scores of -155.428 and -142.786, respectively. The in silico physicochemical properties of the best compounds were also determined. Additionally, these compounds suggested a good pharmacokinetic profile as per Lipinski's rule of five (orally active drugs). Conclusion:: Novel imidazo (2,1-b)-1,3,4 thiadiazole derivatives were strategically designed, and their binding affinity was meticulously evaluated against the SGLT2 protein. This endeavor yielded pioneering lead compounds characterized by ultimate binding affinity, coupled with optimal ADMET properties in adherence to Lipinski's rule of five and favourable noncarcinogenic profile.

Structural characterization of three acidic polysaccharides from Opuntia dillenii Haw. fruits and their protective effect against hydrogen peroxide-induced oxidative stress in Huh-7 cells

Three novel acidic polysaccharide fractions (OFPP-1, OFPP-2, OFPP-3) with different molecular weights (803.7, 555.1 and 414.5 kDa) were isolated from the peeled Opuntia dillenii Haw. fruits by alkali-extraction, graded alcohol precipitation and column chromatography. Structural analysis indicated that OFPPs were pectic polysaccharides consisting of rhamnose, arabinose and galactose residues. The backbone of OFPP-1 consisted of a repeating unit →6-α-D-GalpA-(1→2)-α-L-Rhap-(1→ with T-α-D-GalpA-(1→6)-α-D-GalpA-(1→4)-α-D-Glcp-(1→, T-β-D-Xylp-(1→6)-α-D-GalpA-(1→4)-α-D-Glcp-(1→ or T-α-D-GalpA-(1→3)-α-L-Araf-(1→ as the side chains. The backbone of OFPP-2 consisted of a disaccharide repeating unit →2)-α-L-Rhap-(1→4)-β-D-GalpA-(1→ with T-β-L-Araf-(1→ as the branches substituted at the O-4 position of →2,4)-α-L-Rhap-(1→. Whereas the backbone of OFPP-3 was →2,4)-α-L-Rhap-(1→2)-α-L-Rhap-(1→3)-β-L-Araf-(1→ or →2,4)-α-L-Rhap-(1→2)-α-L-Rhap-(1→4)-β-D-GalpA-(1→, which was branched at the O-4 position of →2,4)-α-L-Rhap-(1→. Moreover, these 3 polysaccharide fractions could protect Huh-7 cells against H2O2-induced oxidative stress to different extents by decreasing the MDA content and increasing the SOD, CAT, GSH-Px activities and the GSH level in the Huh-7 cells. These results suggest that OFPPs have the potential to be used as natural antioxidants.

Description and In silico ADME Studies of US-FDA Approved Drugs or Drugs under Clinical Trial which Violate the Lipinski’s Rule of 5

Background & Objective: Christopher A. Lipinski, in 1997, formulated Lipinski’s rule of five for drug-likeness prediction of potent molecules. It states that molecular weight (less than 500 Daltons), octanol/water partition coefficient (not exceeding more than 5), hydrogen bond acceptor (no more than 10), and hydrogen bond donor (no more than 5) are important for good oral bioavailability. Many drugs among various important classes such as antibiotics, anti-cancer, HIV and HCV protease inhibitors, immunosuppressants, cardiovascular, antifungal, and other miscellaneous classes are approved by FDA or other drug regulatory authorities as clinical use lie beyond the rule of five. In this review, beyond the rule of 5 drugs belonging to these classes (which are either currently approved or under clinical study) are explored and their ADME properties are analyzed. Methods: Data of 73 beyond the rule of 5 drugs, belonging to various classes, were collected and their ADME properties were calculated using the Qikprop prediction program of maestro 12.9 module of Schrodinger software. Result: Out of 73 drugs, 4 had at least 1 Rule of 5 (Ro5) violation, 16 had at least 2, 31 had at least 3 out of which 22 drugs had 4, Ro5 violations. Conclusion: Drugs not obeying the rule of five may also serve as good clinical candidates and potential candidates should not be discarded only on the basis of this rule.

Laccase/caffeic acid-catalyzed crosslinking coupled with galactomannan alters the conformational structure of ovalbumin and alleviates Th2-mediated allergic asthma

Ovalbumin (OVA) is the major allergenic protein that can induce T helper 2 (Th2)-allergic reactions, for which current treatment options are inadequate. In this study, we developed a polymerized hypoallergenic OVA product via laccase/caffeic acid (Lac/CA)-catalyzed crosslinking in conjunction with galactomannan (Man). The formation of high molecular weight crosslinked polymers and the IgG-binding were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. The study indicated that Lac/CA-catalyzed crosslinking plus Man conjugation substantially altered secondary and tertiary structures of OVA along with the variation in surface hydrophobicity. Gastrointestinal digestion stability assay indicated that crosslinked OVA exhibited less resistance in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Mouse model study indicated that Lac-Man/OVA ameliorated eosinophilic airway inflammatory response and efficiently downregulated the expression of Th2-related cytokines (interleukin (IL)-4, IL-5, and IL-13), and upregulated IFN-γ and IL-10 expression. Stimulation of bone marrow-derived dendritic cells with Lac-Man/OVA suppressed the expression of phenotypic maturation markers (CD80 and CD86) and MHC class II molecules, and suppressed the expression levels of proinflammatory cytokines. The knowledge obtained in the present study offers an effective way to acquire a hypoallergenic OVA product that can have a therapeutic effect in alleviating OVA-induced allergic asthma.

Three anti-inflammatory polysaccharides from Lonicera japonica Thunb.: Insights into the structure-function relationships

This study demonstrates the feasibility of producing three polysaccharides (neutral LJP-1, acidic LJP-2 and acidic LJP-3) with significant in vitro and in vivo anti-inflammatory activities from the flowers of Lonicera japonica. The three polysaccharides differed in chemical composition, molecular weight distribution, glycosidic linkage pattern, functional groups and morphology. They exhibited excellent protective effects (in a dose-dependent manner) in lipopolysaccharide-injured RAW264.7 macrophages and CuSO4-damaged zebrafish via reducing NO production and inhibiting the overexpressions of inflammation-related transcription factors, inflammatory proteins and cytokines in the NF-κB/MAPK signaling pathways. Their anti-inflammatory effects varied owing to their different molecular characteristics and chemical compositions. Overall, LJP-2 at 400μg/mL was the most effective. LJP-2 consisted mainly of → 5)-α-L-Araf (1→, →4)-α-L-GalpA (1→ and →2)-α-L-Rhap (1→ residues with terminal T-β-D-Glcp. Thus, honeysuckle flowers are good sources of anti-inflammatory polysaccharides, and precise fractionation enables the production of potent anti-inflammatory agents for the development of functional foods and healthcare products.

Structural characterization and prebiotic potential of polysaccharides from Polygonatum sibiricum

Polygonatum sibiricum has been widely used due to its excellent biological activities. We prepared a novel polysaccharide from P. sibiricum (PSP) in this study. According a monosaccharide composition analysis, PSP was mainly composed of fructose and glucose with a molar percentage of 93.81:5.12. The main linkage types were identified as α-D-Glcp-1→ and →2-β-D-Fruf-1→. The molecular weight of PSP showed no significant change after simulated salivary and gastrointestinal digestion. However, PSP could be broken down by intestinal bacteria. Our findings revealed that PSP administration increased the abundance of probiotics such as Bifidobacterium. Furthermore, the results showed that gut microbes could utilize PSP to produce short-chain fatty acids including acetic acid, propionic acid, and butyric acid. Also, the PSP fermentation broth displayed an excellent scavenging effect on free radicals, including 2,2-diphenyl-1-picrylhydrazyl radical, superoxide radical, and hydroxyl radical. In summary, this study will help to promote the application of PSP as prebiotics in functional food and the medical industry.

Effects of low molecular weight polysaccharide from Sargassum thunbergii against palmitic acid-induced intracellular lipid accumulation in 3T3-L1 adipocyte and HepG2 cells

Low molecular weight polysaccharides can be isolated from Sargassum thunbergii (LMPST) and in vitro experiments were conducted to evaluate the inhibitory effects on lipids. Two natures of LMPST were attained from S. thunbergii and appraised their LMPST on palmitic acid (PA) induced lipid accretion in HepG2, and 3T3-L1 cells. LMPST treatment lessened lipid deposition and intracellular free fatty acid and triglyceride intensities in PA-treated above mentioned cells. The mechanistic study publicized that LMPST2 significantly suppressed adipogenesis and stimulated the PA-treated 3T3-L1 cells occupied in the lipolysis pathway. Furthermore, in PA-treated HepG2 cells, the free fatty acid oxidation was significantly increased by LMPST2. Given these constructive properties of LMPST2 from S. thunbergii, is a potential candidate for diminishing the intracellular lipids, and for a therapeutic agent in those conditions.

A Novel Phytotherapy Application: Preparation, Characterization, Antioxidant Activities and Determination of Anti-inflammatory Effects by In vivo HET-CAM Assay of Chitosan-based DDSs Containing Endemic Helichrysum pamphylicum P.H. Davis & Kupicha Methanolic Extract.

Numerous pharmaceutical applications for chitosan, a polysaccharide made from the shells of crustaceans by deacetylating chitin that occurs naturally, are currently being researched. Chitosan, a natural polymer, is successfully used to prepare many drug-carrier systems, such as gel, film, nanoparticle, and wound dressing. Preparing chitosan gels without external crosslinkers is less toxic and environmentally friendly. Chitosan-based gels containing Helichrysum pamphylicum P.H. Davis & Kupicha methanolic extract (HP) were produced successfully. The F9-HP coded gel prepared with high molecular weight chitosan was chosen as the optimum formulation in terms of pH and rheological properties. The amount of HP was found to be 98.83% ± 0.19 in the F9-HP coded formulation. The HP release from the F9-HP coded formula was determined to be slower and 9 hours prolonged release compared to pure HP. It was determined that HP release from F9-HP coded formulation with the DDSolver program was by anomalous (non-fickian) diffusion mechanism. The F9-HP coded formulation significantly showed DPPH free radical scavenger, ABTS•+ cation decolorizing and metal chelating antioxidant activity while weakly reducing antioxidant potential. According to the HET-CAM scores, strong anti-inflammatory activity was obtained by the F9-HP coded gel at a dose of 20 μg.embryo-1 (p<0.05 compared with SDS). In conclusion, it can be said that chitosan-based gels containing HP, which can be used in both antioxidant and anti-inflammatory treatment, were successfully formulated and characterized.

In English

The use of hydrophobic silicas as medical adsorbents in comparison with hydroxyl silicas allows to increase the adsorption of some toxins on their surface due to the reduction of water adsorption. The purpose of this study was to find a co-adsorbate that, adsorbed on a hydrophobic surface, would allow the preparation of aqueous suspensions of an enterosorbent based on methylsilica, and, once inside the body, would be easily destroyed by the enzymes of the gastrointestinal tract, freeing its surface for the adsorption of toxins on it. The structure of the hydrate shell and the adsorption capacity of composite materials based on methyl silica and gelatin obtained by different methods were investigated by a set of physical and chemical methods. Low-temperature 1H NMR-spectroscopy has been used to study of water clusters bound to composite surface. It has been found that the water in the composite on the basis of hydrophobic methyl silica and gelatin gel is present in the form of clusters with a radius of 0.5–15 nm and is in a strongly associated state when measured in air. When a liquid hydrophobic medium is added, the water partially passes into a weakly associated state. The bound water reacts to the presence of chloroform by changing the radial distribution of the adsorbed water clusters. It has been shown that for the composite system methyl silica AM-1/gelatin (5/1), the introduction of chloroform into the interfacial space leads to a significant decrease in the interfacial energy, which indicates a partial displacement of water by the hydrophobic solvent at the interface. At the same time, for composites made on the basis of dry powders, this effect is not observed and its interfacial energy has an intermediate value between the interfacial energies of methyl silica and gelatin containing the same amount of water. Adsorption of Congo red as the medium molecular weight toxins marker from aqueous solutions on the studied composites was studied in comparison with methylsilica. It has been found that gelatin in the composition of composites contributes to increasing dye adsorption. The amount of adsorbed Congo red depends on the method of preparation of the composite and the ratio of silica to gelatin. It is concluded that AM-1/gelatin composite systems can serve as effective adsorbents for removing medium molecular weight molecules from aqueous solutions.

A robust and biodegradable hydroxyapatite/poly(lactide-co-ε-caprolactone) electrospun membrane for dura repair.

Typically occurring after trauma or neurosurgery treatments, dura mater defect and the ensuing cerebrospinal fluid (CSF) leakage could lead to a number of serious complications and even patient's death. Although numerous natural and synthetic dura mater substitutes have been reported, none of them have been able to fulfill the essential properties, such as anti-adhesion, leakage blockage, and pro-dura rebuilding. In this study, we devised and prepared a series of robust and biodegradable hydroxyapatite/poly(lactide-co-ε-caprolactone) (nHA/PLCL) membranes for dura repair via an electrospinning technique. In particular, PLLA/PCL (80/20) was selected for electrospinning due to its mechanical properties that most closely resembled natural dural tissue. Studies by SEM, XRD, water contact angle and in vitro degradation showed that the introduction of nHA would destroy PLCL's crystalline structure, which would further affect the mechanical properties of the nHA/PLCL membranes. When the amount of nHA added increased, so did the wettability and in vitro degradation rate, which accelerated the release of nHA. In addition, the high biocompatibility of nHA/PLCL membranes was demonstrated by in vitro cytotoxicity data. The in vivo rabbit dura repair model results showed that nHA/PLCL membranes provided a strong physical barrier to stop tissue adhesion at dura defects. Meanwhile, the nHA/PLCL and commercial group's CSF had a significantly lower number of inflammatory cells than the control groups, validating the nHA/PLCL's ability to effectively lower the risk of intracranial infection. Findings from H&E and Masson-trichrome staining verified that the nHA/PLCL electrospun membrane was more favorable for fostering dural defect repair and skull regeneration. Moreover, the relative molecular weight of PLCL declined dramatically after 3 months of implantation, according to the results of the in vivo degradation test, but it retained the fiber network structure and promoted tissue growth, demonstrating the good stability of the nHA/PLCL membranes. Collectively, the nHA/PLCL electrospun membrane presents itself as a viable option for dura repair.

Characterization Electrospun Nanofibers Based on Cellulose Triacetate Synthesized from Licorice Root Cellulose

Cellulose triacetate (CTA) nanofibers were formed by electrospinning using two binary solvent systems: methylene chloride/ethanol and chloroform/acetone. Previously, licorice root cellulose (LRC) with a degree of polymerization (DP) of 710 was extracted from licorice root waste by alkaline treatment and hydrogen peroxide bleaching at high temperatures. Then CTA with a degree of substitution (DS) of 2.9 and an average molecular weight of 175 kDa was synthesized from LRC using acetic acid and acetic anhydride, sulfuric acid was as a catalyst. The influence of the electrospinning process and various solvent systems on the morphology and structure of nanofibers is studied. The structure and morphology of the nanofibers were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction, scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), and the sorption characteristics were also investigated. The results showed that the morphology and structure of nanofibers depended on the solvent mixture used. The average diameters of the CTA nanofibers with grooved morphology varied 200-700 nm (solvent methylene chloride/ethanol) and the dumbbell-shaped (flat ribbon) CTA nanofibers in a wide range from 200 nm to 4 mkm (solvent chloroform/acetone).

Leveraging Electron Push-Pull Effect for Catalytic Polymerization and Degradation of a Cyclobutane Monomer System.

Ring-opening polymerization (ROP) offers a striking solution to solve problems encountered in step-growth condensation polymerization, including precise control over molecular weight, molecular weight distribution, and topology. This has inspired our interest in ROP of cycloalkanes with an ultimate goal to rethink polyolefins, which clearly poses a number of challenges. Practicality of ROP of cycloalkanes is actually limited by their low polymerizability and elusive mechanisms which arise from significantly varied ring size and non-polar C-C bonds in monomers. In this work, by using Lewis acid/Brønsted base/C(sp3)-H initiator system previously developed in our laboratory, we focus on cyclobutanes and explore the positional and electronic effects of substituents on the ring, namely electron push-pull effect, in promoting controlled polymerization to afford densely functionalized poly(cyclobutanes), as well as catalytic degradation of obtained polymers for upcycling. More importantly, experiments and DFT calculations unveil considerable population of Lewis-acid-induced thermostabilized 1,4-zwitterions, which distinguish cyclobutanes from cyclopropanes and others. All these findings would shed light on catalytic synthesis and degradation of saturated all-carbon main-chain polymers, as well as small molecule transformations of cyclobutanes.

Leveraging Electron Push‐Pull Effect for Catalytic Polymerization and Degradation of a Cyclobutane Monomer System

AbstractRing‐opening polymerization (ROP) offers a striking solution to solve problems encountered in step‐growth condensation polymerization, including precise control over molecular weight, molecular weight distribution, and topology. This has inspired our interest in ROP of cycloalkanes with an ultimate goal to rethink polyolefins, which clearly poses a number of challenges. Practicality of ROP of cycloalkanes is actually limited by their low polymerizability and elusive mechanisms which arise from significantly varied ring size and non‐polar C−C bonds in monomers. In this work, by using Lewis acid/Brønsted base/C(sp3)‐H initiator system previously developed in our laboratory, we focus on cyclobutanes and explore the positional and electronic effects of substituents on the ring, namely electron push‐pull effect, in promoting controlled polymerization to afford densely functionalized poly(cyclobutanes), as well as catalytic degradation of obtained polymers for upcycling. More importantly, experiments and DFT calculations unveil considerable population of Lewis‐acid‐induced thermostabilized 1,4‐zwitterions, which distinguish cyclobutanes from cyclopropanes and others. All these findings would shed light on catalytic synthesis and degradation of saturated all‐carbon main‐chain polymers, as well as small molecule transformations of cyclobutanes.

Hyaluronic Acid-Coated Silica Nanoparticles for Targeted Delivery of Nitric Oxide to Cancer Cells.

Drug resistance and off-target toxicity are two of the greatest challenges to chemotherapeutic melanoma treatments. Nitric oxide (NO) represents an attractive alternative to conventional therapeutics due to its numerous anticancer properties and low probability of engendering resistance. As NO is highly reactive, macromolecular NO donors are needed for the controlled and targeted delivery of NO for therapeutic applications. Herein, mesoporous silica nanoparticles (MSNs) coated with hyaluronic acid (HA) were developed as a NO delivery system to facilitate controlled delivery to cancer cells through both passive and active targeting via the enhanced permeation and retention effect and directed binding of HA with CD44 receptors, respectively. The aminosilane modification, HA concentration, and HA molecular weight were systematically evaluated to facilitate the MSN coating and NO loading. The hydrodynamic diameter and dispersity of the nanoparticles increased after HA coating due to the hydrophilic nature of HA, with greater increases observed at higher HA molecular weight. Lower starting concentrations of HA and aminosilanes with longer alkyl chains favored more efficient HA coating. Faster NO-release kinetics and lower NO payloads were observed for the HA-coated MSNs relative to uncoated MSNs. However, the localized delivery of NO to cancer cells through the active targeting conferred by HA increased levels of oxidative stress and induced mitochondria-mediated apoptosis in melanoma cells. Cytotoxicity was also evaluated against human dermal fibroblasts, with the use of 6 kDa HA-coated MSNs resulting in the greatest therapeutic indices. Enhanced internalization of HA-coated nanoparticles into melanoma cells versus uncoated nanoparticles was visualized with confocal microscopy and quantified by fluorescence spectroscopy. In total, HA-coated MSNs represent a promising NO delivery system for potential use as a chemotherapeutic for skin melanomas.

Autocombustion Route Derived Zinc Ferrite Nanoparticles as Chemiresistive Sensor for Detection of Alcohol Vapors.

Prolonged exposure to alcohol vapors can have detrimental effects on human health, potentially leading to eye irritation, dizziness, and in some cases, damage to the nervous system. The present article aims to provide a comprehensive understanding on the synthesis and characterization of zinc ferrite (ZnFe2O4) nanoparticles, as well as their interactions with a range of alcohol vapors, including methanol, ethanol, n-propanol, and isopropanol. These alcohols differ in their molecular weight, boiling points, diffusivity, and other properties. The study reveals the semiconducting ZnFe2O4 nanoparticulate sensor's capability for reversible, repeatable, and sensitive detection of alcohol vapors. The sensor exhibits the highest response to ethanol within operating temperature range (225-300 °C). An attempt is made to establish a correlation between the properties of the target analytes and the observed sensing signals. Additionally, the response conductance transients of ZnFe2O4 under the exposure to the studied alcohol vapors are modeled based on the Langmuir-Hinshelwood adsorption mechanism. The characteristic time constants obtained from this modeling are justified with respect to the properties of the analytes.

Collagen-Mesenchymal Stem Cell Microspheres Embedded in Hyaluronic Acid Solutions as Biphasic Stem Niche Delivery Systems for Pulmonary Differentiation.

Cell therapy has the potential to become a feasible solution for several diseases, such as those related to the lungs and airways, considering the more beneficial intratracheal administration route. However, in lung diseases, an impaired pulmonary extracellular matrix (ECM) precludes injury resolution with a faulty engraftment of mesenchymal stem cells (MSCs) at the lung level. Furthermore, a shielding strategy to avoid cell damage as well as cell loss due to backflow through the injection path is required. Here, an approach to deliver cells encapsulated in a biomimetic stem niche is used, in which the interplay between cells and physiological lung ECM constituents, such as collagen and hyaluronic acid (HA), can occur. To this aim, a biphasic delivery system based on MSCs encapsulated in collagen microspheres (mCOLLs) without chemical modification and embedded in an injectable HA solution has been developed. Such biphasic delivery systems can both increase the mucoadhesive properties at the site of interest and improve cell viability and pulmonary differentiation. Rheological results showed a similar viscosity at high shear rates compared to the MSC suspension used in intratracheal administration. The size of the mCOLLs can be controlled, resulting in a lower value of 200 μm, suitable for delivery in alveolar sacs. Biological results showed that mCOLLs maintained good cell viability, and when they were suspended in lung medium implemented with low molecular weight HA, the differentiation ability of the MSCs was further enhanced compared to their differentiation ability in only lung medium. Overall, the results showed that this strategy has the potential to improve the delivery and viability of MSCs, along with their differentiation ability, in the pulmonary lineage.

МУЛЬТИСИСТЕМНЫЙ ВОСПАЛИТЕЛЬНЫЙ СИНДРОМ, АССОЦИИРОВАННЫЙ С COVID-19 У ДЕТЕЙ, ОСЛОЖНЕННЫЙ ВЕНОЗНЫМИ И АРТЕРИАЛЬНЫМИ ТРОМБОЗАМИ: СЕРИЯ КЛИНИЧЕСКИХ НАБЛЮДЕНИЙ

SARS-CoV-2 causative agent may result in adulthood in hyperinflammatory syndrome and cytokine storm in some patients leading to the microvascular bed thromboses as well as those of large venous and arterial vessels. In the COVID-19 critical form, multisystem inflammatory syndrome in children (MIS-C), thromboses are less common. Authors represent a series of 8 patients’ cases with both thromboses and MIS-C associated with COVID-19 of different localization hospitalized in Nov. 2020-Nov. 2022 aged 4 months to 17 years old (Me 7.5 y/o): 4 aged 4 m/o to 5 y/o and 4 aged 8 to 17 y/o; 6 boys/2 girls. The incidence of thromboses was 13.3% (8/60 pediatric patients with MIS-C); venous thrombosis occurred in 6 (10% of 60), arterial thrombosis in 4 (6.6%), large cerebral vessels thrombosis coupled with the development of bilateral stroke occurred in 2 (3.3%), secondary thrombotic microangiopathy (TMA) in 3 (5%), distal gangrene in a single case (1.7%) and the cerebral venous sinus thrombosis in a single case (1.7%) as well. Treatment was carried out with anticoagulants, aspirin, immunomodulators (intravenous immunoglobulin, glucocorticosteroids, genetically engineered biological drugs). One of 8 patients with thromboses had died from pulmonary embolism (1.7% among all 60 patients with MIS-C), 6 of the 7 survivors continue to be followed up without complications and a single patient continues to have residual severe neurological deficits. Conclusion: venous thrombosis, secondary TMA and large cerebral arteries thrombosis predominated. Treatment of thrombosis with unfractionated heparin intravenously by continuous infusion with a transition to low molecular weight heparins against the background of pathogenetic therapy for MIS-C with immunomodulators was effective in most patients. Acetylsalicylic acid was used in 3 (with coronary dilatation and/or absence of severe thrombocytopenia). Risk factors for thromboses were male gender, severe congenital underlying diseases.

Perioperative Administration of Tranexamic Acid and Low Molecular Weight Heparin for Enhanced Blood Management in Intertrochanteric Fractures: A Randomized Controlled Study.

BACKGROUND This prospective study from a single center aimed to compare the perioperative blood loss (PBL) in 79 patients with intertrochanteric fractures (IF) treated with intramedullary nailing (IMN) using 3 regimens of combined tranexamic acid (TXA) and low molecular weight heparin (LMWH), proposing a novel therapy of 4-dose TXA. MATERIAL AND METHODS We recruited 79 patients and randomly divided them into 3 groups. The 4-dose TXA group (22 patients) received 1.0 g intravenous TXA 30 min before surgery and 1.0 g at intervals of 3, 6, and 9 h before surgery. The 1-dose TXA group (25 patients) received 1.0 g intravenous TXA 30 min before surgery, while the control group (32 patients) did not receive TXA. LMWH was applied 12 h after surgery in each group. The primary metrics evaluated included hidden blood loss (HBL), total blood loss (TBL), and the number and incidence rate of deep vein thrombosis (DVT). RESULTS Analysis of the HBL revealed that the 4-dose TXA group had the lowest average (583.13±318.08 ml), followed by the 1-dose TXA group (902.94±509.99 ml), and the control group showed the highest (1154.39±452.06 ml) (P<0.05). A similar result was observed for TBL (4-dose group: 640.86±337.22 ml, 1-dose group: 971.74±511.14 ml, control group: 1226.27±458.22 ml, P<0.05). Regarding DVT, the 4-dose TXA group had 5 cases (incidence rate 22.73%), the 1-dose TXA group had 6 cases (incidence rate 24.00%), and the control group had 8 cases (incidence rate 25.00%), with no significant difference among groups (P>0.05). CONCLUSIONS Treatment using 4-dose TXA and LMWH can effectively reduce PBL without increasing the DVT risk in IF patients with IMN.

Development of thermosensitive liposome-containing in-situ gel systems for intranasal administration of thiocolchicoside and in vivo evaluation in a rabbit model

Aim Thiocolchicoside (THC) is a drug under the category of BCS III. Due to its high molecular weight, it has poor oral bioavailability and low skin permeability. This study aims to find an alternative delivery method for THC that enhances its bioavailability through nasal application approach. In situ gels containing plain or liposomal THC with different combinations of Pluronic® F127 and PEG 400 were prepared. Method Liposome formulations were prepared using the thin film hydration method and tested for their characterization such as for drug content, particle size, and zeta potential. In vivo pharmacokinetic parameters of formulations such as Cmax, Tmax, and AUC were tested on the rabbit model. The formulations were also scrutinized for their cell viability properties. Result Formulation composition with 2% soybean phosphatidylcholine and 10 mg THC exhibited ∼94% entrapment efficiency, minimum particle size 101.32 nm, low polydispersity index 0.225 and +0.355 zeta potential. In situ liposomal dispersion containing 15% Pluronic® F127 turned into gel at nasal temperature. Cell lines were unharmed for 48 h. İn situ liposomal gels showed 1.5x higher blood concentration than the control formula. Conclusion In situ gels of liposomal THC formulations offer advantages over traditional nasal solutions, demonstrating comparable bioavailability to parenteral medication while also preserving the health of nasal mucosa cells.

Arg1 from Cryptococcus neoformans lacks PI3 kinase activity and conveys virulence roles via its IP3-4 kinase activity.

Inositol tris/tetrakis phosphate kinases (IP3-4K) in the human fungal priority pathogens, Cryptococcus neoformans (CnArg1) and Candida albicans (CaIpk2), convey numerous virulence functions, yet it is not known whether the IP3-4K catalytic activity or a scaffolding role is responsible. We therefore generated a C. neoformans strain with a non-functional kinase, referred to as the dead-kinase (dk) CnArg1 strain (dkArg1). We verified that, although dkARG1 cDNA cloned from this strain produced a protein with the expected molecular weight, dkArg1 was catalytically inactive with no IP3-4K activity. Using recombinant CnArg1 and CaIpk2, we confirmed that, unlike the IP3-4K homologs in humans and Saccharomyces cerevisiae, CnArg1 and CaIpk2 do not phosphorylate the lipid-based substrate, phosphatidylinositol 4,5-bisphosphate, and therefore do not function as class I PI3Ks. Inositol polyphosphate profiling using capillary electrophoresis-electrospray ionization-mass spectrometry revealed that IP3 conversion is blocked in the dkArg1 and ARG1 deletion (Cnarg1Δ) strains and that 1-IP7 and a recently discovered isomer (4/6-IP7) are made by wild-type C. neoformans. Importantly, the dkArg1 and Cnarg1Δ strains had similar virulence defects, including suppressed growth at 37°C, melanization, capsule production, and phosphate starvation response, and were avirulent in an insect model, confirming that virulence is dependent on IP3-4K catalytic activity. Our data also implicate the dkArg1 scaffold in transcriptional regulation of arginine metabolism but via a different mechanism to S. cerevisiae since CnArg1 is dispensable for growth on different nitrogen sources. IP3-4K catalytic activity therefore plays a dominant role in fungal virulence, and IPK pathway function has diverged in fungal pathogens.IMPORTANCEThe World Health Organization has emphasized the urgent need for global action in tackling the high morbidity and mortality rates stemming from invasive fungal infections, which are exacerbated by the limited variety and compromised effectiveness of available drug classes. Fungal IP3-4K is a promising target for new therapy, as it is critical for promoting virulence of the human fungal priority pathogens, Cryptococcus neoformans and Candida albicans, and impacts numerous functions, including cell wall integrity. This contrasts to current therapies, which only target a single function. IP3-4K enzymes exert their effect through their inositol polyphosphate products or via the protein scaffold. Here, we confirm that the IP3-4K catalytic activity of CnArg1 promotes all virulence traits in C. neoformans that are attenuated by ARG1 deletion, reinforcing our ongoing efforts to find inositol polyphosphate effector proteins and to create inhibitors targeting the IP3-4K catalytic site, as a new antifungal drug class.