Although chemotherapy represents a predominant anti-cancer therapeutic modality, drug treatment efficacy is often limited due to the development of resistant tumor cells. The pregnane X receptor (PXR) affects chemotherapeutic effects by regulating targets involved in drug metabolism and transportation, but the regulatory mechanism is poorly understood. Oxaliplatin (L-OHP) content in tumor cells was analyzed by mass cytometry. The roles of PXR on cancer cell proliferation, apoptosis and tumor growth with L-OHP-treated were investigated by MTS, colony formation, flow cytometry and xenograft tumor assays. Luciferase reporter, Chromatin-immunoprecipitation and Site-directed mutagenesis were evaluated the mechanisms. The PXR and multidrug resistance-related protein 3 (MRP3) expressions were examined by western blot, RT-PCR or immunohistochemistry of TMA. Kaplan-Meier and Cox regression were adopted to analyze the prognostic value of PXR in colorectal cancer (CRC). PXR over-expression significantly increased oxaliplatin (L-OHP) transport capacity with a reduction of its content and repressed the effects of L-OHP on tumour cell proliferation and apoptosis. Conversely, PXR knockdown augments L-OHP-mediated cellular proliferation and apoptosis. Moreover, PXR significantly reduced the therapeutic effects of L-OHP on tumor growth in nude mice. Further studies indicated a positive correlation between PXR and MRP3 expression and this finding was confirmed in two independent cohorts. Significantly increased MRP3 expression was also found in PXR over-expressing cell lines. Mechanistically, PXR could directly bind to the MRP3 promoter, activating its transcription. The PXR binding sites were determined to be at -796 to -782bp (CTGAAGCAGAGGGAA) and the key binding sites were the “AGGGA” (-787 to -783bp) on the MRP3 promoter. Accordingly, blockade of MRP3 diminishes the effects on drug resistance of PXR. In addition, PXR expression is significantly associated with poor overall survival and represents an unfavorable and independent factor for male or stage I + II CRC patient prognosis. PXR is a potential biomarker for predicting outcome and activates MRP3 transcription by directly binding to its promoter resulting in an increased L-OHP efflux capacity, and resistance to L-OHP or platinum drugs in CRC. Our work reveals a novel and unique mechanism of drug resistance in CRC.

Radiotherapy (RT) is one of the important treatment modalities for non-small cell lung cancer (NSCLC). However, the maximum radiation dose that NSCLC patient can receive varies little. Therefore, the exploitation of novel RT sensitization approaches is a critical need for the clinical treatment. RT resistance in NSCLC is linked to tumor microenvironment (TME) hypoxia, cell cycle arrest and associated genetic alterations. Here, we designed a novel method for targeted delivery of quercetin (QT) and CeO₂ to enhance RT sensitivity. We loaded QT into CeO₂@ZIF-8-HA nanoparticles to prevent its degradation in the circulatory system and successfully delivered QT and CeO₂ targeted to NSCLC tumors. Under the protection and targeted delivery of Zeolitic Imidazolate Framework-8 (ZIF-8), the nanocomplexes exhibited excellent catalytic mimetic activity in decomposing H₂O₂ into O₂, thus significantly reversing the hypoxia of TME, while the radiosensitizer QT caused DNA damage directly after RT. In a subcutaneous tumor model, CeO₂@ZIF-8-HA overcame radiation resistance and enhanced therapeutic efficacy. This multiple sensitization strategy combining delivery of QT and CeO₂@ZIF-8-HA nanozymes opens a promising approach for RT of NSCLC.

There were no ideal markers to predict the development of radiation pneumonitis (RP). We want to investigate the value of variations of lymphocytes and T lymphocyte subsets in predicting RP after radiotherapy (RT) of lung cancer based on previous clinical findings. A total of 182 lung cancer patients who received RT were retrospectively analyzed. Circulating lymphocytes and T lymphocyte subsets were measured before, during, and after RT. Patients were evaluated from the start of RT to 6 months post‐RT. A mice model with acute radiation‐induced lung injury was established and circulating lymphocytes were measured weekly until 8 weeks after irradiation. Univariate and multivariate analyses were adopted to identify risk factors of RP. Lymphocyte levels significantly decreased (P < .001) in patients before RP symptoms developed that also was able to be seen in the mice model and the values recovered during remission of symptoms. The decrease in lymphocyte count reflected the severity of RP. Meanwhile, CD4⁺ T lymphocyte count was significantly lower during the occurrence of symptoms in patients with RP than in those without RP (P < .001), and it improved along with RP recovery. Levels of lymphocytes and CD4⁺ T lymphocyte subsets proved as independent predictors of RP. Here we showed that lower peripheral blood levels of lymphocytes and CD4⁺ T lymphocyte were associated with an increased risk of RP, which was validated by this mice model, and thus are associated with differences in radiation‐induced lung toxicity among individuals and help identify those who are susceptible to developing RP after RT.

Parkinson's disease (PD) is a neurodegenerative disorder that has a high incidence during the aging process and is characterized by the loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunctions and non‑motor symptoms. Impaired clearance and excessive accumulation of aberrantly modified proteins or damaged organelles, such as aggregated α‑synuclein and dysfunctional mitochondria, are regarded as the main causes of nigrostriatal neurodegeneration. As one of the major degradation pathways, autophagy can recycle these useless or toxic substances to maintain cellular homeostasis and it plays a crucial role in PD progression. MicroRNAs (miRNAs) are a group of small non‑coding RNA molecules that regulate gene expression by silencing targeted mRNAs. Recent studies have illustrated that autophagy‑regulating miRNA has been implicated in pathological processes of PD, including α‑synuclein accumulation, mitochondrial damage, neuroinflammation and neuronal apoptosis, which suggests that targeting autophagy‑regulating miRNAs may provide novel therapeutic strategies for this disease. The present review summarizes the role of autophagy in PD and emphasizes the role of miRNA‑mediated autophagy in PD, for the development of promising interventions in this disease.