Methyl Research Articles

Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes.

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10-10-10-1 M) and insulin (10-8-10-4 M) in control sites and sites treated with 15 mM l-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine (P = 0.006) and insulin (P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC (P = 0.009) but had no effect in GDM (P = 0.306). Ascorbate treatment increased acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC (P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

Artificial neural network based forecasting of diesel engine performance and emissions utilizing waste cooking biodiesel

Ecological and environmental problems resulting from fossil fuels are due to the harmful emissions released into the atmosphere. The rising interest in searching for alternative fuels like biodiesel is growing to solve these problems. Waste cooking oil (WCO) is transformed into methyl ester and combined with biodiesel in percentages of 25, 50, 75, and 100%. Research is done on the impacts of methyl ester blends on engine performance and emissions. Compared to diesel, the methyl ester combination showed 25% lower brake power and 24% loss in thermal efficiency at maximum load and 1500 rpm. However, diesel fuel showed 23% lower specific fuel consumption increase than biodiesel. Compared to diesel, methyl ester exhibits 15% lower air-fuel ratio and 4% volumetric efficiency. Biodiesel lowers CO, HC, and smoke concentrations by 12, 44, and 48%, respectively, compared to diesel. Biodiesel emits 23% higher NOx at 1500 rpm and 100% engine load. To predict the emissions and performance of different percentages of biodiesel at engine speed variation, an artificial neural network (ANN) model is presented. ANN modeling minimizes labor, time, and finances and uses nonlinear data. Predictions were produced about the brake output power, specific fuel consumption, thermal efficiency, air-fuel ratio, volumetric efficiency, and emissions of smoke, CO, HC, and NOx as a function of engine speed and blend ratio. All correlation coefficients (r) over 0.99 and R2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$R^{2}$$\\end{document} values were beyond 0.98 for all variables. There were low values of MSE, MAPE, and MSLE with significant predictive ability. WCO’s biodiesel is a viable diesel engine replacement fuel.

Research on the Improvement of Endothelial Cell Function and Trophoblast Apoptosis in Rats with Preeclampsia by Tanshinone IIA

Background Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of damage to another organ system, often the kidneys. Recent studies suggest that endothelial dysfunction and trophoblast apoptosis are involved in the pathogenesis of preeclampsia. Purpose To investigate the effects of tanshinone IIA (TIIA) on clinical symptoms, vascular endothelial function, and placental trophoblast apoptosis in preeclampsia rats. Materials and Methods Twenty-four pregnant Sprague-Dawley rats, between 8 and 10 weeks old, were randomly divided and allocated into three groups: Control, model, and treatment, with each group consisting of 8 rats. The control group received normal saline injections via the tail vein; the model group received NG-nitro-l-arginine methyl ester (l-NAME) to induce preeclampsia, followed by normal saline injections; and the treatment group received TIIA (10 mg/kg) via tail vein injection after preeclampsia induction with l-NAME. Various parameters were measured, including tail artery systolic pressure, 24-hour proteinuria, offspring and placental weight, levels of endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), placental growth factor (PLGF), and soluble FMS-like tyrosine kinase 1 (sFlt-1) in serum, and expression of B-cell lymphoma-2 (Bcl-2) and Bcl-2-related X protein (Bax) in placental trophoblasts. Results TIIA treatment led to decreased tail artery systolic pressure and 24-hour urine protein levels, increased body and placental weights of offspring, and favorable changes in serum levels of ET-1, sFlt-1, eNOS, and PLGF. Moreover, TIIA treatment resulted in decreased Bax levels and apoptosis in placental trophoblasts, along with increased Bcl-2 levels. Conclusion TIIA can improve the clinical symptoms of preeclampsia in rats induced by l-NAME, alleviate the apoptosis of placental trophoblast cells, and improve vascular endothelial function.

Prebiotic Environmental Conditions Impact the Type of Iron‐Sulfur Cluster Formed

Iron‐sulfur clusters are ancient cofactors that could have played a role in the prebiotic chemistry leading to the emergence of protometabolism. Previous research has shown that certain iron‐sulfur clusters can form from prebiotically plausible components, such as cysteine‐containing oligopeptides. However, it is unclear if these iron‐sulfur clusters could have survived in prebiotically plausible environments. To begin exploring this possibility, we tested the stability of iron‐sulfur clusters coordinated to a tripeptide and to N‐acetyl‐L‐cysteine methyl ester in a variety of solutions meant to mimic prebiotically plausible environments. We also assessed the impact of individual chemical components on stability. We find that iron‐sulfur clusters form over a wide variety of conditions but that the type of iron‐sulfur cluster formed is strongly impacted by the chemical environment and the coordinating scaffold. These findings support the general hypothesis that iron‐sulfur clusters were present on the prebiotic Earth and that different types of iron‐sulfur cluster predominated in different environments.

Anti-inflammatory activity and identification of two ‘Sarpagan’ indole alkaloids from the leaf methanolic extract of Rauvolfia densiflora (Wall.) Benth. ex Hook. f.

The Apocynaceae plant group contains many bioactive compounds that are pharmacologically relevant and are used as potential medicine for many diseases. Rauvolfia densiflora Benth. ex Hook.f. (syn- Rauvolfia verticillata (Lour.) Baill.) coming under the same family known for its diverse medicinal properties. The current study was carried out to evaluate the bioactive compounds present in the extract using GC-MS analysis and to find out the anti-inflammatory potential of the extract using in-vitro methods. GC-MS analysis revealed the presence of 16 bioactive compounds with diverse pharmacological activities. Among them, Oleic Acid, 17-hydroxy-, methyl ester, trans-decahydroquinoline, and Spiro-(1,3-dioxolane-2, 3’-indolin]-2’-one possesses more important properties. Two important sarpagan indole alkaloids were also identified namely Sarpagan-16-carboxylic acid or (Z) Akuammidine and sarpagan-17-ol or Vellosiminol, which are pharmacologically important compounds with anti-inflammatory, anti-asthmatic activities. The in-vitro anti-inflammatory activity was carried out using the COX assay. COX assay showed 55.27% inhibition at a concentration of 200 μg/mL with an IC50 value of 155.38 μg/mL, this is an indication that the methanolic leaf extract R. densiflora has the potential to be developed as a non-steroidal anti-inflammatory drug (NSAID).

Terrigenous or not? δ13C reveals the origin of the retene and dehydroabietic acid methyl ester

Retene and dehydroabietic acid methyl ester (DAME) are biomarkers linked mostly to terrigenous organic matter. However, their aquatic origin from algae and/or cyanobacteria has been discussed in the past few years. The complex origin of retene and DAME can lead to misinterpretation during biomarker interpretation, which can be minimalised with the support of isotopic analyses. This study contains the results of thirty-two compound-specific isotope analyses (CSIA) of δ13C performed on retene and forty-six CSIA analyses of δ13C performed on DAME. Obtained δ13C results were compared with simple biomarker results to tie isotopic data with the origin of organic matter. Pure aquatic retene and DAME were present within the Middle Cambrian and Early Ordovician samples, as the first appearance of plants was noted in the Middle Ordovician.CSIA was performed on a wide spectrum of the Cambrian-Silurian, Late Triassic-Middle Jurassic, and Neogene samples. Cambrian-Silurian strata include aquatic-origin retene and DAME, as evidenced by their comparatively low carbon isotopic signature. The average δ13C for retene and DAME within Cambrian-Silurian strata was equal to −31.7 ‰ and − 30.8 ‰, respectively. The Late Triassic-Middle Jurassic strata were dominated by terrigenous organic matter, resulting in higher δ13C values in comparison with the Cambrian-Silurian strata. The average δ13C for retene and DAME within the Late Triassic–Middle Jurassic strata was equal to −25.2 ‰ and − 26.3 ‰, respectively. The average δ13C for retene and DAME within the Neogene strata was equal to −27.3 ‰ in both cases, as these strata also contain a significant input of terrigenous organic matter. Some Neogene samples containing strong aquatic organic matter admixture are characterised by a lower δ13C for retene and/or DAME, oscillating around −28.0 ‰ to −30.0 ‰ for both compounds. Despite possible terrigenous input within some Silurian samples, the δ13C for retene and DAME still shows values typical for aquatic origin. These results suggest that retene and DAME within the Silurian strata should not be linked with non-vascular plants or that, due to their affinity with algae and cyanobacteria, the early plants were characterised by a relatively low δ13C composition, characteristic for phytoplankton organic matter. δ13C of retene and DAME were compared with δ13C of C16-C30n-alkanes and stigmastane, which supported the thesis about isotopic differences in aquatic and terrigenous retene and DAME.

Enhancement of Electron Transport Characteristics Using MXene-MnFeO3 Nanocomposite Integration with Fullerene Derivatives for the Perovskite-Based Solar Cells and Detectors.

In this study, we prepared a hybrid film incorporating the MnFeO3-decorated conducting two-dimensional (2D) MXene sheet-suspended [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) electron transfer layer (ETL) for the perovskite solar cells (PSCs) and detectors. The incorporation of MXene-MnFeO3 with the PCBM ETL could drive exceptional conducting features for the PSCs. Moreover, the presence of MXene-MnFeO3 facilitated superior charge transfer pathways, thereby enhancing the electron extraction and collection processes. This enhancement was directed to improve the electron mobility within the device, resulting in high photocurrents. The designed interface engineering with the MXene-MnFeO3 nanocomposite-tuned PCBM ETL has produced a remarkable power conversion efficiency of 17.79% ± 0.27. Moreover, X-ray detectors employing PCBM modulated with the MXene-MnFeO3 ETL achieved notable performance metrics including 18.47 μA/cm2 CCD-DCD, 5.53 mA/Gy·cm2 sensitivity, 7.64 × 10-4 cm2/V·s electron mobility, and 1.51 × 1015 cm2/V·s trap density.

Studies on fuels and engine attributes powered by bio-diesel and bio-oil derived from stone apple seed (Aegle marmelos) for bioenergy

Biofuel is an alternative fuel for diesel engines which is necessary to reduce exhaust emissions and helps to balance the depletion of fossil fuels. This study details the synthesis of bio-diesel and bio-oil from stone apple seeds ( Aegle marmelos) through transesterification, direct oxygenate additive, and pyrolysis processes. The diesel engine is powered by the resulting stone apple methyl ester bio-diesel/diesel and bio-oil/diesel mixtures. In a test engine rig, the effectiveness and emission uniqueness of test fuel mixes were examined at various engine loads (EL = 3 kg–12 kg) and compression ratios (CR = 16–17.5) while maintaining a steady speed of 1500 r/min. Furthermore, engine performance and emissions for bio-diesel and bio-oil are measured and compared. The oxides of nitrogen (NOx) emission by bio-diesel and bio-oil opus were higher than neat diesel (FD). Also, carbon monoxide (CO) and hydrocarbon (HC) emissions were measured to be lower. The improvements of BTE by 4.87% and decrement of CO by 18.8%, HC by 13.26% were observed with the trans-esterified bio-diesel/diesel opus compared to diesel at a higher CR and rated load conditions. The engine analysis responses revealed that the FBD blend showed enhanced performance and lower emissions except NOx compared to diesel fuel. Hence, trans-esterified bio-diesel is a greater diesel alternative than FBDE and FBO.

Effect of Piston Geometry on Performance Characteristics of VCR Engine with and without EGR when Fueled with Blends of Methyl Ester

The growing population and exhaustion of fossil fuels necessitate our search for new sources of energy. The study for this research encompasses an amalgamation of interest in alternative fuels, advanced engine technology such as variable compression ratio VCR, engine component modification, and a methodical approach to testing for assessing the effects on key performance of the engine. A 3.5 kW compression ignition (CI) engine was fueled with blends of behada, chicken fat, and turmeric oil methyl ester. Engine operating parameters, such as the compression ratio (CR), rate of exhaust gas recirculation (EGR), and piston top geometry, are optimized to maximize engine performance. CI engine was modified by changing the piston head (square and tangential groove top) for methyl ester diesel blend operations. In the study, diesel fuel is designated as B00 and methyl ester as B20. The influence of compression ratio (CR16 and CR18) with exhaust gas re-circulation (EGR 0% and EGR 10%) was evaluated. The key performance indicators: brake thermal efficiency (BTE), brake-specific energy consumption (BSEC), brake-specific fuel consumption (BSFC), air-to-fuel ratio (AFR), and exhaust gas temperature (EGT) are investigated. Results indicate that an increase in BTE accompanies an increase in load, suggesting enhanced thermal efficiency with increased power output. The consequence of VCR is also investigated, and it is determined that a higher CR results in a higher BTE due to an increase in compression pressure and temperature, thereby enhancing combustion. Due to the re-combustion of unburned hydrocarbons with the addition of EGR at a 10% rate, BTE increases further. Utilizing a piston geometry with tangential grooves and methyl ester blends also contributes to increased BTE. BSEC increases with increasing load, with an important rise observed when operating at maximum capacity. However,at CR 18, BSEC decreases as a result of enhanced combustion efficiency. EGR has different effects on BSEC depending on the geometry of the piston and the kind of fuel used. Enhanced air-fuel blending and re-combustion of unburned hydrocarbons reduce the BSEC of the engine. The tangential groove top piston operates with 10% EGR. Similar to BSEC, BSFC decreases with increasing CR and improves with the use of a piston with a tangential groove and 10% EGR operation. AFR decreases as the consumption of fuel increases to meet the power demand, and higher CR values result in a lower AFR. EGT rises with load, and CR18 has a lower EGT than CR16 as a result of a higher compressing temperature and pressure. 10% EGR operation reduces EGT by decreasing the concentration of oxygen in the combustible area.

Cell Membrane-Camouflaged Biomimetic Magnetic Fluorescent Nanoparticles with Enhanced Stability for High-Performance Lead Drug Discovery.

Biomimetic nanoengineering empowers nanoparticles with enhanced biointerfacial capabilities by directly utilizing cell membranes (CMs) of natural origin. This top-down technique provides a powerful tool for the screening of potentially active compounds in complex matrices. Herein, cartilaginous end plate (CEP) cell membrane biomimetic Nile red (NR)-loaded zeolitic imidazolate frameworks-8 (ZIF-8) modified magnetic graphene oxide (CEP/MGO-ZIF-8-NR) nanocomposites with enhanced stability were accurately prepared by chemical bonding and used as a drug discovery platform for the specific identification and effective extraction of drug leads with anti-intervertebral disc degeneration (IDD) in Yaobitong capsules (YBTCs). The constructed CEP/MGO-ZIF-8-NR exhibited excellent magnetic properties, fluorescence properties, and stability. In addition, drug binding experiments showed that the CEP/MGO-ZIF-8-NR nanocomposites possessed higher adsorption capacity, faster adsorption rate, and superior selectivity compared with uncoated MGO-ZIF-8-NR. Ultimately, four potential bioactive molecules, including ginsenoside Ro, ginsenoside Rg1, astringin, and chikusetsusaponin V methyl ester, were successfully screened and identified in vitro from YBTC. The results of the CCK-8 assay and BrdU ELISA kit showed that the screened compounds promoted CEP cell proliferation in a concentration-dependent manner. Cellular distribution experiments revealed that CEP/MGO-ZIF-8-NR could rapidly escape from lysosomes and into the cytoplasm. And the pharmacological activity of these compounds was further confirmed by real-time cytomorphological imaging of CEP cells by confocal laser scanning microscopy (CLSM). Overall, this surface engineering strategy endows bioaffinity sample pretreatment materials with tremendous versatility, improves drug screening efficiency, and broadens the horizons and methodologies for drug lead discovery.

Study on gas–liquid sulfonation reaction under annular flow pattern in micro-reactor: Mechanism, model and process optimization

Micro-sulfonation is a new sulfonation method with great development potential. The gas–liquid micro-sulfonation are safe, efficient and low-cost, however, limited by the research progress and application scope of micro-reactors, the development of gas–liquid micro-sulfonation technique is far from enough. The gas–liquid sulfonation reaction process under annular flow pattern in micro-reactor is experimentally studied in this paper. The maximum MESA (fatty acid methyl ester sulfonic acid) yield under the experimental conditions in this study achieves 89.771 %, which is obviously higher than that (64.1 % for gas–liquid sulfonation and 76.82 % for liquid–liquid sulfonation) in conventional reactors and should be higher if the micro-reactor structure or operating conditions being further optimized. Based on the analyses of experimental results, the effect mechanisms of mass transfer and reaction on the gas–liquid micro-sulfonation efficiency are explored, and the sulfonation efficiency models and pressure drop model of four micro-reactors are established by dimensional analysis method. On account of both the mass transfer characteristics of gas–liquid two-phase flow and the high-viscosity of sulfonation products, enhancing the local disturbance of liquid phase can significantly improve the reaction efficiency. Finally, the operating conditions of two-phase flow rates and reaction time are optimized to ensure the high sulfonation product yield meanwhile reduce the fluid pressure drop or energy consumption of sulfonation process using the improved NSGA-II algorithm.

Organic molecular intercalation regulated hydrated vanadate cathodes with improved electrochemical properties and fast kinetics for aqueous zinc-ion batteries

Due to the large hydrated zinc ion radius resulting from the stable solvation structure with six water molecules in electrolyte, the interlayer spacing of most vanadium-based materials fails to meet the requirements for efficient insertion and extraction of Zn2+. Therefore, it is crucial to optimize and reconstruct the VO layer structure in order to achieve rapid and stable zinc storage. In this paper, composites of phenylalanine methyl ester (PM) inserted hydrated V2O5 (PMVO) are prepared using a one-step hydrothermal method. With the increase of PM insertion, the electrochemical properties initially exhibit enhancement followed by subsequent decline. Notably, PMVO-1.6 presents exceptional electrochemical performance, including a high capacity of 464 mAh g−1 at 0.1 A g−1, excellent rate capability with 220 mAh g−1 at 7 A g−1, and superior cycling stability with 97.5 % capacity retention after 1000 cycles at 4 A g−1. The incorporation of PM not only serves as stable structural pillars, but also reduces the solubilization of vanadium, facilitates the diffusion kinetics of hydrated zinc ions, and enhances the surface pseudo-capacitance effect.

Multi-site esterification: a tunable, reversible strategy to tailor therapeutic peptides for delivery.

Peptides are naturally potent and selective therapeutics with massive potential; however, low cell membrane permeability limits their clinical implementation, particularly for hydrophilic, anionic peptides with intracellular targets. To overcome this limitation, esterification of anionic carboxylic acids on therapeutic peptides can simultaneously increase hydrophobicity and net charge to facilitate cell internalization, whereafter installed esters can be cleaved hydrolytically to restore activity. To date, however, most esterified therapeutics contain either a single esterification site or multiple esters randomly incorporated on multiple sites. This investigation provides molecular engineering insight into how the number and position of esters installed onto the therapeutic peptide α carboxyl terminus 11 (αCT11, RPRPDDLEI) with 4 esterification sites affect hydrophobicity and the hydrolysis process that reverts the peptide to its original form. After installing methyl esters onto αCT11 using Fischer esterification, we isolated 5 distinct products and used 2D nuclear magnetic resonance spectroscopy, reverse-phase high performance liquid chromatography, and mass spectrometry to determine which residues were esterified in each and the resulting increase in hydrophobicity. We found esterifying the C-terminal isoleucine to impart the largest increase in hydrophobicity. Monitoring ester hydrolysis showed the C-terminal isoleucine ester to be the most hydrolytically stable, followed by the glutamic acid, whereas esters on aspartic acids hydrolyze rapidly. LC-MS revealed the formation of transient intramolecular aspartimides prior to hydrolysis to carboxylic acids. In vitro proof-of-concept experiments showed esterifying αCT11 to increase cell migration into a scratch, highlighting the potential of multi-site esterification as a tunable, reversible strategy to enable the delivery of therapeutic peptides.

Phytochemical screening and quantitative analysis, FTIR and GC-MS analysis of Costus pictus D. Don ex Lindl. Leaf extracts – A potential therapeutic herb

Many medicinal plants play an essential role in medicine to prevent diseases due to the presence of several active chemicals. An effective strategy to combat non-communicable disease epidemics has been to introduce bioactive compounds from natural sources. Costus pictus is a versatile species which have exhibited beneficial properties against a variety of diseases. Multiple bioactive substances found in C. pictus have properties that are hypolipidemic, anti-hypertension, and anti-diabetic. GC-MS profiling revealed that the presence of (1alpha,2beta,5alpha)-2,6,6-trimethyl bicyclo [3.1.1] heptane, (Z)-9-Octadecenoic acid methyl ester, 1,2,4-Benzenetricarboxylic acid,-dodecyl dimethyl ester, 1-Hexanol, 2-ethyl-, 2,4-bis(1,1-dimethyl ethyl)-phenol, 2-Methoxy-4-vinylphenol, Benzeneethanamine, D-delta-tocopherol, Hexadecanoic acid, methyl ester, Methyl stearate, Phytol, and Phytol, acetate, β-Lapachone, 1,2,3-Propanetriol, 1-acetate, 2,6-Dihydroxynaphthalene, Benzene, (1- methyldodecyl)-, Curan-17-oic acid, 2,16-didehydro-20-hydroxy-, methyl ester, Phytol, (R)-(−)-(Z)-14-Methyl-8-hexadecen-1-ol, and Docosatrienoic acid and FTIR spectrum confirmed the presence of identified chemical compounds in C. pictus. The current findings support the necessity for further scientific studies that are beneficial to human health and therapeutic potential.

Bixin Combined with Metformin Ameliorates Insulin Resistance and Antioxidant Defenses in Obese Mice

Bixin (C25H30O4; 394.51 g/mol) is the main apocarotenoid found in annatto seeds. It has a 25-carbon open chain structure with a methyl ester group and carboxylic acid. Bixin increases the expression of antioxidant enzymes, which may be interesting for counteracting oxidative stress. This study investigated whether bixin-rich annatto extract combined with metformin was able to improve the disturbances observed in high-fat diet (HFD)-induced obesity in mice, with an emphasis on markers of oxidative damage and antioxidant defenses. HFD-fed mice were treated for 8 weeks with metformin (50 mg/kg) plus bixin-rich annatto extract (5.5 and 11 mg/kg). This study assessed glucose tolerance, insulin sensitivity, lipid profile and paraoxonase 1 (PON-1) activity in plasma, fluorescent AGEs (advanced glycation end products), TBARSs (thiobarbituric acid-reactive substances), and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver and kidneys. Treatment with bixin plus metformin decreased body weight gain, improved insulin sensitivity, and decreased AGEs and TBARSs in the plasma, liver, and kidneys. Bixin plus metformin increased the activities of PON-1, SOD, CAT, and GSH-Px. Bixin combined with metformin improved the endogenous antioxidant defenses in the obese mice, showing that this combined therapy may have the potential to contrast the metabolic complications resulting from oxidative stress.

USP8 promotes intracellular infection by enhancing ESCRT-mediated membrane repair, limiting xenophagy, and reducing oxidative stress

ABSTRACT The host ESCRT-machinery repairs damaged endolysosomal membranes. If damage persists, selective macroautophagy/autophagy clears the damaged compartment. Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that damages the phagosomal membrane and targets ESCRT-mediated repair as part of its virulence program. The E3 ubiquitin ligases PRKN and SMURF1 promote autophagic capture of damaged, Mtb-containing phagosomes. Because ubiquitination is a reversible process, we anticipated that host deubiquitinases (DUBs) would also be involved. Here, we screened all predicted mouse DUBs for their role in ubiquitin targeting and control of intracellular Mtb. We show that USP8 (ubiquitin specific peptidase 8) colocalizes with intracellular Mtb, recognizes phagosomal membrane damage, and is required for ESCRT-dependent membrane repair. Furthermore, we show that USP8 regulates the NFE2L2/NRF2-dependent antioxidant signature. Taken together, our study demonstrates a central role of USP8 in promoting Mtb intracellular growth by promoting phagosomal membrane repair, limiting ubiquitin-driven selective autophagy, and reducing oxidative stress. Abbreviation: BMDMs: bone marrow-derived macrophages; CFUs: colony-forming units; DUB: deubiquitinase; ESCRT: endosomal sorting complexes required for transport; LLOMe: L-leucyl-L-leucine methyl ester; MFI: mean fluorescence intensity; MOI: multiplicity of infection; Mtb: Mycobacterium tuberculosis; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; PMA: phorbol 12-myristate 13-acetate; ROS: reactive oxygen species; USP8: ubiquitin specific peptidase 8

Interpenetrated Donor-Acceptor Heterojunctions in 2D Conjugated Dibenzo[g,p]chrysene-Based Kagome Covalent Organic Frameworks.

Dibenzo[g,p]chrysene can be viewed as a constrained propeller-shaped tetraphenylethylene with reduced curvature and has been utilized to construct dual-pore kagome covalent organic frameworks (COFs) with tightly packed two-dimensional (2D) layers owing to its rigid and more planar structural characteristics. Here, we introduce 2D COFs based on the node 4,4',4″,4‴-(dibenzo[g,p]chrysene-2,7,10,15-tetraphenyl)tetraamine (DBCTPTA) featuring extended conjugation compared to the dibenzo[g,p]chrysene-3,6,11,14-tetraamine (DBCTA) node. We establish two exceptionally crystalline imine-linked 2D COFs with a hexagonal dual-pore kagome structure based on the DBCTPTA core. The newly synthesized thienothiophene (TT) and benzodithiophene (BDT)-based DBCTPTA COFs show a tight stacking behavior between adjacent layers. Furthermore, we obtained an unprecedented, interpenetrated electron-donor/acceptor host-guest system with an electron-donating BDT DBCTPTA COF synthesized in situ with the soluble fullerene derivative [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) serving as molecular acceptor. The BDT DBCTPTA COF@PCBM film shows a much shorter amplitude-averaged PL lifetime of 7 ± 2 ps compared to 30 ± 4 ps of the BDT DBCTPTA COF film, indicating the light-induced charge transfer process. The successful in situ formation of interpenetrated donor-acceptor heterojunctions within 2D COFs offers a promising strategy for establishing D-A heterojunctions in diverse framework materials with open channel systems.

Blocking HXA3-mediated neutrophil elastase release during S. pneumoniae lung infection limits pulmonary epithelial barrier disruption and bacteremia.

Streptococcus pneumoniae (Sp), a leading cause of community-acquired pneumonia, can spread from the lung into the bloodstream to cause septicemia and meningitis, with a concomitant threefold increase in mortality. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that target pathogenic immune processes. Polymorphonuclear leukocytes (PMNs) are essential for infection control but can also promote tissue damage and pathogen spread. The major Sp virulence factor, pneumolysin, triggers acute inflammation by stimulating the 12-lipoxygenase (12-LOX) eicosanoid synthesis pathway in epithelial cells. This pathway is required for systemic spread in a mouse pneumonia model and produces a number of bioactive lipids, including hepoxilin A3 (HXA3), a hydroxy epoxide PMN chemoattractant that has been hypothesized to facilitate breach of mucosal barriers. To understand how 12-LOX-dependent inflammation promotes dissemination during Sp lung infection and dissemination, we utilized bronchial stem cell-derived air-liquid interface cultures that lack this enzyme to show that HXA3 methyl ester (HXA3-ME) is sufficient to promote basolateral-to-apical PMN transmigration, monolayer disruption, and concomitant Sp barrier breach. In contrast, PMN transmigration in response to the non-eicosanoid chemoattractant N-formyl-L-methionyl-L-leucyl-phenylalanine (fMLP) did not lead to epithelial disruption or bacterial translocation. Correspondingly, HXA3-ME but not fMLP increased the release of neutrophil elastase (NE) from Sp-infected PMNs. Pharmacologic blockade of NE secretion or activity diminished epithelial barrier disruption and bacteremia after pulmonary challenge of mice. Thus, HXA3 promotes barrier-disrupting PMN transmigration and NE release, pathological events that can be targeted to curtail systemic disease following pneumococcal pneumonia.IMPORTANCEStreptococcus pneumoniae (Sp), a leading cause of pneumonia, can spread from the lung into the bloodstream to cause systemic disease. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that limit pathologic host immune responses to Sp. Excessive polymorphonuclear leukocyte (PMN) infiltration into Sp-infected airways promotes systemic disease. Using stem cell-derived respiratory cultures that reflect bona fide lung epithelium, we identified eicosanoid hepoxilin A3 as a critical pulmonary PMN chemoattractant that is sufficient to drive PMN-mediated epithelial damage by inducing the release of neutrophil elastase. Inhibition of the release or activity of this protease in mice limited epithelial barrier disruption and bacterial dissemination, suggesting a new host-directed treatment for Sp lung infection.

Unveiling the Bioactive Potential of Bacterial Isolates from Extreme Environments of Pakistan by In Vitro and In Silico Approaches.

The soil hosts a wide array of bacterial species capable of producing diverse bioactive compounds. This research aimed to screen bacterial isolates for their bioactive potential from extreme environments in Pakistan. Out of the 69 isolates examined, only 7 exhibited antagonistic activity against Bacillus sp. and Escherichia coli test strains. Notably, the B. cereus DS-2 strain demonstrated the highest antibacterial potential (31mm and 15mm) against the Bacillus and E. coli test strains, respectively. Mode-of-action studies suggested that the crude extract might have induced morphological abnormalities in the Bacillus sp. (test strain), causing cell contraction, chain breakage, and deformation. Furthermore, the B. cereus DS-2 strain displayed significant antioxidant potential (64.8%) as revealed by the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Thin-layer chromatography (TLC) of the DS-2crude extract led to the separation of six components, with only spots 3 and 4 exhibiting the antibacterial potential (3mm and 5mm, respectively). Subsequently, gas chromatography-mass spectrometry (GC-MS) analysis of the bioactive fraction extracted from TLC revealed the presence of diisooctyl phthalate, dibutyl phthalate, hexadecanoic acid methyl ester, and octadecanoic acid methyl ester. Molecular docking analysis of diisooctyl phthalate and dibutyl phthalate revealed their binding affinity against E. coli and Bacillus sp. targets. ADMET analysis confirmed the solubility, toxicity, and drug-like properties of the ligands based on Lipinski's rule of five. Current findings suggest that these compounds hold promise as antibacterial agents in drug development. This study underscores the diverse microbial community present in extreme environments and highlights the versatile applications of natural products derived from these strains.

Discovering the anti-diabetic potential of pomegranate peel metabolites by examining molecular interplay with the thioredoxin-interacting protein

IntroductionMedicinal plants like Punica granatum (pomegranate) have traditional uses against diabetes, inflammation and other diseases. The study was initiated to get an insight into the interaction tendency of P. granatum derived compounds with diabetes associated human thioredoxin-interacting protein (TXNIP). High glucose in diabetes induces production of TXNIP resulting in β-cells apoptosis. Its inhibition might reduce the diabetes incidence.MethodsTo elucidate the therapeutic potential of P. granatum peel against diabetes through GC-MS based identification of extracted compounds followed by application of computational algorithms. P. granatum peel extracts were screened for antioxidant, anti-inflammatory, anti-diabetic, antimicrobial and wound healing properties. Phytochemical and GC-MS based analysis were performed to identify the bioactive compounds. Molecular docking analysis was performed by Auto Dock Vina to predict the binding tendency of P. granatum derived compounds with TXNIP.Results and DiscussionThe peel exhibited antioxidant, anti-inflammatory and anti-diabetic activities, which were attributed to phytochemicals like phenols, tannins and steroids. GC-MS analysis identified 3,5-octadien-2-one, 1H-pyrrole -2,5-dione, Beta-D-lyxofuranoside, 5-O-(beta-D-lyxofuranosyl)-decyl, diethyl phthalate, 9-octadecenoic acid (Z)-, methyl ester, hexadecanoic acid, methyl ester, n-hexadecanoic acid, tetradecane, 2,6,10-trimethyl, bis (2-ethylhexyl) phthalate, decane, 3,8-dimethyl, 9-octadecenoic acid (Z)-, methyl ester and bis (2-ethylhexyl) phthalate in P. granatum peel extracts. Docking analysis revealed high binding affinities of bis (2-ethylhexyl) phthalate and 9-octadecenoic acid with TXNIP i.e., –4.5 and –5.0 kcal/mol, respectively, reflecting these compounds as potent antidiabetic agents. This study validates the traditional uses of P. granatum peel and demonstrates how computational approaches can uncover pharmacologically active phytochemicals. The results suggest P. granatum peel is a promising source of novel therapeutics against diabetes, inflammation, and oxidation. Further studies on the optimization of identified ligands are warranted.