Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

Background Severe acute pancreatitis (SAP) manifests as a critical state marked by acute abdominal symptoms, often associated with intestinal barrier dysfunction, exacerbating SAP retroactively. Ganoderic acid A (GAA) demonstrates anti-inflammatory properties in various inflammatory disorders. Nonetheless, its potential therapeutic impact on SAP and the underlying mechanisms remain unexplored. Methods In both wild-type and TLR4^-/- mice, experimental SAP was induced using caerulein plus lipopolysaccharide. Caerulein injections were administered intraperitoneally following 7 days of intragastric GAA administration. Additionally, the potential mechanisms by which GAA ameliorates SAP were further investigated using fecal microbiota transplantation and TLR4-overexpressing IEC-6 cells. Results We observed that GAA treatment significantly ameliorated serum levels of amylase, lipase, and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in SAP mice. Pretreatment with GAA mitigated pathological injuries and reduced M1 macrophage and neutrophil infiltration in pancreatic or ileal tissues. Additionally, GAA treatment down-regulated TLR4-MAPK/NF-κB signaling and NLRP3 inflammasome activation in the pancreatic and ileal tissues of SAP mice. The results further revealed that the gavage of GAA decreased bacterial translocation (Escherichia coli and EUB338), repaired intestinal barrier dysfunction (ZO-1, occludin, DAO, and FITC), increased lysozyme and MUC2 expression, and raised the levels of short-chain fatty acids. Analysis of the gut microbiome showed that the beneficial effects of GAA treatment were associated with improvements in pancreatitis-associated gut microbiota dysbiosis, characterized by notable increases in α-diversity and the abundance of probiotics such as Akkermansia, GCA-900066575, and Parvibacter. Fecal transplantation experiments further confirmed that GAA exerts protective effects by modulating intestinal flora. The protective role of GAA in intestinal and pancreatic injuries is mediated by the inhibition of TLR4 signaling, as further evidenced in TLR4-deficient mice and TLR4-overexpressed IEC-6 cells. The results of docking indicated that GAA interacts with TLR4 via a hydrophobic interaction. Conclusions The study demonstrates that GAA significantly alleviates SAP through its anti-inflammatory and antioxidant capacities, as well as by restoring intestinal homeostasis, thereby providing insights into novel treatments for SAP.

Gynecological cancers seriously affect the reproductive system of females; diseases include ovarian tumors, uterine tumors, endometrial cancers, cervical cancers, and vulva and vaginal tumors. At present, the diagnosis methods of gynecological cancer are insufficiently sensitive and specific, leading to failure of early disease detection. N⁶-methyladenosine (m⁶A) plays various biological functions in RNA modification and is currently studied extensively. m⁶A modification controls the fate of transcripts and regulates RNA metabolism and biological processes through the interaction of m⁶A methyltransferase (“writer”) and demethylase (“erasers”) and the binding protein decoding m⁶A methylation (“readers”). In the field of epigenetics, m⁶A modification is a dynamic process of reversible regulation of target RNA through its regulatory factors. It plays an important role in many diseases, especially cancer. However, its role in gynecologic cancers has not been fully investigated. Thus, we review the regulatory mechanism, biological functions, and therapeutic prospects of m⁶A RNA methylation regulators in gynecological cancers.

Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the “ClinicalTrials.gov” for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.

Background: Liver cancer is a highly malignant disease and the third leading cause of cancer death worldwide. Abnormal activation of PI3K/Akt signaling is common in cancer, but whether phosphoinositide‐3‐kinase regulatory subunit 3 (PIK3R3) plays a role in liver cancer is largely unexplored.Methods: We determined the expression of PIK3R3 in liver cancer by using TCGA data and our clinical samples and knocked it down by siRNA or overexpressing it by the lentivirus vector system. We also investigated the function of PIK3R3 by colony formation, 5‐Ethynyl‐2‐Deoxyuridine, flow cytometry assay, and subcutaneous xenograft model. The downstream of PIK3R3 was explored by RNA sequence and rescue assays.Results: We found that PIK3R3 was significantly upregulated in liver cancer and correlated with prognosis. PIK3R3 promoted liver cancer growth in vitro and in vivo by controlling cell proliferation and cell cycle. RNA sequence revealed that hundreds of genes were dysregulated upon PIK3R3 knockdown in liver cancer cells. CDKN1C, a cyclin‐dependent kinase inhibitor, was significantly upregulated by PIK3R3 knockdown, and CDKN1C siRNA rescued the impaired tumor cell growth. SMC1A was partially responsible for PIK3R3 regulated function, and SMC1A overexpression rescued the impaired tumor cell growth in liver cancer cells. Immunoprecipitation demonstrated there is indirect interaction between PIK3R3 and CNKN1C or SMC1A. Importantly, we verified that PIK3R3‐activated Akt signaling determined the expression of CDKN1C and SMC1A, two downstream of PIK3R3 in liver cancer cells.Conclusion: PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDNK1C and SMC1A. Targeting PIK3R3 could be a promising treatment strategy for liver cancer that deserves further investigation.