Qian Zhou

Background: Diabetic nephropathy (DN) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease. Chronic inflammation plays a pivotal role in the pathogenesis of DN. Lycorine (LY), a complex tetracyclic pyrrolo [de] phenanthridine alkaloid derived from the Amaryllidaceae family, possesses notable anti-inflammatory activity, yet its therapeutic potential in DN remains insufficiently defined. Methods: We evaluated the renoprotective effects of LY both in vivo and in vitro. Streptozotocin (STZ)-induced diabetic mice were treated with LY, and renal function and histopathological alterations were assessed. In vitro, human renal tubular epithelial HK-2 cells were exposed to high glucose plus palmitic acid (HG + PA) with or without LY. RNA-seq analysis was performed to identify LY-regulated pathways. Molecular docking, surface plasmon resonance (SPR) assay, and cellular thermal shift assay (CETSA) were used to evaluate the interaction between LY and receptor for advanced glycation end products (RAGE). RAGE siRNA-mediated knockdown was further conducted to determine whether RAGE is required for the protective effects of LY. Activation of the HMGB1/RAGE/NF-κB signaling axis and associated inflammatory mediators was analyzed by Western blotting and RT-PCR. Results: LY markedly alleviated renal injury in STZ-induced diabetic mice, as evidenced by reduced albuminuria, improved renal function, and attenuated renal fibrosis, apoptosis, oxidative stress, and inflammation. Notably, LY did not significantly alter blood glucose levels or body weight, indicating that its renoprotective effect was independent of glycemic control. In HG + PA-treated HK-2 cells, LY significantly suppressed apotosis, oxidative stress, and inflammatory cytokine expression. Mechanistically, RNA-seq analysis identified AGE-RAGE and NF-κB signaling pathways as key pathways modulated by LY. Molecular docking, SPR, and CETSA confirmed that LY directly interacted with RAGE. Moreover, RAGE knockdown largely abolished the additional protective effects of LY, supporting RAGE as a critical molecular target. LY inhibited HMGB1/RAGE-mediated NF-κB activation, as reflected by reduced HMGB1, RAGE, p-p65, and p-IκBα levels. Conclusion: LY ameliorates diabetic nephropathy without affecting blood glucose levels by directly targeting RAGE and suppressing the HMGB1/RAGE/NF-κB signaling axis. These findings identify LY as a potential RAGE-targeting therapeutic candidate for inflammation-driven diabetic kidney injury.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death, which indicates that efficient intervention agents or strategies against HCC are urgently needed. In the present study, we firstly found that a combination of gefitinib (an epidermal growth factor receptor (EGFR) inhibitor) and BI6727 (a polo-like kinase 1 (PLK1) inhibitor) could significantly inhibit cell proliferation of HCC cells, which attenuated acquired resistance of gefitinib in HCC cells. Interestingly, our results showed that these anti-tumor effects of gefitinib in combination with BI6727 were associated with G2/M arrest. Moreover, further study revealed that BI6727 could downregulate the protein levels of cell division cycle 25C (Cdc25C) via ubiquitination-dependent pathway, which subsequently induced G2/M arrest. Furthermore, two critical checkpoints proteins ataxia telangiectasia-mutated (p-ATM)/ ATM and Rad-3 related(p-ATR) and another hallmark phosphorylated H2AX (gamma-H2AX) of DNA damage were positively regulated in HCC cells exposed to gefitinib in combination with BI6727. These results indicated that co-treatment induced G2/M arrest was closely related to DNA damage. In summary, the present study discov-ered that gefitinib synergizing with BI6727 could significantly facilitate DNA damage and overcome acquired resistance of HCC cells to gefitinib. Our study provides a promising approach for the combination of EGFR inhibitors and PLK1 inhibitors in the clinical treatment for HCC.

Osteosarcoma is the most prevalent bone cancer, and chemotherapy is still an indispensable treatment in its clinical practice. Cisplatin (CDDP) has become the most commonly used agent for osteosarcoma, although the outcomes of CDDP chemotherapy remain unsatisfactory because of frequent resistance. Here, we report on a promising combination therapy where curcumol, a bioactive sesquiterpenoid, enhanced CDDP-induced apoptosis to eradicate osteosarcoma cells, and revealed that M2-like macrophages might be the underlying associated mechanisms. First, we observed that curcumol enhanced the CDDP-mediated inhibition of cell proliferation and augmented the apoptosis in osteosarcoma cell lines. Curcumol contributed to preventing the migration of osteosarcoma cells when combined with CDDP. Moreover, this drug combination showed more potent tumor-growth suppression in the orthotopic transplantation of osteosarcoma K7M2 WT cells. We then estimated chemotherapy-associated drug-resistant genes, including ABCB1, ABCC1 and ABCG2, and found that curcumol significantly reversed the mRNA levels of CDDP-induced ABCB1, ABCC1 and ABCG2 genes in the tumor tissue. Moreover, M2-like macrophages were enriched in osteosarcoma tissues, and were largely decreased after curcumol and CDDP treatment. Taken together, these findings suggest that curcumol inhibits the polarization of M2-like macrophages and could be a promising combination strategy to synergize with CDDP in the osteosarcoma.

Brain tumors are the most widespread malignancies in children around the world. Chemotherapy plays a critical role in the treatment of these tumors. Although the current chemotherapy process has a remarkable outcome for a certain subtype of brain tumor, improving patient survival is still a major challenge. Further intensive treatment with conventional non-specific chemotherapy could cause additional adverse reactions without significant advancement in survival. Recently, patient derived brain tumor, xenograft, and whole genome analysis using deep sequencing technology has made a significant contribution to our understanding of cancer treatment. This realization has changed the focus to new agents, targeting the molecular pathways that are critical to tumor survival or proliferation. Thus, many novel drugs targeting epigenetic regulators or tyrosine kinase have been developed. These selective drugs may have less toxicity in normal cells and are expected to be more effective than non-specific chemotherapeutics. This review will summarize the latest novel targets and corresponding candidate drugs, which are promising chemotherapy for brain tumors according to the biological insights.

Forchlorfenuron (CPPU) is a plant growth regulator extensively used in agriculture. However, studies on CPPU pharmacokinetics are lacking. We established and validated a rapid, sensitive, and accurate liquid chromatography–mass spectrometry method for CPPU detection in rat plasma. CPPU pharmacokinetics was evaluated in adult and juvenile rats orally treated with 10, 30, and 90 mg/kg of the compound. The area under the plasma drug concentration–time curve from 0 to 24 h (AUC), at the final time point sampled (AUC_0–t), and the maximum drug concentration of CPPU increased in a dose-dependent manner. The pharmacokinetic parameters AUC_0–t and absolute bioavailability were higher in the juvenile rats than in adult rats. The mean residence time and AUC_0–t of juvenile rats in the gavage groups, except for the 10 mg/kg dose, were significantly higher in comparison to those observed for adult rats (p < 0.001). The plasma clearance of CPPU in juvenile rats was slightly lower than that in the adult rats. Taken together, juvenile rats were more sensitive to CPPU than adult rats, which indicates potential safety risks of CPPU in minors.

Emerging evidence indicates that M2-polarized tumor-associated macrophages (TAMs) directly participate in tumor initiation, progression and metastasis. However, to date, few studies have investigated novel strategies for inhibiting TAMs in order to overcome osteosarcoma. In this study, we reported that M2 macrophages were enriched in osteosarcoma tissues from patients, and M2-polarized TAMs enhanced cancer initiation and stemness of osteosarcoma cells, thereby establishing M2-polarized TAMs as a therapeutic target for blocking osteosarcoma formation. We also found that all-trans retinoic acid (ATRA) weakened TAM-induced osteosarcoma tumor formation by inhibiting M2 polarization of TAMs in vivo, and inhibited the colony formation, as well as sphere-formation capacity of osteosarcoma cells promoted by M2-type macrophages in vitro. Furthermore, M2-type macrophages enhanced cancer stem cells (CSCs) properties as assessed by increasing the numbers of CD117⁺Stro-1⁺ cells accompanied by the upregulation of CSC markers (CD133, CXCR4, Nanog, and Oct4), which could clearly be reduced by ATRA. Taken together, the results of this study demonstrated the role of M2-polarized TAMs in osteosarcoma initiation and stemness by activating CSCs, and indicated that ATRA treatment is a promising approach for treating osteosarcoma by preventing M2 polarization of TAMs.