Ji Zhong Zhao

Background: Diabetes is associated with increased colorectal cancer (CRC) risk and mortality, but the molecular links remain incompletely understood. We aimed to characterize shared molecular features of diabetes and CRC, and identify compounds capable of modulating the candidate axis at this interface. Methods: Shared disease-associated genes were identified using integrated bioinformatics and protein-protein interaction network analysis, followed by analyses of TCGA and single-cell RNA-sequencing data. Deep learning-based (DeepPurpose) and structure-based (AutoDock Vina) virtual screening were used to prioritize multi-target ligands. Binding was assessed by surface plasmon resonance (SPR) and molecular dynamics simulations. Cellular effects were evaluated in a diabetic-mimetic model using high glucose, insulin, and palmitic acid (three factors; TF), with HCT116 cells and THP-1-derived macrophages. Results: The IL1β-CXCL8-CXCR2 axis was prioritized as a candidate inflammatory module at the diabetes-CRC interface. TCGA and single-cell RNA-seq analyses associated axis-related expression with immune infiltration and macrophage polarization-related transcriptional signatures; higher axis expression was also associated with longer overall survival. Hupehenine (HU), a steroidal alkaloid, was identified as a multi-target ligand engaging IL1β, CXCL8, and CXCR2. SPR showed concentration-dependent binding (KD: CXCR2, 505 nM; CXCL8, 2.2 μM; IL1β, 12.7 μM) and interference with CXCL8-CXCR2 binding. In a diabetic-mimetic model, HU reduced HCT116 cell viability, migration, and invasion. TF-conditioned cells were more sensitive to HU than non-TF cells, whereas a corresponding increase in sensitivity was not observed for 5-fluorouracil or oxaliplatin. HU also decreased M2-associated and increased M1-associated macrophage markers. Conclusion: These findings support the IL1β-CXCL8-CXCR2 axis as a candidate immunomodulatory module at the diabetes-CRC interface and identify HU as an in vitro multi-target ligand. The observed changes in macrophage markers and differential sensitivity under diabetic-mimetic conditions warrant further mechanistic and preclinical evaluation, including direct assessment of macrophage function.

Thermal processing of foods generates hepatotoxic dietary advanced glycation end products (dAGEs), with Nε-carboxymethyl-lysine (CML) serving as a primary carcinogen. Chronic exposure to physiologically relevant CML concentrations (25 μg/mL) induced centrosome amplification (CA)─a hallmark of genomic instability─in human hepatocytes (THLE2/THLE3), driving malignant transformation marked by 5-fold increased proliferation, 3-fold enhanced migration, and murine tumorigenicity. Critically, CML-treated cells exhibited 8-10-fold higher CA frequencies, with CA-positive subpopulations showing elevated oncogenicity. Mechanistically, CML activated the PLK1-CEP20-CCDC116 axis through EGR1-mediated PLK1 transcriptional upregulation and DNMT3B-suppression-driven CEP20 promoter hypomethylation, culminating in the PLK1-dependent phosphorylation of CEP20 at Ser46. This post-translational modification enabled high-affinity CCDC116 binding and centrosomal recruitment, driving centriole overduplication. Critically, both the CEP20-S46A mutation and CCDC116 knockdown abolished centrosomal localization and CA induction. These findings establish exogenous CML as a direct inducer of organelle-level carcinogenesis and provide molecular targets for developing food safety interventions against thermally processed food toxicity.

Aim: In the present study, the natural products levistolide A (LA) and periplogenin (PPG) were studied for their growth inhibitory effects on the development of gastric cancer cells in vitro and, more critically, in vivo, alone or in combination with the therapeutic medication 5-fluorouracil (5-FU). Methods: Methyl thiazolyl tetrazolium (MTT), also known as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays were used for the cell viability study. Apoptosis was detected by western blot to detect the cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick-end labelling (TUNEL) assays. The nude mice bearing gastric cancer cells were used for the anti-cancer activity detection of LA and its combinational treatment effect with 5-FU. Results: The results in the present study shown that the two compounds were able to inhibit the viability of the cancer cells in a dose- and time-dependent manner by MTT method. They could trigger apoptosis when used alone, and more potently, in combination with 5-FU detected by TUNEL positivity and the cleavage of caspase substrate PARP. In nude mice bearing gastric cancer cells, injection (i.p.) of LA or PPG alone inhibited the growth of the cancer cells. The treatment using one of the compounds in combination with 5-FU inhibited the cancer cell growth at a higher level than the treatment by a compound alone. Conclusions: LA and PPG could inhibit the growth of the cancer cells, alone or in combination with 5-FU, in vitro and in vivo, suggesting that they are promising investigational drugs for therapeutic development.

Background Hexavalent chromium can promote centrosome amplification (CA) as well as tumorigenesis. Since CA can lead to tumorigenesis, it is plausible that the chromium promotes the development of cancer via CA. In the present study, we investigated the signaling pathways of the chromium-induced CA. Results Our results showed that sub-toxic concentration of chromium was able to cause CA in HCT116 cells, and decreased the expression of TMOD2 and NPM2. Furthermore, TMOD2 and NPM2 interacted to each other via their C-terminal and the N-terminal, respectively, which was inhibited by the chromium. Overexpression of TMOD2 and NPM2 increased their binding and significantly attenuated the CA. Moreover, TMOD2 and NPM2 were co-localized with the centrosomes. The chromium inhibited the centrosomeal localization of NPM2, which is reversed by the overexpression of TMOD2, C-termianl of TMOD2, but not the N-terminal of NPM2. Conclusion Our results suggest that the chromium induces CA via inhibiting the binding between TMOD2 and NPM2, and the dissociation of NPM2 from centrosomes.

Objective: Diabetes increases the risk for cancers. However, whether it is associated with hematologic malignancies is not clear. The present study investigated the association between diabetes and acute lymphocytic leukemia (ALL), acute myeloid leukemia (ML), non-Hopkin lymphoma (NHL), and multiple myeloma (MM). Methods: Newly diagnosed adult cancer patients were recruited consecutively from our clinical database. Peoples from a local enterprise were recruited to create a small-scale population-based dataset. We compared the diabetes prevalence between the cancer patients and the local people; an increase in diabetes prevalence in the cancer patients suggests an association between diabetes and the cancer(s). Results: We found that the prevalence of diabetes was 19.7%, 21.3%, 12.5%, and 12.0% in ALL, AML, NHL, and MM, respectively, which was higher than that (9.1%) in the local people. Despite that there were more male than female cancer patients, there were more female than male diabetic patients. The increase in diabetes prevalence occurred in ALL and NHL patients aged 18 to 39 years old as well as in AML patients over 40. In MM patients, the increase in diabetes prevalence (18.6%) occurred only in females. Approximately 70% of the diabetic patients were undiagnosed before the diagnosis of the blood cancer. Approximately half of the pre-existing diabetic patients had anti-diabetic treatment, with over 70% of them still had poor glycemic control. Conclusions: Our results suggest that diabetes is associated with ALL, AML, NHL, and MM, at least in adult patients.