Chemical investigation on a marine sponge, Dactylospongia elegans, yielded five new γ-oxygenated butenolide sesterterpene derivatives, dactylospenes A–E (1–5), as well as two known biosynthetically related compounds, luffariellolide (6) and furospinosulin B (7). The structures of these compounds were elucidated on the basis of their spectroscopic data, experimental and calculated electronic circular dichroism (ECD) analysis, as well as comparison of the NMR data with those of known analogs. These metabolites are the first γ-oxygenated butenolide sesterterpenes to be reported from this genus. These compounds were evaluated in antimicrobial, anti-inflammatory, and cytotoxic assays. Only compounds 1, 3, and 6 exhibited moderate cytotoxicity against DU145, SW1990, Huh7, and PANC-1 cancer cell lines with IC₅₀ values in the range of 2.11–13.35 μM. Furthermore, compound 2, without cytotoxicity, exhibited significant inhibitory effects (inhibitory rate 77.5%) on nitric oxide production induced by lipopolysaccharide at 10 μM.

Purpose: The 8th edition of the American Joint Committee on Cancer (AJCC) tumor-lymph node-metastasis (TNM) staging system for gallbladder cancer (GBC) recommended that at least six lymph nodes (LNs) should be examined. But most patients with GBC had fewer than six LNs resected. This study aimed to establish an alternative index for assessing the LN status during the staging system for GBC patients with fewer than six LNs retrieved. Patients and Methods: Patient data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database (cases between 2004 and 2013). X-tile software was used to determine the optimal cutoff value for lymph node ratio (LNR) and a concordance index (C-index) was used to evaluate the discriminatory powers of the two staging systems. Results: The majority of GBC patients in our cohort (1353, 78.5%) had fewer than six LNs examined. Among patients with inadequate LN examination, the higher number of LNs examined correlated with a lower proportion of patients. Using the TNM staging system, the C-index for patients with fewer than six LNs and patients with six or more LNs screened were 0.636 and 0.704, respectively. Using the staging system based on LNR (TNrM), the C-index for patients with fewer than six LNs retrieved and patients with six or more LNs retrieved were 0.649 and 0.694, respectively. Similar results were observed in patients with gallbladder adenocarcinoma (GBA). Conclusion: TNrM might be superior to the 8th AJCC TNM staging system for stratifying GBC patients with fewer than six LNs examined, and it can complement TNM for more accurate risk stratification. Future prospective studies are needed to validate our findings.

Background: Nephrolithiasis seriously affects people’s health with increasing prevalence and high recurrence rates. However, there is still a lack of effective interventions for the clinical prevention of kidney stones. Hyperoxaluria-induced renal tubular epithelial cell (TEC) injury is a known key factor in kidney stone formation. Thus, developing new drugs to inhibit the hyperoxaluria-induced TEC injury may be the best way. Methods: We synthesized the Se@SiO₂ nanocomposites as described in Zhu’s study. The size and morphology of the Se@SiO₂ nanocomposites were captured by transmission electron microscopy. Cell viability was measured by a Cell Counting Kit-8 (CCK-8) assay. The mice were randomly divided into the following four groups: (I) the control group (n=6); (II) the Se@SiO₂ group (n=6); (III) the glyoxylic acid monohydrate (GAM) group; and (IV) the GAM + Se@SiO₂ group (n=6). The concentration of Se in the mice was quantified using inductively coupled plasma atomic emission spectroscopy. Results: The CCK-8 assays showed that Se@SiO₂ nanocomposites had almost no obvious cytotoxicity on the Transformed C3H Mouse Kidney-1 (TCMK-1) cell. The mice kidney Se concentration levels in the Se@SiO₂ groups (Se@SiO₂ 6.905±0.074 mg/kg; GAM + Se@SiO₂ 7.673±2.85 mg/kg) (n=6) were significantly higher than those in the control group (Control 0.727±0.072 mg/kg; GAM 0.747±0.074 mg/kg) (n=6). The Se@SiO₂ nanocomposites reduced kidney injury, calcium oxalate crystal deposition, and the osteoblastic-associated proteins in the hyperoxaluria mice models. Conclusions: Se@SiO₂ nanocomposites appear to protect renal TECs from hyperoxaluria by reducing reactive oxygen species production, suggesting the potential role of preventing kidney stone formation and recurrence.

Worldwide, lung cancer is the most common cause of cancer-related death, which is made worse by the development of drug resistance during treatment. It is urgent to develop new therapeutic methods and small molecule drugs for tumor resistance. Chaetocin, extracted from Chaetomium minutum, is a natural compound with good antitumor activity. However, there are few studies on its tumor resistance. In this paper, firstly, chaetotocin significantly inhibited the viability and migration of cisplatin-resistant non-small cell lung cancer (NSCLC) cells and inhibited the xenograft growth of nude mice. Chaetocin at 4 mg/kg significantly inhibited A549/DDP xenograft growth with an inhibition rate of 70.43%. Subsequently, the underlying mechanism behind the actions of chaetocin was explored. It was discovered that chaetocin can inhibit transketolase (TKT), thereby inhibiting the growth of NSCLC cells and inducing cell death. Compared with cisplatin-sensitive cells, a lower concentration of chaetocin can inhibit cisplatin-resistance cell viability and migration. Mechanistically, TKT was identified as a potential target for chaetocin. The KD value of the interaction between chaetocin and TKT was 63.2 μM. An amount of 0.2 μM chaetocin may suppress the enzyme activity and expression level of TKT. We found the TKT expression is higher in cisplatin-resistant cells, which further explains why these cells were more vulnerable to chaetocin in terms of cell phenotype. Additionally, the muti-omics analysis and RNA interference suggested that chaetocin can inhibit the PI3K/Akt signaling pathway through TKT. In conclusion, chaetocin could directly bind to TKT, inhibiting its enzyme activity and expression, which interfered with intracellular metabolism and oxidation-reduction balance, and then regulated the PI3K/Akt signaling pathway to inhibit the growth of NSCLC and induce apoptosis.

The incidence and mortality rates of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are gradually increasing worldwide. Numerous studies have demonstrated that N-methyl-D-aspartic acid receptor (NMDAR)-mediated excitotoxicity contributes to neurodegenerative diseases. Ifenprodil, a subtype-selective NMDAR antagonist, showed strong therapeutic potential. However, it suffers from low oral bioavailability and off-target side effects. In this study, natural compounds were identified for selective inhibition of GluN1/GluN2B NMDAR of human. We obtained a set of natural compounds (n = 81,366) from COCONUT, TIPdb, PAMDB, CMNPD, YMDB, and NPAtlas databases, and then virtually screened by an ifenprodil-structure-based pharmacophore model and molecular docking. The top 100 compounds were selected for binding affinity prediction via batch drug-target affinity (BatchDTA). Then, the top 50 compounds were analyzed by absorption, distribution, metabolism, excretion, toxicity (ADMET). Molecular dynamics involving molecular mechanics/position-Boltzmann surface area (MM-PBSA) calculation were performed to further screening. The top 15 compounds with strong binding affinity and ifenprodil, a proven GluN2B-selective NMDAR antagonist, were subjected to molecular dynamic simulations (100 ns), root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), H-bonds, solvent accessible surface area (SASA), principal component analysis (PCA), and binding free energy calculations. Based on these analyses, one possible lead compound carrying positive charges (CNP0099440) was identified, with great binding affinity and less off-target activity by contrast to ifenprodil. CNP0099440 has great potential to be a GluN1/GluN2B NMDAR antagonist candidate and can be further detected via in vitro and in vivo experiments.

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