Significance: Our work reveals the genome-wide prevalence of G4 structural variations (G4Vs) associated with single-nucleotide variations (SNVs) in the human genome and how such G4Vs interact with gene-regulatory elements and subsequently affect the activities of genes accommodating the G4Vs. The G4Vs are enriched in genes around transcription start sites, implying their potential involvement in gene expression. Because G4 structures participate in essential physiological and pathological processes, the G4Vs should make crucial contributions to the genotype and phenotype connection and serve as potential therapeutic targets for personalized remedies and medicine.

Pancreatic cancer is a fatal malignancy worldwide and urgently requires valid therapies. Previous research showed that the HDAC inhibitor chidamide is a promising anti-cancer agent in pancreatic cancer cell lines. In this study, we elucidate a probable underlying anti-cancer mechanism of chidamide involving the degradation of Mcl-1. Mcl-1 is frequently upregulated in human cancers, which has been demonstrated to participate in oxidative phosphorylation, in addition to its anti-apoptotic actions as a Bcl-2 family member. The pancreatic cancer cell lines BxPC-3 and PANC-1 were treated with chidamide, resulting in Mcl-1 degradation accompanied by induction of Mcl-1 ubiquitination. Treatment with MG132, a proteasome inhibitor reduced Mcl-1 degradation stimulated by chidamide. Chidamide decreased O₂ consumption and ATP production to inhibit aerobic metabolism in both pancreatic cancer cell lines and primary cells, similar to knockdown of Mcl-1, while overexpression of Mcl-1 in pancreatic cancer cells could restore the aerobic metabolism inhibited by chidamide. Furthermore, chidamide treatment or Mcl-1 knockdown significantly induced cell growth arrest in pancreatic cancer cell lines and primary cells, and Mcl-1 overexpression could reduce this cell growth inhibition. In conclusion, our results suggest that chidamide promotes Mcl-1 degradation through the ubiquitin-proteasome pathway, suppressing the maintenance of mitochondrial aerobic respiration by Mcl-1, and resulting in inhibition of pancreatic cancer cell proliferation. Our work supports the claim that chidamide has therapeutic potential for pancreatic cancer treatment.

Pancreatic cancer is a fatal human malignancy associated with an exceptionally poor prognosis. Novel therapeutic strategies are urgently required to treat this disease. In addition to immunosuppressive activity, triptolide possesses strong antitumor activity and synergistically enhances the antitumor activities of conventional chemotherapeutic drugs in preclinical models of pancreatic cancer. The present study investigated the antitumor effects of triptolide in pancreatic cancer cells, either in combination with gemcitabine, or alone. The pancreatic cancer BxPC‑3 and PANC‑1 cell lines were treated with triptolide, which resulted in time‑ and dose‑dependent growth arrest. When incorporated into a sequential schedule, triptolide synergistically increased gemcitabine‑induced cell growth inhibition and apoptosis, in addition to the cooperative regulation of B‑cell lymphoma 2 family proteins and loss of mitochondrial membrane potential. Furthermore, triptolide enhanced gemcitabine‑induced S phase arrest and DNA double‑strand breaks, possibly through checkpoint kinase 1 suppression. The results of the present study suggest that triptolide has therapeutic potential for the treatment of pancreatic cancer, particularly when administered in combination with gemcitabine.

The NOD-like receptor protein (NLRP)3 inflammasome plays a critical role in acute respiratory distress syndrome (ARDS) by activating caspase-1, which cleaves the precursor forms of IL-1β and IL-18 into active cytokines and induces pyroptosis by cleaving gasdermin D (GSDMD). LBH589, a pan-histone deacetylase inhibitor, exhibits promising anti-inflammatory and immunomodulatory properties. However, the protective effect and underlying mechanism of LBH589 against ARDS is still unclear. In this study, we aim to determine whether and how LBH589 inhibits NLRP3 inflammasome activation while exerting its anti-inflammatory effect. Our data demonstrated that LBH589 effectively suppressed NLRP3 inflammasome activation in lipopolysaccharides (LPS)-primed and adenosine triphosphate (ATP)-stimulated J774A.1 cells and bone marrow-derived macrophages (BMDMs), evidenced by attenuated cleaved caspase-1 and IL-1β, IL-18, IL-16 release, as along with reduced GSDMD-mediated pyroptosis and ASC speck formation. Additionally, LBH589 significantly decreased mitochondrial reactive oxygen species (mtROS) and oxidized mitochondrial DNA (Ox-mtDNA), key triggers of inflammasome activation. Importantly, both prophylactic and therapeutic administration of LBH589 inhibited the pro-inflammatory cytokines secretion in lung tissue and ameliorated lipopolysaccharide (LPS)-induced ARDS in mice. These findings suggest that LBH589 may provide therapeutic benefits in ARDS by attenuating NLRP3 inflammasome activation and pyroptosis.