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Bioorganic & Medicinal Chemistry Letters Jun 2024We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility...
We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats.
PubMed: 38942126
DOI: 10.1016/j.bmcl.2024.129864 -
Journal of the American Chemical Society Jun 2024Identifying the active phase with the highest activity, which is long-believed to be a steady state of the catalyst, is the basis of rational design of heterogeneous...
Identifying the active phase with the highest activity, which is long-believed to be a steady state of the catalyst, is the basis of rational design of heterogeneous catalysis. In this work, we performed detailed investigations, successfully capturing the instantaneous structure-activity change in oscillating Pd nanocatalysts during methane oxidation, which reveals an unprecedented oscillatory active state. Combining quantitative environmental transmission electron microscopy and highly sensitive online mass spectrometry, we identified two distinct phases for the reaction: one where the Pd nanoparticles refill with oxygen, and the other, a period of abrupt pumping of oxygen and boosted methane oxidation within about 1 s. It is the rapid reduction process that shows the highest activity for total oxidation of methane, not a PdO or Pd steady state under the conditions applied here (methane:oxygen = 5:1). This observation challenges the traditional understanding of the active phase and requires a completely different strategy for catalyst optimization.
PubMed: 38942067
DOI: 10.1021/jacs.4c02830 -
Experimental and Clinical Endocrinology... Jun 2024Spermatozoa are susceptible to oxidative radicals when antioxidant defenses are inadequate. The extent to which oxidative radicals contribute to sperm damage in patients...
OBJECTIVE
Spermatozoa are susceptible to oxidative radicals when antioxidant defenses are inadequate. The extent to which oxidative radicals contribute to sperm damage in patients with acromegaly remains unclear. This study aimed to investigate and elucidate this relationship.
METHODS
The overall status of oxidants and antioxidants in both seminal plasma and serum of patients with acromegaly compared to a control group of healthy individuals was investigated. In addition, sperm parameters, including important measures such as growth hormone and insulin-like growth factor-1 concentrations.
RESULTS
Twenty-two patients with acromegaly with controlled disease and 14 healthy controls were included. The total oxidant status was significantly higher in the semen samples of the patients with acromegaly. A negative correlation was found between sperm total oxidant status and total sperm count and sperm concentration. Similarly, a negative correlation was found between the total sperm count and the sperm oxidative stress index. In individuals diagnosed with acromegaly, there was a statistically significant increase in sperm growth hormone levels. Conversely, the level of insulin-like growth factor 1 was significantly increased in the sperm of the control group, which consisted of healthy individuals. The correlation analysis revealed a significant relationship between venous total oxidant status and growth hormone levels in semen.
CONCLUSION
The elevated levels of reactive oxygen radicals in individuals with acromegaly suggest a possible link between oxidative stress and its effects on semen quality.
PubMed: 38942036
DOI: 10.1055/a-2329-2998 -
Journal of Colloid and Interface Science Jun 2024Membrane technology holds great potential for separation applications and also finds critical needs in biomedical fields, such as blood oxygenation. However, the...
Membrane technology holds great potential for separation applications and also finds critical needs in biomedical fields, such as blood oxygenation. However, the bottlenecks in gas permeation, plasma leakage, and especially hemocompatibility hamper the development of membrane oxygenation. It remains extremely challenging to design efficient membranes and elucidate underlying principles. In this study, we report biomimetic decoration of asymmetric nanoporous membranes by ultrathin Fe-tannic acid metal-ligand networks to realize fast gas exchange with on plasma leakage and substantially enhance hemocompatibility. Because the intrinsic nanopores facilitate gas permeability and the Fe-catechol layers enable superior hydrophilicity and electronegativity to original surfaces, the modified membranes exhibit high transport properties for gases and great resistances to protein adsorption, platelet activation, coagulation, thrombosis, and hemolysis. Molecular docking and density functional theory simulations indicate that more preferential adsorption of metal-ligand networks with water molecules than proteins is critical to anticoagulation. Moreover, benefiting from the better antiaging property gave by biomimetic decoration, the membranes after four-month aging present gas permeances similar to or even larger than those of pristine ones, despite the initial permeation decline. Importantly, for blood oxygenation, the designed membranes after aging show fast O and CO exchange processes with rates up to 28-17 and 97-47 mL m min, respectively, accompanied with no detectable thrombus and plasma leakage. We envisage that the biomimetic decoration of nanoporous membranes provide a feasible route to achieve great biocompatibility and transport capability for various applications.
PubMed: 38941931
DOI: 10.1016/j.jcis.2024.06.173 -
Journal of Colloid and Interface Science Jun 2024To achieve high-performance Zn-air batteries (ZABs), the development of bifunctional air electrodes capable of efficiently mediating both the oxygen reduction reaction...
To achieve high-performance Zn-air batteries (ZABs), the development of bifunctional air electrodes capable of efficiently mediating both the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) is imperative. In this study, we present an N-doped carbon hollow nanorod encapsulating a semi-coherent Co-Ni/CoMoC heterojunction, tailored for reversible oxygen catalysis. This nanohybrid demonstrated an ORR half-wave potential of 0.907 V alongside an OER overpotential of η = 352 mV. When incorporated into ZABs, this catalyst exhibited extraordinary performance metrics, including a high-power density of 343.7 mW/cm, a specific capacity of 681 mAh/g, and enhanced durability. The distinctive electric field within the heterojunction facilitated electron transfer across the semi-coherent interface during reversible oxygen electrocatalysis, enhancing the adsorption and release of active intermediates. Thus, this heightened ORR-OER catalytic efficiency culminated in superior ZABs performance. Our findings afford a pivotal design paradigm for the advancement of productive bifunctional catalysts within the field of energy conversion technologies.
PubMed: 38941930
DOI: 10.1016/j.jcis.2024.06.162 -
Biomedicine & Pharmacotherapy =... Jun 2024In cell-based bone augmentation, transplanted cell dysfunction and apoptosis can occur due to oxidative stress caused by the overproduction of reactive oxygen species...
In cell-based bone augmentation, transplanted cell dysfunction and apoptosis can occur due to oxidative stress caused by the overproduction of reactive oxygen species (ROS). Edaravone (EDA) is a potent free radical scavenger with potential medical applications. This study aimed to investigate the effect of controlling oxidative stress on bone regeneration using EDA. Bone marrow-derived cells were collected from 4-week-old rats, and EDA effects on cell viability and osteogenic differentiation were evaluated. Collagen gels containing PKH26-prelabeled cells were implanted into the calvarial defects of 12-week-old rats, followed by daily subcutaneous injections of normal saline or 500 μM EDA for 4 d. Bone formation was examined using micro-computed tomography and histological staining. Immunofluorescence staining was performed for markers of oxidative stress, macrophages, osteogenesis, and angiogenesis. EDA suppressed ROS production and hydrogen peroxide-induced apoptosis, recovering cell viability and osteoblast differentiation. EDA treatment in vivo increased new bone formation. EDA induced the transition of the macrophage population toward the M2 phenotype. The EDA group also exhibited stronger immunofluorescence for vascular endothelial growth factor and CD31. In addition, more PKH26-positive and PKH26-osteocalcin-double-positive cells were observed in the EDA group, indicating that transplanted cell survival was prolonged, and they differentiated into bone-forming cells. This could be attributed to oxidative stress suppression at the transplantation site by EDA. Collectively, local administration using EDA facilitates bone regeneration by improving the local environment and angiogenesis, prolonging survival, and enhancing the osteogenic capabilities of transplanted cells.
PubMed: 38941894
DOI: 10.1016/j.biopha.2024.117032 -
Biomedicine & Pharmacotherapy =... Jun 2024Myocardial ischemia (MI) is a significant contributor to ischemic heart diseases like angina pectoris and myocardial infarction. Reactive oxygen species produced during...
Salvia miltiorrhiza stem-leaf of total phenolic acid conversion products alleviate myocardial ischemia by regulating metabolic profiles, intestinal microbiota and metabolites.
Myocardial ischemia (MI) is a significant contributor to ischemic heart diseases like angina pectoris and myocardial infarction. Reactive oxygen species produced during MI can trigger lipid peroxidation, damaging cell structure and function. Salvia miltiorrhiza (SM) has been widely used clinically in the treatment of cardiovascular diseases. However, in the process of rooting, the aboveground parts of this plant are usually discarded by tons. To make better use of these plant resources, the phenolic acids extracted and purified from the aerial part of SM were studied and chemically transformed, and the potential protective effect and possible mechanism of salvianolic acids containing a higher content of salvianolic acid A on MI were obtained. The transformed products of SM stem-leaves total phenolic acids with 8.16 % salvianolic acid A showed a better protective effect on the isoproterenol (ISO)-induced acute MI injury rat model. It can improve ST segment changes and has good antioxidant, anti-inflammatory and anticoagulant effects. In addition, the dysbiosis of gut microbiota and the related metabolic levels of short chain fatty acids (SCFAs), phenylalanine and glycerophospholipids were improved. This was achieved by reducing the abundance of Bacteroides, Faecalibaculum, and L-phenylalanine levels. In addition, the abundance of probiotics in Butyricoccus, Roseburia, and norank_f_Eubacterium_coprostanoligenes_group, as well as the contents of propionic acid and isobutyric acid, LPCs and PCs were increased. In conclusion, total phenolic acids of SM stem-leaves showed protective effects against ISO-induced rats, especially the strongest effect after conversion, which is a new option for the prevention and treatment of MI.
PubMed: 38941891
DOI: 10.1016/j.biopha.2024.117055 -
Water Research Jun 2024Dissolved black carbon (DBC) released from biochar, is an essential group in the dissolved organic matter (DOM) pool and is widely distributed in aquatic environments....
Dissolved black carbon (DBC) released from biochar, is an essential group in the dissolved organic matter (DOM) pool and is widely distributed in aquatic environments. In various advanced oxidation processes (AOPs), DBC exhibits enhanced free radical scavenging compared to typical DOM, attributed to its smaller molecular weight and more compacted aromatic structure; however, the molecular-level transformations of DBC in different AOPs, such as UV/HO, UV/PDS, and UV/Chlorine, remain unclear. This study employed a DBC derived from wheat biochar for experimentation. Characterization involved ultraviolet-visible (UV-Vis) spectroscopy and fluorescence excitation-emission-matrix (EEM) spectroscopy, revealing the transformation of DBC through diminished SUVA values and reduced intensity of three-dimensional fluorescence peaks. Further insights into the transformation were gained through Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). After each UV-AOP treatment, a conspicuous augmentation in the oxygen content of DBC was observed. The detailed oxygenation processes were elucidated through mass difference analysis, based on 23 types of typical reactions. Results indicated that oxygenation reactions were most frequently detected in all three UV-AOP treatments. Specifically, the hydroxylation (+O) predominated in UV/HO, while the di-hydroxylation (+2O) prevailed in UV/PDS. UV/Chlorine treatments commonly exhibited tri-hydroxylation (+3O), with the identification of 1194 Cl-BPs of unknown structures. This study contributes to a comprehensive understanding of the molecular transformations of DBC induced by various free radicals in different UV-AOP processes, leading to a better understanding of the different fates of DBC in UV-AOP processes. In addition, the identification of DBC as a precursor of by-products will also contribute to the understanding of how to inhibit the generation of by-products.
PubMed: 38941867
DOI: 10.1016/j.watres.2024.121962 -
Journal of Environmental Management Jun 2024Oil refineries produce annually large quantities of oily sludge and non-biodegradable wastewater during petroleum refining that require adequate management to minimize...
Oil refineries produce annually large quantities of oily sludge and non-biodegradable wastewater during petroleum refining that require adequate management to minimize its environmental impact. The fraction solid of the oily sludge accounts for 25 wt% and without treatment for their valorization. This work is focused on the valorization of these solid particles through their transformation into porous materials with enhanced properties and with potential application in the catalytic wet air oxidation (CWAO) of a non-biodegradable spent caustic refinery wastewater. Hence, dealing with the valorization and treatment of both refinery wastes in a circular approach aligned with the petrol refinery transformations by 2050. The obtained oily sludge carbonaceous materials showed improved surface area (260-762 m/g) and a high Fe content. The good catalytic performance of these materials in CWAO processes has been attributed to the simultaneous presence of surface basic sites and iron species. Those materials with higher content of Fe and basic sites yielded the highest degradation of organic compounds present in the spent caustic refinery wastewater. In particular, the best-performing material ACT-NP 1.1 (non-preoxidated and thermically treated with 1:1 mass ratio KOH:solid) showed a chemical oxygen demand (COD) removal of 60 % after 3 h of reaction and with a higher degradation rate than that achieved with thermal oxidation without catalyst (WAO) and that using an iron-free commercial activated carbon. Moreover, the biodegradability of the treated wastewater increased up to 80% (from ca. 31% initially of the untreated effluent). Finally, this material was reused up to three catalytic cycles without losing metal species and keeping the catalytic performance.
PubMed: 38941846
DOI: 10.1016/j.jenvman.2024.121606 -
Phytomedicine : International Journal... Jun 2024Hypoxic pulmonary vascular remodeling (HPVR) is a key pathological feature of hypoxic pulmonary hypertension (HPH). Oxygen-sensitive potassium (K) channels in pulmonary...
BACKGROUND
Hypoxic pulmonary vascular remodeling (HPVR) is a key pathological feature of hypoxic pulmonary hypertension (HPH). Oxygen-sensitive potassium (K) channels in pulmonary artery smooth muscle cells (PASMCs) play a crucial role in HPVR. Luteolin (Lut) is a plant-derived flavonoid compound with variety of pharmacological actions. Our previous study found Lut alleviated HPVR in HPH rat.
PURPOSE
To elucidate the mechanism by which Lut mitigated HPVR, focusing on oxygen-sensitive voltage-dependent potassium channel 1.5 (Kv1.5).
METHODS
HPH rat model was established using hypobaric chamber to simulate 5000 m altitude. Isolated perfused/ventilated rat lung, isolated pulmonary arteriole ring was utilized to investigate the impact of Lut on K channels activity. Kv1.5 level in lung tissue and pulmonary arteriole of HPH rat was assessed. CyclinD1, CDK4, PCNA, Bax, Bcl-2, cleaved caspase-3 levels in lung tissue of HPH rat were tested. The effect of Lut on Kv1.5, cytoplasmic free calcium concentration ([Ca]), CyclinD1, CDK4, PCNA, Bax/Bcl-2 was examined in PASMCs under hypoxia, with DPO-1 as a Kv1.5 specific inhibitor. The binding affinity between Lut and Kv1.5 in PASMCs was detected by drug affinity responsive target stability (DARTS). The overexpression of KCNA5 gene (encoding Kv1.5) in HEK293T cells was utilized to confirm the interaction between Lut and Kv1.5. Furthermore, the impact of Lut on mitochondrial structure, SOD, GSH, GSH-Px, MDA and HIF-1α levels were evaluated in lung tissue of HPH rat and PASMCs under hypoxia.
RESULTS
Lut dilated pulmonary artery by directly activating Kv and Ca-activated K channels (K) in smooth muscle. Kv1.5 level in lung tissue and pulmonary arteriole of HPH rat was upregulated by Lut. Lut downregulated CyclinD1, CDK4, PCNA while upregulating Bax/Bcl-2/caspase-3 axis in lung tissue of HPH rat. Lut decreased [Ca], reduced CDK4, CyclinD1, PCNA, increased Bax/Bcl-2 ratio, in PASMCs under hypoxia, by upregulating Kv1.5. The binding affinity and the interaction between Lut and Kv1.5 was verified in PASMCs and in HEK293T cells. Lut also decreased [Ca] and inhibited proliferation via targeting Kv1.5 of HEK293T cells under hypoxia. Furthermore, Lut protected mitochondrial structure, increased SOD, GSH, GSH-Px, decreased MDA, in lung tissue of HPH rat. Lut downregulated HIF-1α level in both lung tissue of HPH rat and PASMCs under hypoxia.
CONCLUSION
Lut alleviated HPVR by promoting vasodilation of pulmonary artery, reducing cellular proliferation, and inducing apoptosis through upregulating of Kv1.5 in PASMCs.
PubMed: 38941817
DOI: 10.1016/j.phymed.2024.155840