Explore the vast range of titles available.

Purpose Glioblastoma (GBM) is a challenging malignancy with a poor prognosis. While the neutrophil-to-lymphocyte ratio (NLR) is reported to correlate with the prognosis, the significance of changes in the NLR and its prognostic value in GBM remain unclear. This study aims to evaluate changes in the NLR and its predictive value for GBM prognosis and recurrence. Methods The cohort included 69 newly-diagnosed GBM patients undergoing a standard treatment protocol. NLR was assessed at multiple time points. The dynamic change in NLR (dNLR), defined as the NLR at the point of interest (post-CCRT or post-Stupp) divided by the preoperative NLR, also was assessed. Univariate and multivariate COX regression analyses were conducted to assess the association between the NLR, dNLR and overall survival (OS) and progression-free survival (PFS). Results Univariate analysis revealed that age at diagnosis ≥ 70 ( p  = 0.019) and post-Stupp dNLR ≥ 1.3 ( p  = 0.006) were significantly associated with shorter OS. Significant correlations were found between pre-operative KPS ≥ 60 ( p  = 0.017), gross total resection ( p  = 0.042), post-Stupp dNLR ≥ 1.3 ( p  = 0.043) and PFS. Multivariate analysis showed age at diagnosis ≥ 70, pre-operative KPS ≥ 60, post-Stupp NLR ≥ 5 and dNLR ≥ 1.3 were significantly associated with a shorter OS. Significant correlation was found between pre-operative KPS ≥ 60 and PFS. Conclusion This study revealed that post-Stupp NLR ≥ 5 and dNLR ≥ 1.3 correlated significantly with a worse glioblastoma prognosis in OS, and dNLR might be more reliable. These two parameters are potentially surveilling markers for glioblastoma recurrence, however further studies are warranted.

This study investigated the clinical significance of postoperative neutrophil-to-lymphocyte ratio (NLR) changes in bladder cancer recurrence. For evaluating the predictive value of postoperative dynamic change of NLR, a retrospective cohort study was performed to analyze 213 patients with bladder cancer who underwent surgical treatment from January 2013 to December 2019 at the Affiliated Tumor Hospital of Guangxi Medical University. Baseline characteristics and recurrence-free survival (RFS) were statistically compared, and a multivariate analysis was used to identify prognostic factors. Compared with preoperative NLR levels, postoperative decreased NLR in 130 patients and postoperative increased NLR in 83 patients were detected. The 1-, 3- and 5-year RFS rates were 88.0%, 75.4% and 75.4% in the decreased postoperative NLR group, respectively, and 51.2%, 25.8% and 16.1% in the increased postoperative NLR group, respectively (P < 0.05). Kaplan-Meier curves showed that the cumulative DFS rate in the increased group was significantly lower than that in the decreased group (P < 0.05). The preoperative NLR showed significant difference with postoperative NLR in the total cohort, high-grade non-muscle-invasive bladder cancer (HG-NMIBC) and muscle-invasive bladder cancer (MIBC) group, while there was no significant difference between postoperative NLR and NLR of recurrence or last follow-up. Multivariate analysis suggested that postoperative-preoperative NLR was an independent predictor for RFS (HR=6.206, 95% CI: 3.826-10.067, P < 0.001) in the total cohort, RFS (HR=9.373, 95% CI: 2.724-32.245, P < 0.001) in the LG-NMIBC group, RFS rates (HR=6.873, 95% CI: 2.486-18.999, P < 0.001) in the HG-NMIBC group and RFS rates (HR=6.109, 95% CI: 2.847-13.109, P < 0.001) in the MIBC group. The dynamic change of postoperative NLR is a potential marker for the early detection of bladder cancer recurrence. Patients with increased NLR after surgery tend to have higher risk of recurrence.

Elevated neutrophil-lymphocyte ratio (NLR) has been reported to be a poor prognostic factor in patients with colorectal cancer (CRC). However, no studies have focused on the dynamic change of preoperative NLR (pre-NLR) in CRC patients. We investigated the prognostic value of the change in NLR (ΔNLR) in CRC patients before and after surgery. We retrospectively analyzed the data from 307 patients with stage II or III CRC. We compared the clinicopathological factors, OS, and DFS among the various NLR factors. The 5-year OS rate of the high ΔNLR group was significantly lower than that of the low ΔNLR group (p<0.01). The 5-year DFS rates of the high ΔNLR groups were worse than those in the low ΔNLR groups. In the multivariate analysis, ΔNLR was an independent prognostic factor (p=0.011). Decreasing post-NLR was related to better OS and DFS even in high pre-NLR patients with CRC.

Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.

Neuroinflammation, mediated by NLR family pyrin domain containing 3 (NLRP3) inflammasome, plays a crucial role in the development of many central nervous system (CNS) diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and stroke. Despite extensive efforts, there are no clinically approved NLRP3 inhibitors due to issues like poor selectivity, undesirable drug-like properties, and safety concerns. In this study, a machine learning-based virtual screening strategy was used to identify phytochemicals that inhibit the NLRP3 NACHT domain, a key region involved in ATP-driven oligomerization and inflammasome activation. A carefully curated set of 1,956 active compounds and 5,476 inactive ones was employed to train various classifiers, with the Random Forest model demonstrating the best predictive performance (AUC = 0.83). This enhanced model was applied to analyze the MPD3 phytochemical library, resulting in 183 drug-like candidates. Molecular docking revealed that PubChem 348,482, ZINC14583344, and PubChem 11,027,076 showed excellent binding affinities (–10.6 to − 11.3 kcal/mol), forming strong interactions with key residues (Ala228, Arg578, Glu629) known to influence NLRP3 conformational dynamics. ADMET analysis confirmed favorable pharmacokinetic and safety profiles, while molecular dynamics simulations over more than 100 ns verified the stability of the protein-ligand complexes through consistent RMSD, RMSF, and hydrogen bonding patterns of ZINC14583344. MM-GBSA free energy calculations further identified ZINC14583344 (–23.99 kcal/mol) as the most promising candidate. Additionally, Density Functional Theory (DFT) analysis indicated that ZINC14583344 has a smaller HOMO–LUMO gap, higher softness, and greater electrophilicity, suggesting superior reactivity and receptor binding flexibility. Conversely, PubChem 348,482 displayed a higher dipole moment and nucleophilicity, indicating stronger hydrogen bonding and electrostatic interactions with polar residues. Collectively, these findings highlight ZINC14583344 and PubChem 348,482 as promising scaffolds for developing selective NLRP3 inhibitors, providing a basis for therapeutic strategies against neuroinflammation-related CNS disorders.

The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure. Ultimately, studies continue to reveal how the ATP-binding and hydrolysis properties of NACHT domains in different NLRs integrate with signaling modules and binding partners to control innate immune responses at the molecular level.

NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) activation has been linked to several chronic pathologies, including atherosclerosis, type-II diabetes, fibrosis, rheumatoid arthritis, and Alzheimer’s disease. Therefore, NLRP3 represents an appealing target for the development of innovative therapeutic approaches. A few companies are currently working on the discovery of selective modulators of NLRP3 inflammasome. Unfortunately, limited structural data are available for this target. To date, MCC950 represents one of the most promising noncovalent NLRP3 inhibitors. Recently, a possible region for the binding of MCC950 to the NLRP3 protein was described but no details were disclosed regarding the key interactions. In this communication, we present an in silico multiple approach as an insight useful for the design of novel NLRP3 inhibitors. In detail, combining different computational techniques, we propose consensus-retrieved protein residues that seem to be essential for the binding process and for the stabilization of the protein–ligand complex.

Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection. Systemic sepsis is a potentially life-threatening illness and immunocompromised individuals are especially vulnerable. Here, using a cohort of patients with intra-abdominal origin sepsis, the authors show an important role for the NLRP3 inflammasome in establishing a host response, and NLRP3 dysfunction is a common feature of sepsis mortality.

NOD-like receptor protein 3 (NLRP3) inflammasome is a key mediator of inflammation and a promising therapeutic target. However, the discovery of novel and effective inhibitors of NLRP3 remains limited. A combined docking-based virtual screening (DBVS) and shape-based screening approach was applied to eight traditional Chinese medicine (TCM) databases to identify potential NLRP3 inhibitors. Structural similarity analysis, ADMET prediction, and molecular dynamics (MD) simulations were performed to evaluate structural novelty, pharmacokinetic properties, and binding stability. A total of 25 potential NLRP3 inhibitors were identified, each exhibiting docking scores higher than those of the reference inhibitor XE3. Structural similarity analysis revealed that the screened compounds exhibited low similarity to previously reported NLRP3 inhibitors, demonstrating their structural novelty. ADMET evaluation indicated that compounds C2, C3, and C4 exhibited favorable physicochemical and pharmacokinetic properties. Molecular dynamics (MD) simulations demonstrated that the complexes of compounds C2, C3, and C4 with NLRP3 remained stable throughout the simulations, exhibiting limited backbone fluctuations and compact conformations, as indicated by Rg values of approximately 6 Å. Solvent-accessible surface area (SASA) and polar surface area (PSA) analyses suggested that compounds C3 and C4 were tightly solvated and maintained favorable membrane permeability. Notably, binding free energy calculations revealed that all three compounds exhibited stronger binding than XE3, with compound C3 showing the most favorable energy (–48.81 ± 3.89 kcal/mol), indicating a highly stable and energetically preferred interaction with NLRP3. This study identified promising TCM-derived compounds as potential NLRP3 inhibitors, offering new directions for anti-inflammatory drug development.

The NLRP3 inflammasome is a multiprotein complex that primes cytokine production in the innate immune system. The inflammasome activation involves the cage-to-disk transition of NLRP3 oligomers, facilitated by the co-factor NEK7 protein. While NEK7's role in promoting cage disassembly has been reported, its involvement in the large conformational changes of the NLRP3 monomer during activation remains elusive. Here, by using multi-scale simulations, we uncovered a stage-dependent role of NEK7 in the inactive-to-active transition. In the early stage, NEK7 reshapes the dynamics of the highly unstable inactive NLRP3 monomer to resemble active state, priming the conformational transition. In the middle stage, NEK7 impedes progression by populating an intermediate state farther from the active conformation than the NEK7-free counterpart, and structures in this state exhibit reduced allosteric potential toward activation. In the late stage, NEK7 has negligible impact, as the active conformation remains inherently isolated by a high energy barrier regardless of NEK7 presence. This highlights the critical role of oligomeric assembly in enabling monomeric NLRP3 to complete its conformational transition, in agreement with experiment observations. Our work suggests a multilayered activation mechanism where oligomer-level assembly and monomeric conformational changes are coupled, providing new mechanistic insights into this physiologically essential macromolecular process.