Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma.

Fumarate hydratase (FH) deficient renal cell carcinoma (RCC) is a type of tumor with definite metabolic disorder, but the mechanism of metabolic remodeling is still unclear. LncRNA was reported to closely correlate with cancer metabolism, however the biological role of LncRNA in the development of progression of FH-deficent RCC was not well studied either. FH-deficient RCC samples were collected in my hospital and used for RNA-sequencing and Mass spectrometry analysis. FH-deficient RCC cell line UOK262 and control pFH cells were used for in vitro experiments, including proliferation assay, transwell assay, western-blot, mass spectrometry and so on. PDX mouse model was used for further drug inhibition experiments in vivo. In this study, we analyzed the profiles of LncRNA and mRNA in FH-deficienct RCC samples, and we found that the LncRNA-MIR4435-2GH was specifically highly expressed in FH-deficient RCC compared with ccRCC. In vitro experiments demonstrated that MIR4435-2HG was regulated by Fumarate through histone demethylation, and the deletion of this gene could inhibit glutamine metabolism. RNA-pulldown experiments showed that MIR4435-2HG specifically binds to STAT1, which can transcriptionally activate GLS1. GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.

Oral Immunotherapy Reshapes Intestinal Immunosuppression via Metabolic Reprogramming to Enhance Systemic Anti-Tumor Immunity.

Tumor immunotherapy offers a new paradigm to treat cancer; however, the existing regimens are accompanied by the dilemma of insufficient therapeutic outcomes and off-target adverse effects. The intestinal immune system contains a bulk of immune cells, which can be important contributors to the maintenance of systemic immune homeostasis. However, manipulating intestinal immunity to achieve systemic anti-tumor immunity is extremely challenging. Here, an oral immunotherapy strategy is reported using immune-enhancing fullerenes (IEF) that can reinvigorate anti-tumor immunity via immune cell-metabolic reprogramming of intestinal immune cells. Findings show that IEF can remodel anti-inflammatory macrophages into tumor-killing macrophages by regulating the energy metabolism pathway from oxidative phosphorylation (OXPHOS) to glycolysis. Consequently, IEF can reprogram the immunosuppressive intestinal immunity and enhance sys temic immunity in vivo, thereby boosting anti-tumor immunity and converting "cold" tumors into "hot" tumors. Oral immunotherapy strategy, modulating autoimmune cells in the intestine and achieving systemic anti-tumor immunity, can ensure safe and efficient tumor immunotherapy.

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase-deficient renal cell carcinoma.

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening, and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified 2 tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as excellent plasma biomarkers for early diagnosis. These 2 molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

Mangostanin Derivatives as Novel and Orally Active Phosphodiesterase 4 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis with Improved Safety.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, and its incidence rate is rapidly rising. However, effective therapies for the treatment of IPF are still lacking. Phosphodiesterase 4 (PDE4) inhibitors were reported to be potential anti-fibrotic agents, but their clinical use was hampered by side effects like emesis and nausea. Herein, structure-based hit-to-lead optimizations of natural mangostanin resulted in the novel and orally active PDE4 inhibitor 18a with potent inhibitory affinity (IC50 = 4.2 nM), favorable physico-chemical properties, and a different binding pattern from roflumilast. Emetic activity tests on dogs demonstrated that 18a cannot cause emesis even at an oral dose of 10 mg/kg, whereas rolipram had severe emetic effects at an oral dose of 1 mg/kg. Finally, the oral administration of 18a (10 mg/kg) exhibited comparable anti-pulmonary fibrosis effects with pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model, indicating its potential as a novel anti-IPF agent with improved safety.

Full near-ultraviolet response photoelectrochemical ultraviolet detector based on TiO2nanocrystalline coated stainless steel mesh photoanode.

In order to solve the 'ultraviolet (UV) filtering problem' caused by traditional sandwich-type structure in photoelectrochemical (PEC) UV detector, we design a special electrode based on stainless steel mesh, which integrates the light absorption layer and the electron collection electrode in a simple way. In combination with an UV-transparent quartz substrate, UV light can directly reach the active material. The improved detector shows good visible-blind, self-powered, and linear response characteristics. The serious recombination caused by metal electrode is suppressed by depositing a barrier layer. The optimized device exhibits a high photoresponse of 0.103 A W-1at 296 nm, a short recovery time of 250 ms, and very sensitive switching ability. Furthermore, the response range of the detector is expanded from 300 to 400 nm to the full near-UV region. Our work provides an efficient strategy to solve the key problem of the PEC UV detector.

Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis.

Hepatic fibrosis commonly exists in chronic liver disease and would eventually develop to cirrhosis and liver cancer with high fatality. Phosphodiesterase-9 (PDE9) has attracted profound attention as a drug target because of its highest binding affinity among phosphodiesterases (PDEs) with cyclic guanosine monophosphate. However, no published study has reported PDE9 inhibitors as potential agents against hepatic fibrosis yet. Herein, structural modification from a starting hit LL01 led to lead 4a, which exhibited an IC50 value of 7.3 nM against PDE9, excellent selectivity against other PDE subfamilies, and remarkable microsomal stability. The cocrystal structure of PDE9 with 4a revealed an important residue, Phe441, capable of improving the selectivity of PDE9 inhibitors. Administration of 4a exerted a significant antifibrotic effect in bile duct-ligation-induced rats with hepatic fibrosis and transforming growth factor-ß-induced fibrogenesis. This therapeutic effect was indeed achieved by selectively inhibiting PDE9 rather than other PDE isoforms, identifying PDE9 inhibitors as potential agents against hepatic fibrosis.

P2X4 receptor in the dorsal horn contributes to BDNF/TrkB and AMPA receptor activation in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.

The mechanism underlying the high incidence of remifentanil-induced postoperative hyperalgesia is unclear. Also, no effective prevention method exists. Inflammatory pain-related studies showed that P2X4 purinergic receptors (P2X4Rs) in the dorsal horn of the spinal cord and dorsal root ganglia are essential for maintaining allodynia caused by inflammation. However, little is known about its role in opioid-induced hyperalgesia. This study aimed to determine the role of P2X4R and related signaling pathways in the remifentanil-induced postoperative hyperalgesia (RIH) model. The study simulated the remifentanil infusion and surgical incision during general anesthesia. The mRNA and protein expression level of P2X4R in rats with RIH model increased from 2 h to 48 h after the surgery. The administration of P2X4R inhibitors prevented the occurrence of RIH, resulting in a reduction in mechanical and thermal pain. Moreover, P2X4R was involved in RIH in male and female rats, indicating no sex-specific difference. P2X4R also increased the expression of AMPA receptor subunit GluA1 in a brain-derived neurotrophic factor (BDNF) / tyrosine receptor kinase B (TrkB) dependent manner. The results from whole-cell patch-clamp recording suggested that P2X4R also regulated AMPA receptor-mediated miniature excitatory postsynaptic currents and participated in the synaptic plasticity of spinal dorsal horn neurons. In summary, P2X4R was involved in AMPAR expression, electrophysiological function, and synaptic plasticity of spinal dorsal horn neurons through BDNF/TrkB signaling. This might be the mechanism underlying RIH, and hence inhibition of P2X4R might be a potential treatment strategy.

Modulation of alternative splicing induced by paclitaxel in human lung cancer.

Paclitaxel is utilized as the first-line chemotherapeutic regimen for the majority of advanced non-small-cell lung carcinoma. However, whether paclitaxel could suppress cancer progression through modulating RNA alternative splicing remains largely unknown. Here, we demonstrated the effects of paclitaxel on cell proliferation inhibition, cell cycle arrest, and apoptosis. Mechanistically, paclitaxel leads to transcriptional alteration of networks involved in DNA replication and repair, chromosome segregation, chromatin silencing at rDNA, and mitosis at the transcriptional level. Moreover, paclitaxel regulates a number of cancer-associated RNA alternative splicing events, including genes involved in cellular response to DNA damage stimulus, preassembly of GPI anchor in ER membrane, transcription, and DNA repair. In particular, paclitaxel modulates the splicing of ECT2, a key factor involved in the regulation of cytokinesis. Briefly, paclitaxel favors the production of ECT2-S, the short splicing isoforms of ECT2, thereby inhibiting cancer cell proliferation. Our study provides mechanistic insights of paclitaxel on RNA alternative splicing regulation, thus to offer a potential novel route for paclitaxel to inhibit cancer progression.