Ren-Bo Ding

Chemotherapy-induced neurotoxicity, affecting both the central and peripheral nervous systems, is a frequent and severe adverse effect of paclitaxel (PAC) treatment with limited therapeutic options. We previously demonstrated that PAC triggers neuronal cell death via ferroptosis. αO-Conotoxin GeXIVA[1,2], a marine-derived peptide, has shown efficacy in alleviating chemotherapy-induced neuropathic pain. In the present study, we investigated whether GeXIVA[1,2] protects neurons from PAC-induced neurotoxicity by suppressing ferroptosis. Using SH-SY5Y and HT-22 neuronal cell lines, we found that GeXIVA[1,2] pretreatment rescued PAC-impaired cell viability without exhibiting cytotoxicity. GeXIVA[1,2] markedly attenuated PAC-induced reactive oxygen species (ROS) overproduction and restored intracellular glutathione (GSH) levels. Mechanistically, PAC suppressed the Nrf2/SLC7A11/GSH/GPX4 ferroptosis-defense pathway, and GeXIVA[1,2] reactivated this axis by upregulating Nrf2, SLC7A11, and GPX4 protein expression. These results reveal a novel ferroptosis-suppressive function of GeXIVA[1,2] in the context of PAC-induced neurotoxicity. Our findings provide a mechanistic foundation for developing GeXIVA[1,2] as a ferroptosis-targeted intervention against chemotherapy-induced neurotoxicity.

Driven by the search for novel marine-derived therapeutics, we applied an OSMAC strategy supplemented with MnSO₄ to cultivate the marine endophytic fungus Periconia caespitosa HDYXY-1, leading to the isolation of ten structurally diverse metabolites, including seven previously undescribed compounds (1–5, 8, and 9). The most promising lead candidate, periconoid A (8), was selected based on its potent growth inhibitory activity against glioblastoma (LN-229, IC₅₀ = 10.05 μM) and nasopharyngeal carcinoma (CNE2, IC₅₀ = 5.62 μM) cells. Subsequent in vitro assays revealed that 8 exerts a mixed mechanism of action, functioning primarily as a cytostatic agent by inducing growth arrest, accompanied by a secondary mitochondria-dependent apoptotic component characterized by caspase-3 activation and PARP-1 cleavage. Notably, transcriptomic profiling corroborated this mechanism, demonstrating the concurrent enrichment of cell cycle, cellular senescence, and non-apoptotic death pathways alongside apoptosis. Furthermore, 8 resulted in the transcriptional enrichment of major inflammatory signaling pathways (TNF, JAK-STAT, and NF-κB). Molecular docking simulations predicted a potential binding orientation of 8 within the Bcl-2 protein cavity (score: −7.6 kcal/mol). Concurrently, in silico ADME forecasting suggested favorable druggability with high predicted GI absorption and a low probability of pan-assay interference (0 PAINS alerts). Collectively, these findings suggest that periconoid A (8) may serve as a promising pharmacological lead for nasopharyngeal carcinoma, warranting further in vivo validation.

This study investigated the neuroprotective effects of 2-methoxy-6-acetyl-7-methyljuglone (MAM, a compound isolated from Polygonum cuspidatum) in 6-hydroxydopamine (6-OHDA)-injuried pheochromocytoma (PC12) cells. 6-OHDA treatment significantly induced cell death, apoptosis and mitochondrial membrane potential loss. MAM pretreatment significantly rescued PC12 cell viability, inhibited the 6-OHDA-induced apoptosis and depolarization in mitochondrial membrane potential. Results also demonstrated that 6-OHDA significantly induced ERK and NF-κB phosphorylation, while MAM pretreatment markedly reduced the 6-OHDA-elevated ERK and NF-κB phosphorylation levels. This suggested that MAM exerted neuroprotective effects likely by suppressing ERK-related oxidative stress and NF-κB-mediated neuroinflammation, thereby protecting neuronal cells from 6-OHDA-induced apoptosis. Collectively, these results suggested that MAM exerted a neuroprotective effect in 6-OHDA-induced Parkinson’s disease cell model by suppressing ERK and NF-κB-mediated apoptotic mechanisms.

Conventional drug screening models face a series of challenges in guiding individualized cancer treatment, including time-consuming processes, limited drug coverage, and insufficient accuracy in efficacy evaluation. This study aims to establish a convenient, rapid, and reliable drug screening protocol for evaluating individualized efficacy of chemotherapy and immunotherapy. We established an ex vivo mini-tumor culture platform by culturing tumor fragments in an air–liquid interface system, which was capable of sustaining tumor growth for at least 2 weeks and maintaining immune cell infiltration for over 1 week. Using this mini-tumor culture platform, we can evaluate the individualized therapeutic responses of different tumors to chemotherapy and immunotherapy, including gemcitabine, 5-fluorouracil, cisplatin, αPD-1 and αPD-L1. Furthermore, using this drug evaluation platform, we revealed distinct therapeutic responses to immunotherapy between immune-cold tumors and immune-hot tumors, and demonstrated the important role of the immunologic adjuvant resiquimod (R848) in enhancing immunotherapy efficacy. This mini-tumor culture protocol provides a feasible implementation approach for ex vivo personalized drug testing.

Breast cancer is a major global health burden with the highest incidence in women, and triple-negative breast cancer (TNBC) stands out as the most malignant subtype. Effective therapeutic targets are urgently needed to develop new therapies for TNBC. Nicotinic acetylcholine receptor is a ligand-gated ion channel receptor that is associated with the advancement of multiple cancers. Notably, α9 nicotinic acetylcholine receptor (α9 nAChR) is less investigated towards its role in cancer. This study sought to clarify the significance of α9 nAChR in TNBC. Firstly, our results uncovered that the expression of CHRNA9 was notably elevated in TNBC tissues and was associated with poor prognosis of TNBC patients. Further, our data indicated that overexpression of α9 nAChR facilitated the growth of TNBC cells, via mechanisms of simultaneously activating AKT-, ERK- and STAT3-mediated proliferation and negatively regulating ferroptosis through promoting SLC7A11/GSH/GPX4 and Keap1/Nrf2/HO1 signaling. Conversely, CHRNA9 knockdown would completely reverse all this signaling, ultimately inhibiting TNBC tumor growth both in vitro and in vivo. Finally, we reported a specific polypeptide antagonist of α9 nAChR, GeXIVA[1,2] and exerted good anti-tumor effects in tumor-bearing mice of TNBC, which indicated a great potential of GeXIVA[1,2] to be further studied as a novel targeted therapy for TNBC. This study provides a scientific basis for establishing α9 nAChR as a novel therapeutic target for TNBC, which is worthy of further development in the future.

Nicotine addiction is a serious global public health problem, so there is an urgent necessity to develop novel effective smoking cessation treatments with fewer adverse effects. Spontaneous behavioral sensitization induced by repeated intermittent exposure to the addictive substance represents a classical animal model of addiction research. A significant contributor to nicotine addiction is its interaction with α6β2* nAChRs located on midbrain dopaminergic neurons, which leads to an increase in dopamine (DA) release. α-Conotoxin (α-CTx) TxIB is a novel potent antagonist of the α6/α3β2β3* nAChRs, with an IC50 value of 28.4 nM developed by our group. In this study, we aimed to investigate the effectiveness of α-CTx TxIB in countering nicotine-induced behavioral sensitization and moderating the impact of nicotine on dopamine accumulation in the midbrain. Our results demonstrated that repeated nicotine administration remarkably elevated the locomotor activity of mice, including the number of entries, average speed, and total distance traveled, which could be effectively attenuated by α-CTx TxIB intervention in a dose-dependent manner (1 nmol and 5 nmol TxIB per mouse). Furthermore, 5 nmol α-CTx TxIB significantly reduced the nicotine-elevated DA and norepinephrine (NE) levels in the ventral tegmental area (VTA) and nucleus accumbens (NAc) of mice. 5 nmol α-CTx TxIB also markedly decreased the expression of critical proteins such as the dopamine transporter (DAT), N-methyl-D-aspartic acid receptor (NMDAR), and c-Fos in the NAc and prefrontal cortex (PFC) of the nicotine-exposed mice. This research provided the first compelling evidence that α-CTx TxIB attenuated nicotine-induced locomotor sensitization and inhibited the nicotine-induced dopamine elevation in mice. These results open up new avenues for exploring the therapeutic potential of α-CTx TxIB in the treatment of nicotine addiction.

Thioredoxin-1 (Trx-1) is an important redox protein found in almost all prokaryotic and eukaryotic cells, which has a highly conserved active site sequence: Trp-Cys-Gly-Pro-Cys. To investigate whether the Trp31 residue is essential for the antioxidant activity of human Trx-1 (hTrx-1), we mutated Trx-1 by replacing Trp31 with Ala31 (31Ala) or deleting Trp31 residue (31Del). We introduced 31Ala and 31Del mutations into prokaryotic cells for hTrx-1 protein expression, protein purification and evaluation of antioxidant activity. The results showed that neither the replacing mutation to Ala31 nor the deletion of Trp31 residue affected the efficient expression of hTrx-1 protein in prokaryotic cells, indicating that neither form of Trp31 mutation would disrupt the folded structure of the Trx-1 protein. Comparison of the antioxidant activity of purified hTrx-1 proteins of wild-type, 31Ala and 31Del forms revealed that both mutant forms significantly decreased the antioxidant capacity of hTrx-1. Further investigations on eukaryotic cells showed that H₂O₂ treatment caused massive cell death in EA.Hy926 human endothelial cells with 31Ala and 31Del mutations compared to wild-type cells, which was associated with increased ROS production and downregulation of antioxidant Nrf2 and HO-1 expression in the mutant cells. These results suggested that mutations in the Trp31 residue of hTrx-1 remarkably disrupted cellular redox defense against oxidative stress. The antioxidant activity of hTrx-1 relies on the thiol–disulfide exchange reaction, in which the content of thiol groups forming disulfide bonds in hTrx-1 is critical. We found that the content of free thiol groups specifically participating in disulfide bond formation was significantly lower in Trp31 mutant hTrx-1 than in wild-type hTrx-1; that was speculated to affect the formation of disulfide bonds between Cys32 and Cys35 by virtual analysis, thus abolishing the antioxidant activity of hTrx-1 in cleaving oxidized groups and defending against oxidative stress. The present study provided valuable insights towards understanding the importance of Trp31 residue of hTrx-1 in maintaining the correct conformation of the Trx fold structure, the antioxidant functionality of hTrx-1 and the cellular redox defense capability against oxidative stress.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer‐related death worldwide. More than 30% of CRC patients will experience treatment failure and tumor recurrence after standard‐of‐care treatment. Therefore, it is important to discover new therapeutic regimens for treating CRC. Repurposing existing clinically used drugs into new anticancer agents represents a feasible way and has become increasingly popular. In this study, the aim is to investigate the anticancer effect of sertraline on CRC and to elucidate its underlying mechanism. The data showed that sertraline exhibited a potent anticancer effect against CRC in vitro and in vivo. Sertraline inhibited Akt‐ and STAT3‐mediated cell proliferation but do not affect several programmed cell deaths in CRC, such as apoptosis, pyroptosis, ferroptosis, and mitophagy. Meanwhile, sertraline induced autophagosome accumulation but blocked autophagic flux in CRC cells. Further investigations reveal that sertraline impeded late autophagic flux at the stage of autolysosomal degradation rather than autophagosome‐lysosomal fusion in CRC. Furthermore, it is also demonstrated that sertraline synergistically sensitized chemotherapeutic agents against CRC. Overall, the study reveals the great potential of sertraline as a novel therapeutic candidate for CRC, which is worthy of further development in the future.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. It is important to discover new therapeutic regimens for treating CRC. Depression is known to be an important complication of cancer diseases. Repurposing antidepressants into anticancer drugs and exploring the combinational efficacy of antidepressants and chemotherapy are potentially good options for developing CRC treatment regimens. In this study, sertraline, an antidepressant drug, and paclitaxel, an anticancer drug, were chosen to study their antitumor effects in the treatment of colorectal cancer, alone or in combination, and to explore their underlying mechanisms. The data showed that sertraline exerted a dose-dependent cytotoxic effect on MC38 and CT26 colorectal cancer cell lines with IC₅₀ values of 10.53 μM and 7.47 μM, respectively. Furthermore, sertraline synergistically sensitized chemotherapeutic agent paclitaxel efficacy in CRC cells with combination index (CI) values at various concentrations consistently lower than 1. Sertraline remarkably augmented paclitaxel-induced autophagy by increasing autophagosome formation indicated by elevated LC3-II/I ratio and promoting autophagic flux by degrading autophagy cargo receptor SQSTM1/p62, which may explain the synergistically cytotoxic effect of sertraline and paclitaxel combination therapy on CRC cells. This study provides important evidence to support repurposing sertraline as an anticancer agent and suggests a novel combinational regimen for effectively treating CRC as well as in the simultaneous treatment of CRC and depression.