A platinum(IV)-artesunate complex triggers ferroptosis by boosting cytoplasmic and mitochondrial lipid peroxidation to enhance tumor immunotherapy.

Ferroptosis is an iron-dependent cell death form that initiates lipid peroxidation (LPO) in tumors. In recent years, there has been growing interest on ferroptosis, but how to propel it forward translational medicine remains in mist. Although experimental ferroptosis inducers such as RSL3 and erastin have demonstrated bioactivity in vitro, the poor antitumor outcome in animal model limits their development. In this study, we reveal a novel ferroptosis inducer, oxaliplatin-artesunate (OART), which exhibits substantial bioactivity in vitro and vivo, and we verify its feasibility in cancer immunotherapy. For mechanism, OART induces cytoplasmic and mitochondrial LPO to promote tumor ferroptosis, via inhibiting glutathione-mediated ferroptosis defense system, enhancing iron-dependent Fenton reaction, and initiating mitochondrial LPO. The destroyed mitochondrial membrane potential, disturbed mitochondrial fusion and fission, as well as downregulation of dihydroorotate dehydrogenase mutually contribute to mitochondrial LPO. Consequently, OART enhances tumor immunogenicity by releasing damage associated molecular patterns and promoting antigen presenting cells maturation, thereby transforming tumor environment from immunosuppressive to immunosensitive. By establishing in vivo model of tumorigenesis and lung metastasis, we verified that OART improves the systematic immune response. In summary, OART has enormous clinical potential for ferroptosis-based cancer therapy in translational medicine.

Influenza A Virus PB1-F2 Induces Affective Disorder by Interfering Synaptic Plasticity in Hippocampal Dentate Gyrus.

Influenza A virus (IAV) infection, which leads to millions of new cases annually, affects many tissues and organs of the human body, including the central nervous system (CNS). The incidence of affective disorders has increased after the flu pandemic; however, the potential mechanism has not been elucidated. PB1-F2, a key virulence molecule of various influenza virus strains, has been shown to inhibit cell proliferation and induce host inflammation; however, its role in the CNS has not been studied. In this study, we constructed and injected PB1-F2 into the hippocampal dentate gyrus (DG), a region closely associated with newborn neurons and neural development, to evaluate its influence on negative affective behaviors and learning performance in mice. We observed anxiety- and depression-like behaviors, but not learning impairment, in mice injected with PB1-F2. Furthermore, pull-down and mass spectrometry analyses identified several potential PB1-F2 binding proteins, and enrichment analysis suggested that the most affected function was neural development. Morphological and western blot studies revealed that PB1-F2 inhibited cell proliferation and oligodendrocyte development, impaired myelin formation, and interfered with synaptic plasticity in DG. Taken together, our results demonstrated that PB1-F2 induces affective disorders by inhibiting oligodendrocyte development and regulating synaptic plasticity in the DG after IAV infection, which lays the foundation for developing future cures of affective disorders after IAV infection.

Linderane Attenuates Complete Freund's Adjuvant-Induced Pain and Anxiety in Mice by Restoring Anterior Cingulate Cortex Microglia M2 Polarization through Activating Cannabinoid 2 Receptor.

Chronic pain is a common condition that causes negative emotions as the disease progresses. The anterior cingulate cortex (ACC) is a key region in the integration of nociceptive perception and emotional response in chronic pain. Linderane (LDR) is an active ingredient from Linderae radix, a traditional Chinese medicine with anti-inflammatory, analgesic, and antibacterial properties. In this study, the analgesic and antianxiety effects of LDR were evaluated using a complete Freund's adjuvant (CFA)-induced inflammatory pain model in C57BL/6 male mice. Mechanical and thermal pain sensitivity were measured through plantar mechanical analgesia and hot plate apparatus, and anxiety-like behavior was evaluated by open field and elevated plus maze tests. The results showed that LDR-alleviated CFA-induced pain and anxiety, reduced the release of inflammatory cytokines, and inhibited ACC microglial activation. Target prediction, molecular docking, and cellular thermal shift assay demonstrated that LDR could bind to the cannabinoid 2 receptor (CB2R), a key component of the endocannabinoid system with an important role in regulating pain and related emotions. Moreover, both the analgesic effect of LDR and its regulation of microglia polarization were reversed by a CB2R antagonist (SR144528) treatment. Therefore, our results suggested that LDR exerted analgesic effects by regulating microglial polarization in ACC via CB2R activation.

Repurposing fluphenazine as an autophagy modulator for treating liver cancer.

Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system with a low early diagnosis rate. Owing to the side effects, tolerance, and patient contraindications of existing therapies, effective drug treatments for HCC remain a major clinical challenge. However, using approved or investigational drugs not initially intended for cancer therapy is a promising strategy for resolving this problem because their safety have been tested in clinic. Therefore, this study evaluated differentially expressed genes between liver cancer and normal tissues in a cohort of patients with HCC from The Cancer Genome Atlas and applied them to query a connectivity map to identify candidate anti-HCC drugs. As a result, fluphenazine was identified as a candidate for anti-HCC therapy in vitro and in vivo. Fluphenazine suppressed HCC cell proliferation and migration and induced cell cycle arrest and apoptosis, possibly owing to disrupted lysosomal function, blocking autophagy flux. Additionally, in vivo studies demonstrated that fluphenazine suppresses HCC subcutaneous xenografts growth without causing severe side effects. Strikingly, fluphenazine could be used as an analgesic to alleviate oxaliplatin-induced pain as well as pain related anxiety-like behavior. Therefore, fluphenazine could be a novel liver cancer treatment candidate.

A novel endomorphin-2/salmon calcitonin hybrid peptide with enhancing anti-allodynic and anti-anxiety effects.

Pain, a worldwide problem with a high incidence and complex pathogenesis, has attracted the attention of pharmaceutical enterprises for the development of safer and more effective drugs. Extensive experimental and clinical evidence has demonstrated the analgesic effects of two endogenous peptides: endomorphin-2 (EM-2) and salmon calcitonin (sCT). However, EM-2 has limitations, such as poor ability to cross the blood-brain barrier (BBB) and little therapeutic effect in chronic pain due to rapid in vivo proteolysis. Herein, we propose the design of a novel hybrid peptide TEM2CT by combining EM-2, sCT16-21, and the cell-penetrating peptide HIV-1 trans-activator protein (TAT) with the aim of enhancing their analgesic effects. TEM2CT treatment attenuated nociceptive behavior in both acute and chronic pain mouse models, exhibiting increased anti-allodynic and anti-anxiety effects compared to sCT treatment. Furthermore, TEM2CT also regulated the excitability of pyramidal neurons in the anterior cingulate cortex (ACC) in spared nerve injury (SNI) model mice. The improved efficacy of this hybrid peptide provides a promising strategy for developing analgesic drugs.

Identification of CCDC115 as an adverse prognostic biomarker in liver cancer based on bioinformatics and experimental analyses.

Liver hepatocellular carcinoma (LIHC) is a major malignant tumor of the digestive system with a high incidence rate and poor early diagnosis. Coiled-coil domain-containing protein 115 (CCDC115), an accessory component of vacuolar-ATPase with dramatically abnormal expression, is associated with survival outcomes of cancer patients. However, the role of CCDC115 in LIHC remains unclear. In this study, we aimed to determine the functional role of CCDC115 in LIHC by examining CCDC115 expression, and its influence on LIHC prognosis. Through extensive statistical analyses, using LIHC patient databases, we observed that CCDC115 expression significantly increased in tumor tissues of LIHC patients. In addition, CCDC115 expression correlated with the poor prognosis. Additionally, CCDC115 was found to be involved in several cancer-related pathways, specifically the PI3K-Akt pathway. The expression of CCDC115 was positively correlated with human leukocyte antigen molecules as well as with immune checkpoint molecules in LIHC patients. We performed in vitro experiments and confirmed that the expression of CCDC115 significantly affects the proliferation potential, metastasis and sorafenib resistance of liver cancer cells, as well as some key protein expression in PI3K-Akt pathway. These results indicate that CCDC115 could serve as a diagnostic and prognostic biomarker of LIHC, and targeting CCDC115 may provide a potential strategy to enhance the efficacy of liver cancer therapy.

Sophoridine alleviates hyperalgesia and anxiety-like behavior in an inflammatory pain mouse model induced by complete freund's adjuvant.

Chronic pain, along with comorbid psychiatric disorders, is a common problem worldwide. A growing number of studies have focused on non-opioid-based medicines, and billions of funds have been put into digging new analgesic mechanisms. Peripheral inflammation is one of the critical causes of chronic pain, and drugs with anti-inflammatory effects usually alleviate pain hypersensitivity. Sophoridine (SRI), one of the most abundant alkaloids in Chinese herbs, has been proved to exert antitumor, antivirus and anti-inflammation effects. Here, we evaluated the analgesic effect of SRI in an inflammatory pain mouse model induced by complete Freund's adjuvant (CFA) injection. SRI treatment significantly decreased pro-inflammatory factors release after LPS stimuli in microglia. Three days of SRI treatment relieved CFA-induced mechanical hypersensitivity and anxiety-like behavior, and recovered abnormal neuroplasticity in the anterior cingulate cortex of mice. Therefore, SRI may be a candidate compound for the treatment of chronic inflammatory pain and may serve as a structural basis for the development of new drugs.