Capsaicin (CAP) exerts a protective effect against ethanol-induced oxidative gastric mucosal injury by modulating the chemokine receptor 4 (CCR4)/Src/p47phox signaling pathway both in vitro and in vivo.

Ethanol (EtOH) is a common trigger for gastric mucosal diseases, and mitigating oxidative stress is essential for attenuating gastric mucosal damage. Capsaicin (CAP) has been identified as a potential agent to counteract oxidative damage in the gastric mucosa; however, its precise mechanism remains unclear. This study demonstrates that CAP alleviates EtOH-induced gastric mucosal injuries through two primary pathways: by suppressing the chemokine receptor 4 (CCR4)/Src/p47phox axis, thereby reducing oxidative stress, and by inhibiting the phosphorylation and nuclear translocation of nuclear factor-κB p65 (NF-κB) p65, resulting in diminished inflammatory responses.

Cationic liposomes overcome neutralizing antibodies and enhance reovirus efficacy in ovarian cancer.

Reovirus (Reo) has shown promising potential in specifically killing tumor cells, and offering new possibilities for ovarian cancer (OC) treatment. However, neutralizing antibodies in the ascites from OC patients greatly limit the further application of Reo. In this study, we employed cationic liposomes (Lipo) to deliver Reo, significantly enhancing its ability to enter OC cells and its effectiveness in killing these cells under ascitic conditions.

Human umbilical cord mesenchymal stem cell exosomes deliver potent oncolytic reovirus to acute myeloid leukemia cells.

In addition to chemotherapy, oncolytic viruses are an efficient treatment for acute myeloid leukemia (AML). Like other oncolytic viruses, the anti-tumor efficacy of reovirus when administered intravenously is reduced due to the presence of neutralizing antibodies. In this study, we evaluated the role of exosomes in human umbilical cord-derived mesenchymal stem cells (UC-MSCs) to deliver reovirus to AML cells.

Computational design of N-linked glycans for high throughput epitope profiling.

Efficient identification of epitopes is crucial for drug discovery and design as it enables the selection of optimal epitopes, expansion of lead antibody diversity, and verification of binding interface. Although high-resolution low throughput methods like x-ray crystallography can determine epitopes or protein-protein interactions accurately, they are time-consuming and can only be applied to a limited number of complexes. To overcome these limitations, we have developed a rapid computational method that incorporates N-linked glycans to mask epitopes or protein interaction surfaces, thereby providing a mapping of these regions.

Large-scale Isolation of Exosomes Derived from NK Cells for Anti-tumor Therapy.

Exosomes are lipid bilayer-enclosed vesicles, actively secreted by cells, containing proteins, lipids, nucleic acids, and other substances with multiple biological functions after entering target cells. Exosomes derived from NK cells have been shown to have certain anti-tumor effects and potential applications as chemotherapy drug carriers. These developments have resulted in high demand for exosomes.

Blood redistribution preferentially protects vital organs under hypoxic stress in Pelteobagrus vachelli.

Blood redistribution occurs in mammals under hypoxia but has not been reported in fish. This study investigated the tissue damage, hypoxia-inducible factor (HIF) activation level, and blood flow changes in the brain, liver, and muscle of Pelteobagrus vachelli during the hypoxia process for normoxia-hypoxia-asphyxia. The results showed that P.

NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering cisplatin and reactivating NK cell functions.

Exosomes are membranous vesicles actively secreted by almost all cells and they deliver certain intracellular molecules, including nucleic acids, proteins, and lipids, to target cells. They are also considered to be good carriers for drug delivery due to their biocompatibility, high permeability, low immunogenicity, and low toxicity. Exosomes from immune cells were also reported to have immunomodulatory activities.

A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice.

Hemophilia A is a bleeding disorder resulting from deficient factor VIII (FVIII), which normally functions as a cofactor to activated factor IX (FIXa) that facilitates activation of factor X (FX). To mimic this property in a bispecific antibody format, a screening was conducted to identify functional pairs of anti-FIXa and anti-FX antibodies, followed by optimization of functional and biophysical properties. The resulting bispecific antibody (Mim8) assembled efficiently with FIXa and FX on membranes, and supported activation with an apparent equilibrium dissociation constant of 16 nM.

Insulin binding to the analytical antibody sandwich pair OXI-005 and HUI-018: Epitope mapping and binding properties.

The insulin epitopes for two monoclonal antibodies (mAbs), OXI-005 and HUI-018, commonly used in combination for insulin concentration determination in sandwich assays, were determined using X-ray crystallography. The crystal structure of the HUI-018 Fab in complex with human insulin (HI) was determined and OXI-005 Fab crystal structures were determined in complex with HI and porcine insulin (PI) as well as on its own. The OXI-005 epitope comprises insulin residues 1,3,4,19-21 (A-chain) and 25-30 (B-chain) and for HUI-018 residues 7,8,10-14,17 (A-chain) and 5-7, 10, 14 (B-chain).

Superhydrophobic Surface Preparation and Wettability Transition of Titanium Alloy with Micro/Nano Hierarchical Texture.

Microstructures are applied to various hydrophobic/hydrophilic surfaces due to the role of adjusting the surface wettability. In this paper, a 1064 nm pulsed picosecond laser was applied to prepare a micro/nano hierarchical structure on the surface of the titanium alloy (Ti-6Al-4V). The microstructures consist of dimple arrays with various diameters, depths, and areal densities.

Exposing the {010} Planes by Oriented Self-Assembly with Nanosheets To Improve the Electrochemical Performances of Ni-Rich Li[NiCoMn]O Microspheres.

A modified Ni-rich Li[NiCoMn]O cathode material with exposed {010} planes is successfully synthesized for lithium-ion batteries. The scanning electron microscopy images have demonstrated that by tuning the ammonia concentration during the synthesis of precursors, the primary nanosheets could be successfully stacked along the [001] crystal axis predominantly, self-assembling like multilayers. According to the high-resolution transmission electron microscopy results, such a morphology benefits the growth of the {010} active planes of final layered cathodes during calcination treatment, resulting in the increased area of the exposed {010} active planes, a well-ordered layer structure, and a lower cation mixing disorder.

Construction of a versatile expression library for all human single-pass transmembrane proteins for receptor pairings by high throughput screening.

Interactions between protein ligands and receptors play crucial roles in cell-cell signalling. Most of the human cell surface receptors have been identified in the post-Human Genome Project era but many of their corresponding ligands remain unknown. To facilitate the pairing of orphan receptors, 2762 sequences encoding all human single-pass transmembrane proteins were selected for inclusion into a mammalian-cell expression library.

GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand.

Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation.

Novel Function of Extracellular Matrix Protein 1 in Suppressing Th17 Cell Development in Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by demyelination and axonal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model for human MS. Although Th17 cells are important for disease induction, Th2 cells are inhibitory in this process.

In-depth analysis of subclass-specific conformational preferences of IgG antibodies.

IgG subclass-specific differences in biological function and in vitro stability are often referred to variations in the conformational flexibility, while this flexibility has rarely been characterized. Here, small-angle X-ray scattering data from IgG1, IgG2 and IgG4 antibodies, which were designed with identical variable regions, were thoroughly analysed by the ensemble optimization method. The extended analysis of the optimized ensembles through shape clustering reveals distinct subclass-specific conformational preferences, which provide new insights for understanding the variations in physical/chemical stability and biological function of therapeutic antibodies.

Fabrication of a Layered Microstructured Polymeric Microspheres as a Cell Carrier for Nucleus Pulposus Regeneration.

This study aimed to investigate the feasibility of nanostructured 3D poly(lactide-co-glycolide) (PLGA) constructs, which are loaded with dexamethasone (DEX) and growth factor embedded hepaiin/poly(L-lysine) nanoparticles by a layer-by-layer system, to serve as an effective scaffold for nucleus pulposus (NP) tissue engineering. Our results demonstrated that the microsphere constructs were capable of simultaneously releasing basic fibroblast growth factor and DEX with approximately zero-order kinetics. The dual bead microspheres showed no cytotoxicity, and promoted the proliferation of the rat mesenchymal stem cells (rMSCs) by lactate dehydrogenase assay and CCK-8 assay.

Crystal structure of TNFalpha complexed with a poxvirus MHC-related TNF binding protein.

The poxvirus 2L protein binds tumor necrosis factor-alpha (TNFalpha) to inhibit host antiviral and immune responses. The 2.8-A 2L-TNFalpha structure reveals three symmetrically arranged 2L molecules per TNFalpha trimer.

Structure of UL18, a peptide-binding viral MHC mimic, bound to a host inhibitory receptor.

UL18 is a human cytomegalovirus class I MHC (MHCI) homolog that binds the host inhibitory receptor LIR-1 and the only known viral MHC homolog that presents peptides. The 2.2-A structure of a LIR-1/UL18/peptide complex reveals increased contacts and optimal surface complementarity in the LIR-1/UL18 interface compared with LIR/MHCI interfaces, resulting in a >1,000-fold higher affinity.

Crystal structures of substrate complexes of malic enzyme and insights into the catalytic mechanism.

Malic enzymes catalyze the oxidative decarboxylation of L-malate to pyruvate and CO(2) with the reduction of the NAD(P)(+) cofactor in the presence of divalent cations. We report the crystal structures at up to 2.1 A resolution of human mitochondrial NAD(P)(+)-dependent malic enzyme in different pentary complexes with the natural substrate malate or pyruvate, the dinucleotide cofactor NAD(+) or NADH, the divalent cation Mn(2+), and the allosteric activator fumarate.

Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase.

Acetyl-coenzyme A carboxylases (ACCs) are required for the biosynthesis and oxidation of long-chain fatty acids. They are targets for therapeutics against obesity and diabetes, and several herbicides function by inhibiting their carboxyltransferase (CT) domain. We determined the crystal structure of the free enzyme and the coenzyme A complex of yeast CT at 2.

Aspartate dehydrogenase, a novel enzyme identified from structural and functional studies of TM1643.

The open reading frame TM1643 of Thermotoga maritima belongs to a large family of proteins, with homologues in bacteria, archaea, and eukaryotes. TM1643 is found in an operon with two other genes that encode enzymes involved in the biosynthesis of NAD. In several bacteria, the gene in the position occupied by TM1643 encodes an aspartate oxidase (NadB), which synthesizes iminoaspartate as a substrate for NadA, the next enzyme in the pathway.

Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate.

The regulation of human mitochondrial NAD(P)+-dependent malic enzyme (m-NAD-ME) by ATP and fumarate may be crucial for the metabolism of glutamine for energy production in rapidly proliferating tissues and tumors. Here we report the crystal structure at 2.2 A resolution of m-NAD-ME in complex with ATP, Mn2+, tartronate, and fumarate.

Structural studies of the pigeon cytosolic NADP(+)-dependent malic enzyme.

Malic enzymes are widely distributed in nature, and have important biological functions. They catalyze the oxidative decarboxylation of malate to produce pyruvate and CO(2) in the presence of divalent cations (Mg(2+), Mn(2+)). Most malic enzymes have a clear selectivity for the dinucleotide cofactor, being able to use either NAD(+) or NADP(+), but not both.