Current Medicinal Chemistry - Volume 31, Issue 39, 2024

Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity.

This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed.

NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.

The clinical symptoms and laboratory markers of Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) can be very similar, so making a differential diagnosis between these two diseases is often difficult. Serological parameters to be used in differential diagnosis can guide the clinician. This study aimed to investigate the usability of 14-3-3η (eta) protein as a biomarker in the differential diagnosis of PsA and RA, and the relationships between eta protein and disease activity scores and joint erosions in PsA and RA.

54 PsA patients, 53 RA patients, and 56 healthy individuals were included in this study. The ELISA (Enzyme-Linked ImunoSorbent Assay) kit was used as a quantitative sandwich enzyme immunoassay technique to detect human eta protein levels. Receiver-operating Characteristic (ROC) curves analysis was used to determine the sensitivity and specificity of the eta protein.

Eta protein levels were found to be significantly higher in the RA group than in the PsA [B: -0.341, OR (95% CI): 0.711 (0.556-0.909), p: 0.007] and control [B: -0.225, OR (95% CI): 0.798 (0.641-0.995), p: 0.045] groups. Eta protein median values were significantly higher in patients with joint erosion than in those without [β= 0.151, OR (95% CI): 1.163 (1.003-1.349), p: 0.046].

Eta protein levels are higher in the serum of RA patients than PsA and are associated with joint erosion. Eta protein may be a potential biomarker in the differential diagnosis of RA and PsA. It may represent a possible therapeutic step in the pathophysiological pathways in the development of joint erosion.

Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities.

The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity.

The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Western Blotting, shRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mice xenograft assay, western blotting.

27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R² = 0.851627) by applying random forest algorithms. The optimal compound J3, which had better activity, concentration-dependently inhibited the formation of gastric cancer cell colonies and led to cell apoptosis by inducing the expression of the pro-apoptotic protein cleaved PARP in a dose-dependent manner. J3 may exert anti-gastric cancer effects by inhibiting the activation of FGFR1/ERK pathway. Moreover, at a dose of 10 mg/kg/day, J3 inhibited tumor growth in nude mice by nearly 70% in vivo with no significant toxic effect on body weight and organs.

In summary, this study outlines a viable method for the synthesis of novel asymmetric bis-chalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug.

Lung adenocarcinoma (LUAD) represents a significant global health issue. Smoking contributes to the development of periodontitis and LUAD. The connections between the two are still ambiguous.

Based on RNA expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, differentially expressed genes (DEGs) in Periodontitis and LUAD were collected. Protein-protein interaction (PPI) networks were produced by mining genes intersecting with crossover DEGs. Genes in the subnetwork and the top 15 genes of the topology score were defined as the crosstalk gene. Feature selection and diagnostic model construction were conducted based on Recursive Feature Elimination (RFE) and support vector machines (SVM). Additionally, we analyzed the immune cells and signaling pathways influenced by the crosstalk gene.

A total of 29 crossover DEGs between Periodontitis and LUAD were filtered, with 20 genes interacting with them in the PPI network. Five subnetworks with similar interaction patterns in the PPI network were detected. Based on the network topology analysis, genes ranking in the top 15 were used to take the intersection with those genes in the 5 subnetworks. Twelve intersecting genes were identified. Based on RFE and SVM algorithms, FKBP11 and MMP13 were considered as the Crosstalk genes for both Periodontitis and LUAD. The diagnostic model composed of FKBP11 and MMP13 showed excellent diagnostic potential. In addition, we found that FKBP11 and MMP13 influenced Macrophages, M1, T cells, CD8 activity, immune-related pathways, and cell cycle pathways.

We identified the crosstalk genes (FKBP11 and MMP13) between periodontitis and LUAD. The two genes affected the comorbidity status between the two diseases through immune cell activity.