Ursolic acid from Carissa carandas L. as a multi-target agent against NSCLC: An Integrative in silico and in vitro study.

NMDA-type ionotropic glutamate receptors mediate excitatory neurotransmission and synaptic plasticity, but aberrant signaling by these receptors is also implicated in brain disorders. Here, we present the binding site and the mechanism of action for UCM-101, a novel negative NMDA receptor modulator that produces full inhibition of NMDA receptor-mediated excitatory postsynaptic currents in hippocampal CA pyramidal neurons from juvenile mouse brain slices. UCM-101 has a 59-fold higher binding affinity at GluN1/2A compared with GluN1/2B receptors and inhibits diheteromeric GluN1/2A and triheteromeric GluN1/2A/2B receptors with IC50 values of 110 and 240 nM, respectively, in the presence of 1 µM glycine. The novel binding mode for UCM-101 is revealed in a high-resolution crystal structure of the GluN1/2A agonist binding domain heterodimer. UCM-101 and its analog TCN-213 inhibit NMDA receptors by negatively modulating co-agonist binding to the GluN1 subunit via an allosteric mechanism that is conserved with previously described GluN2A-selective antagonists, TCN-201 and MPX-004. Despite the shared mechanism of action, the structural determinants that mediate subunit selectivity for UCM-101 are distinct from those of TCN-201 and MPX-004. These findings provide detailed insights into the binding site and mechanism of action of a novel NMDA receptor modulator and open new avenues for the development of NMDA receptor ligands with therapeutic potential.

The evolving landscape of mitochondrial base editing: advances in precision, modeling, and therapeutic potential.

Hirudin promotes peripheral nerve repair and alleviates pain by regulating the EGFR-PI3K/AKT/mTOR pathway.

Philological analysis of ancient Egyptian recipes supported by modern chemical profiling approaches.

TMEM165 promotes glioblastoma progression through epithelial-mesenchymal transition-mediated invasion and temozolomide chemoresistance.

Hydra as a dual-utility model for cytotoxicity and genotoxicity: Bridging environmental toxicology and therapeutic applications.

The role of histone acetyltransferases in tumorigenesis and their therapeutic potential: A review.

Melatonin alleviates intestinal damage in neonate mice following Salmonella Typhimurium and LPS challenges involving gut microbiota remodeling.

Salvianolic acid B alleviates rheumatoid arthritis by inhibiting oxidative stress and pyroptosis through the Keap1-Nrf2/ROS/NLRP3 axis.

Syringic acid suppresses inflammation by upregulation of SOCS3.

Laminin β1 stimulates the Hippo-YAP1 pathway to advance the progression and lenvatinib resistance in hepatocellular carcinoma.

Protective and immunostimulatory roles of yeast-derived vacuoles in immune suppression.

Rationale: Transmembrane 4 superfamily member 4 (TM4SF4) has been identified as a key regulator of epithelial-mesenchymal transition (EMT)-associated stemness in non-small cell lung cancer (NSCLC) cells through autocrine signaling involving insulin-like growth factor 1 (IGF1) and osteopontin (OPN). Given its pivotal role in tumor progression and therapy resistance, TM4SF4 represents a promising therapeutic target. Methods: To develop a therapeutic antibody against TM4SF4, we generated anti-TM4SF4 monoclonal antibodies in mice by targeting the large extracellular loop (LEL) of human TM4SF4 using a 15-mer peptide, hTM4SF4 (T126-E140). Among the generated clones, the 2B7 antibody exhibited high specificity and reactivity to TM4SF4. Mechanistic studies were conducted to evaluate the effects of 2B7 on key signaling pathways, EMT-associated stemness, immune checkpoint ligand (ICL) expression, and immune responses. To facilitate clinical translation, 2B7 was humanized, generating the Hz2B7-1.1 antibody, which underwent affinity maturation to select the lead candidate, Hz2B7-1.2. Functional assays, including antibody-dependent cellular cytotoxicity (ADCC) and preclinical evaluations in xenograft models, were performed to assess its therapeutic potential. Results: The 2B7 antibody demonstrated significant antitumor efficacy in both A549 xenograft and patient-derived xenograft (PDX) models. Mechanistically, 2B7 inhibited key signaling pathways, including PI3K/AKT/GSK3β/β-catenin and JAK2/STAT3, leading to a reduction in EMT-associated stemness and therapy resistance. Additionally, 2B7 downregulated the expression of ICLs, such as PD-L1 and B7-H4, promoting T-cell activation and mitigating immune evasion. Furthermore, 2B7 reduced the secretion of exosomal ICLs by tumor cells and enhanced antitumor immune responses. The humanized antibody Hz2B7-1.2 retained binding properties and antitumor activity comparable to the parental 2B7 antibody and effectively induced ADCC as an IgG1-type antibody. Conclusions: The humanized anti-TM4SF4 antibody, Hz2B7-1.2, exhibits strong antitumor activity through multiple mechanisms, including inhibition of oncogenic signaling pathways, reduction of EMT-associated stemness, and modulation of immune responses. These findings support Hz2B7-1.2 as a promising therapeutic candidate for TM4SF4-positive cancers, warranting further clinical investigation.

Bilobalide isolated from Ginkgo leaf tea alleviates Parkinson's disease via suppressing neuroinflammation and remodeling gut microbiota.

The emergence of novel viral infections, such as SARS-CoV-2, H5N2, and H7N9, among recently identified viruses, has highlighted the urgent need for new antiviral therapeutics. The SARS-CoV-2 virus binds to ACE2 on host cell surfaces, reducing ACE2 expression, increasing Angiotensin II, and activating the RAAS system. On the other sides, marine organisms like Navicula salinicola are a significant unexplored source of bioactive compounds with potential antiviral activity. However, investigation on marine-derived poly-unsaturated fatty acids (PUFAs) as antiviral agents for SARS-CoV-2 is a priority, as they have shown promising antiviral properties. This exploration highlights the ongoing efforts to explore natural compounds for their therapeutic potential against viral infections, including COVID-19. This study aims to investigate the antiviral potential of PUFAs from N. salinicola against SARS-CoV-2 using molecular docking and molecular dynamics simulations. A total of 14 PUFAs from N. salinicola were subjected to molecular docking with the SARS-CoV-2 spike protein, and the three best-ranked ligands, DHA (-7.56kcal/mol), AA (-6.61kcal/mol), and EPA (-6.5kcal/mol), were further analyzed by molecular dynamics. Our study identified all PUFAs with promising binding affinities toward the SARS-CoV-2 spike protein, suggesting their potential as effective inhibitors of viral entry or replication mechanisms. Molecular dynamics simulations revealed that the ligands docosahexaenoic acid (DHA), arachidonic acid (AA), and eicosapentaenoic acid (EPA) exhibited ∆ETotal values of -46.45, -48.31, and -43.65kcal/mol, respectively, indicating a relatively stable interaction with ACE2. AA, the most potent marine-derived PUFA from N. salinicola, has been identified as the lead compound for SARS-CoV-2 inhibitors, requiring further research for in vitro or in vivo experiments.

Discovery of benzimidazole-based Mcl-1 inhibitors via AlphaShape-enabled virtual screening.

Cacalia firma is known for its unique fragrance, and its young shoots are traditionally used as culinary herbs and for their active constituents. The leaves of C. firma and the residual material remaining after enzymatic treatment exhibit both nutritional and therapeutic potentials. Despite this, the application of enzyme-treated C. firma leaf residues in functional food development has received limited attention. According to existing research, these residues are abundant in health-promoting compounds, such as antioxidants and polyphenols. Moreover, preliminary in vitro studies have suggested their potential to alleviate gut microbiota-modulatory problems. Expanding studies in this field could support the future use of enzyme-treated C. firma residues as valuable components in functional food formulations. This study aims to detail the bioactive profiles and nutraceutical potential of various enzyme-treated C. firma leaf residues and assess their applicability in health-oriented food products.

Activity-guided isolation of sesquiterpene coumarins from Ferula assa-foetida as monoamine oxidase inhibitors: Investigation on their therapeutic implications in a mice model of Parkinson's disease.

Anti-NSCLC efficacy of a novel ROR1/PI3Kα/BRD4 multi-target inhibitor.