Biochemical and biophysical research communications最新文献

FMRFamide peptides are highly conserved across invertebrates and are involved in various physiological responses. In nematodes, FMRFamide-like peptides (FLPs) and their receptor candidates, the neuropeptide receptors (NPRs), play a significant role in regulating physiological processes. In this study, we further investigated the molecular genetics of the npr-22 gene to determine its role in larval development in the free-living soil nematode model species, Caenorhabditis elegans. Our findings revealed the following: (1) NPR-22 inhibits larval development by interacting with insulin-like signaling pathway, as well as transforming growth factor-β (TGF-β)-like signaling pathway. This interaction leads to dauer diapause, a form of developmental arrest; (2) NPR-22 is expressed in the intestine and modulates the dauer diapause by regulating the production and secretion of insulin-like peptide 35 (INS-35), a predominant ligand of the sole insulin receptor-like protein, DAF-2. This study highlights the finding that a G protein-coupled receptor, expressed in various tissues, regulates the expression of distinct growth hormones involved in C. elegans development.

Postmenopausal osteoporosis (PMOP) is a common disease linked to aging, and estrogen deficiency is considered to be the primary cause of PMOP. Inflammation and the gut microbiota (GM) have emerged as promising therapeutic targets for treating PMOP. Taraxasterol (Tara), a pentacyclic triterpenoid primarily derived from Taraxacum officinale, demonstrates broad biological functions and pharmacological properties. However, whether Tara in question exerts an anti-osteoporosis (OP) effect remains unclear. To investigate the potential anti-OP effects of Tara, an experimental OP model was developed using female C57BL/6 mice via bilateral ovariectomy (OVX). The mice of Tara groups received treatments via oral gavage once daily for 8 consecutive weeks. Bone microstructure parameters, the NLRP3 inflammasome, intestinal barrier and GM were assessed. Network pharmacology was employed to predict and validate its anti-OP-related molecular targets and pathways. The results revealed that Tara treatment significantly reduced bone loss and improved bone metabolism. ELISA revealed that Tara reduced proinflammatory cytokine levels, suppressed the NLRP3 inflammasome (caspase-1, IL-1β and IL-18) and affected adipokine content. The expression levels of Occludin and ZO-1 exhibited a significant increase in the Tara groups. Moreover, 16S rRNA sequencing demonstrated that the relative abundances of Ileibacterium, Erysipelotrichaceae and Oscillospiraceae decreased significantly, whereases the relative abundance of Parabacteroides increased after Tara administration. Network pharmacology identified 75 core anti-OP targets. The binding energy of target proteins and Tara ranged from approximately -5.0 to -9.0 kcal/mol, with EGFR showing the lowest binding energy. Overall, Tara ameliorated OVX-induced OP by suppressing the NLRP3 inflammasome and modulating the GM.

Background: Ischemic stroke (IS) significantly impairs quality of life, yet current therapies are limited by narrow therapeutic windows and risks such as hemorrhagic transformation. Genistein (Gen) is a natural compound with anti-inflammatory and antioxidant properties capable of crossing the blood-brain barrier (BBB); however, its clinical application is hindered by poor solubility. This study aimed to develop genistein nanoparticles (Gen NPs) with reduced particle size and enhanced solubility, and investigate their neuroprotective effects against IS.

Methods: Gen NPs with improved solubility were synthesized using the emulsion-solvent evaporation method and characterized by mass spectrometry and electron microscopy. Neuroprotective efficacy was evaluated in a mouse middle cerebral artery occlusion (MCAO) model. Infarct volumes were quantified by TTC staining, and behavioral tests were conducted to assess sensorimotor function. Network pharmacology and molecular docking approaches were utilized to identify therapeutic targets related to apoptosis and inflammatory pathways. BBB integrity was assessed through Evans blue (EB) dye extravasation and IgG permeability assays. Neuronal preservation was confirmed by Nissl and Fluoro-Jade C (FJ-C) staining.

Results: Gen NPs exhibited rod-like nanostructures with enhanced solubility, smaller particle sizes, and improved uniformity. Experimental findings demonstrated that Gen NPs had superior efficacy compared to free Gen in reducing infarct volume and enhancing neurobehavioral outcomes, with an optimal therapeutic dose identified as 2 mg/kg. Additionally, Gen NPs modulated multiple pathological mechanisms, including apoptosis and inflammation, thereby preserving BBB integrity and attenuating neuronal injury.

Conclusion: We successfully synthesized Gen NPs exhibiting improved water solubility, reduced particle size, and enhanced uniformity, demonstrating their superior therapeutic potential for IS treatment. These findings highlight the multifaceted neuroprotective mechanisms of Gen NPs, suggesting promising prospects for clinical translation.

Radioresistance is a key challenge in colorectal cancer (CRC) therapy. Through integrative analysis of TCGA datasets and RNA-seq of irradiated CRC cells, we identified PLS3-AS1 as a radiation-inducible lncRNA upregulated in recurrent tumors and post-irradiation. Functional assays revealed that PLS3-AS1 promotes CRC cell proliferation, survival, and radioresistance in vitro and in vivo. Mechanistically, PLS3-AS1 enhances NF-κB signaling by directly binding to p65 and IκBα, disrupting their interaction and facilitating p65 nuclear translocation. Moreover, PLS3-AS1 expression is itself induced by NF-κB activation, forming a positive feedback loop. Inhibition of NF-κB with BAY 11-7082 suppressed PLS3-AS1 expression and reversed its pro-tumorigenic effects. These findings identify PLS3-AS1 as a critical mediator of NF-κB-driven radioresistance in CRC and a potential therapeutic target to improve radiotherapy efficacy.

Additives like arginine, while known to enhance protein stability, were observed to improve the solubility of proteins in an equimolar mixture of arginine and glutamic acid. This study examines the conformational stability of a model protein, chymotrypsin inhibitor 2, in arginine, glutamic acid, and their mixture over a temperature range of 300-440 K using Replica Exchange Molecular Dynamics. The study demonstrates that arginine stabilized CI2 through hydrogen bonds and electrostatic interactions with polar and charged residues, thereby restricting conformational fluctuations and reducing solvent penetration. Glutamic acid enhanced its stability by promoting preferential hydration and maintaining a hydration shell that minimized hydrophobic exposure during thermal fluctuations. The arginine-glutamic acid mixture exhibited intermediate stabilizing behavior, where hydrogen bonding interactions between the oppositely charged amino acids reduced arginine self-association, resulting in a balanced hydrophilic-hydrophobic environment around the protein. Free energy landscape analysis showed no significant unfolding transitions across temperatures, supporting a kinetically stable ensemble. Radial distribution and cluster analyses indicated that arginine formed compact clusters near the protein surface, whereas glutamic acid remained dispersed, allowing higher water mobility. Water diffusion and dipole-dipole correlation studies revealed faster hydration dynamics in glutamic acid and slower, more confined motion in arginine, with intermediate behavior in the mixed solution.