Exosomal circPVT1 promotes angiogenesis in laryngeal cancer by activating the Rap1b-VEGFR2 signaling pathway.

Laryngeal cancer (LC) is the second most common head and neck cancer and has a decreasing 5-year survival rate worldwide. Circular RNAs regulate cancer development in diverse ways based on their distinct biogenesis mechanisms and expansive regulatory roles. However, currently, there is little research on how exosomal circular RNAs are involved in the development of laryngeal cancer. Here, we demonstrated that circPVT1, a circular RNA derived from the well-studied long noncoding RNA PVT1, is correlated with disease progression in LC and promotes angiogenesis both in vivo and in vitro. Mechanistically, circPVT1 is loaded into LC cell-secreted exosomes and taken up by vascular epithelium cells. By sponging miR-30c-5p, exosomal circPVT1 promotes Rap1b expression, which dramatically enhances VEGFR2 and PI3K/AKT pathway activation, ultimately resulting in the induction of angiogenesis. Furthermore, our xenograft models demonstrated that the combination of shRNA-circPVT1 and cetuximab showed high efficacy in inhibiting tumor growth and angiogenesis. Collectively, these findings uncover a novel mechanism of exosomal circular RNA-mediated angiogenesis modulation and provide a preclinical rationale for testing this analogous combination in patients with LC.

m 6 A reader IGF2BP1 reduces the sensitivity of nasopharyngeal carcinoma cells to Taxol by upregulation of AKT2.

Taxol is widely used in the treatment of nasopharyngeal carcinoma (NPC); nevertheless, the acquired resistance of NPC to Taxol remains one of the major obstacles in clinical treatment. In this study, we aimed to investigate the role and mechanism of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in Taxol resistance of NPC. Taxol-resistant NPC cell lines were established by exposing to gradually increased concentration of Taxol. Relative mRNA and protein levels were tested using qRT-PCR and western blot, respectively. NPC cell viability and apoptosis were assessed by cell counting kit-8 and flow cytometry analysis, respectively. Cell migration and invasion capacities were measured using transwell assay. Interaction between IGF2BP1 and AKT2 was examined by RNA immunoprecipitation assay. The N6-methyladenosine level of AKT2 was tested using methylated RNA immunoprecipitation-qPCR. IGF2BP1 expression was enhanced in Taxol-resistant NPC cell lines. Knockdown of IGF2BP1 strikingly enhanced the sensitivity of NPC cells to Taxol and repressed the migration and invasion of NPC cells. Mechanistically, IGF2BP1 elevated the expression of AKT2 by increasing its mRNA stability. Furthermore, overexpression of AKT2 reversed the inhibitory roles of IGF2BP1 silence on Taxol resistance and metastasis. Our results indicated that IGF2BP1 knockdown enhanced the sensitivity of NPC cells to Taxol by decreasing the expression of AKT2, implying that IGF2BP1 might be promising candidate target for NPC treatment.

Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis.

CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-γ secretion and suppresses TGF-ß1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-γ mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.

The genome of the rice planthopper egg parasitoid wasps Anagrus nilaparvatae casts light on the chemo- and mechanosensation in parasitism.

BACKGROUND: Mymaridae is an ancient insect group and is a basal lineage of the superfamily Chalcidoidea. Species of Mymaridae have great potential for biological control. Anagrus nilaparvatae, a representative species of Mymaridae, is ideal for controlling rice planthopper due to its high rate of parasitism and ability to find hosts efficiently in paddy ridges and fields. RESULTS: Using both PacBio single-molecule real-time and Illumina sequencing, we sequenced and assembled the whole genome of A. nilaparvatae, a first for the family Mymaridae. The assembly consists of 394 scaffolds, totaling 488.8 Mb. The assembly is of high continuity and completeness, indicated by the N50 value of 25.4 Mb and 98.2% mapping rate of Benchmarking Universal Single-Copy Orthologs. In total, 16,894 protein-coding genes in the genome were annotated. A phylogenomic tree constructed for A. nilaparvatae and other 12 species of Hymenoptera confirmed that the family Mymaridae is sister to all remaining chalcidoids. The divergence time between A. nilaparvatae and the other seven Chalcidoidea species was dated at ~ 126.9 Mya. Chemoreceptor and mechanoreceptor genes are important in explaining parasitic behavior. We identified 17 odorant binding proteins, 11 chemosensory proteins, four Niemann-Pick type C2 proteins, 88 olfactory receptors, 12 gustatory receptors, 22 ionotropic receptors and 13 sensory neuron membrane proteins in the genome of A. nilaparvatae, which are associated with the chemosensory functions. Strikingly, there is only one pickpocket receptors and nine transient receptor potential genes in the genome that have a mechanosensory function. CONCLUSIONS: We obtained a high-quality genome assembly for A. nilaparvatae using PacBio single-molecule real-time sequencing, which provides phylogenomic insights for its evolutionary history. The small numbers of chemo- and mechanosensory genes in A. nilaparvatae indicate the species-specific host detection and oviposition behavior of A. nilaparvatae might be regulated by relatively simple molecular pathways.

Low expression of lncRNA SBF2-AS1 regulates the miR-302b-3p/TGFBR2 axis, promoting metastasis in laryngeal cancer.

The 5-year survival rate of laryngeal cancer continues to decline, and the laryngeal particularity of the anatomy adversely affects the patient's quality of life. Emerging evidence suggests that long noncoding RNAs (lncRNAs) are closely correlated to key steps in the malignant progression of cancer cells. In this study, we report the role of lncRNA SBF2-AS1/miR-302b-3p/TGFBR2 interactions in the metastasis of laryngeal squamous cell carcinoma (LSCC). We verified that SBF2-AS1 was significantly downregulated in LSCC tissues and cell lines using qRT-PCR analysis. Its low expression was correlated to lymph node metastasis and an advanced clinical stage. More importantly, LSCC patients with low expression of SBF2-AS1 tended to have a poor prognosis. Based on this, we performed gain-of-function and loss-of-function experiments in LSCC cell lines. The results confirmed that knocking down SBF2-AS1 can promote the metastasis of LSCC cells and enhance epithelial-mesenchymal transition phenotype, while the upregulation of SBF2-AS1 expression resulted in the opposite. Our in vivo model verified that SBF2-AS1 overexpression could inhibit LSCC cell metastasis. Subsequent mechanistic studies revealed that SBF2-AS1 acted as a competing endogenous RNA that upregulated the expression of TGFBR2 by endogenous sponging for miR-302b-3p in LSCC cell lines. Moreover, miR-302b-3p overexpression reversed the inhibitory effects on LSCC metastasis induced by upregulation of SBF2-AS1 expression, and inhibition of TGFBR2 expression reversed the effect of SBF2-AS1 on metastasis. Our study proposes SBF2-AS1 as a biomarker to predict the prognosis of LSCC patients and a novel potential therapeutic target.

Mast cell marker gene signature in head and neck squamous cell carcinoma.

BACKGROUND: Mast cells can reshape the tumour immune microenvironment and greatly affect tumour occurrence and development. However, mast cell gene prognostic and predictive value in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study was conducted to identify and establish a prognostic mast cell gene signature (MCS) for assessing the prognosis and immunotherapy response of patients with HNSCC. METHODS: Mast cell marker genes in HNSCC were identified using single-cell RNA sequencing analysis. A dataset from The Cancer Genome Atlas was divided into a training cohort to construct the MCS model and a testing cohort to validate the model. Fluorescence in-situ hybridisation was used to evaluate the MCS model gene expression in tissue sections from patients with HNSCC who had been treated with programmed cell death-1 inhibitors and further validate the MCS. RESULTS: A prognostic MCS comprising nine genes (KIT, RAB32, CATSPER1, SMYD3, LINC00996, SOCS1, AP2M1, LAT, and HSP90B1) was generated by comprehensively analysing clinical features and 47 mast cell-related genes. The MCS effectively distinguished survival outcomes across the training, testing, and entire cohorts as an independent prognostic factor. Furthermore, we identified patients with favourable immune cell infiltration status and immunotherapy responses. Fluorescence in-situ hybridisation supported the MCS immunotherapy response of patients with HNSCC prediction, showing increased high-risk gene expression and reduced low-risk gene expression in immunotherapy-insensitive patients. CONCLUSIONS: Our MCS provides insight into the roles of mast cells in HNSCC prognosis and may have applications as an immunotherapy response predictive indicator in patients with HNSCC and a reference for immunotherapy decision-making.

Copper exposure enhances Spodoptera litura larval tolerance to ß-cypermethrin.

Environmental xenobiotics can influence the tolerance of insects to chemical insecticides. Heavy metals are widespread distributed, can be easily bio-accumulated in plants and subsequently within phytophagous insects via the food chains. However, less attention has been paid to the effect of heavy metal exposure on their insecticide tolerance. In this study, pre-exposure of copper (Cu, 25-100 mg kg-1) significantly enhanced the subsequent tolerance of Spodoptera litura to ß-cypermethrin, a widely used pyrethroid insecticide in crop field. Cytochrome P450 monooxygenases (CYPs) activities were cross-induced in larvae exposed to Cu and ß-cypermethrin, while the activities of glutathione S-transferase (GST) and carboxylesterase (CarE) were not affected. Application of piperonyl butoxide (PBO), a P450 synergist, effectively impaired the tolerance to ß-cypermethrin in Cu-exposed S. litura larvae with a synergistic ratio of 1.72, indicating that P450s contribute to larval tolerance to ß-cypermethrin induced by Cu exposure. Among the four CYP6AB family genes examined, only larval midgut-specific CYP6AB12 was found to be cross-induced by Cu and ß-cypermethrin. RNA interference (RNAi)-mediated silencing of CYP6AB12 effectively decreased the mRNA levels of the target gene, and significantly reduced the larval tolerance to ß-cypermethrin following exposure to Cu. These results showed that pre-exposure of heavy metal Cu enhanced larval tolerance to ß-cypermethrin in S. litura, possibly through the cross-induction of P450s. Our findings provide new insights on the relationship between heavy metals and chemical insecticides that may benefit both the risk evaluation of heavy metal contamination and development of pest management strategies.

Copper-induced H2O2 accumulation confers larval tolerance to xanthotoxin by modulating CYP6B50 expression in Spodoptera litura.

In the plant-insect arms race, plants synthesize toxic compounds to defend against herbivorous insects, whereas insects employ cytochrome P450 monooxygenases (P450s) to detoxify these phytotoxins. As ubiquitous environmental contaminants, heavy metals can be easily absorbed by plants and further accumulated in herbivorous insects through the food chains, resulting in tangible consequences for plant-insect interactions. However, whether heavy metals can influence P450 activities and thereby cause further effects on larval tolerance to phytotoxins remains unknown. In this study, we shown that prior exposure to copper (Cu) enhanced larval tolerance to xanthotoxin in Spodoptera litura, a major polyphagous pest of agriculture. P450 activities were induced in larvae exposed to Cu or xanthotoxin, and a midgut specific expressed P450 gene, CYP6B50 was cross-induced after exposure to these two toxic xenobiotics. Knocking down CYP6B50 by RNA interference (RNAi) rendered the larvae more sensitive to xanthotoxin. As defense against oxidative stress following metal exposure has been demonstrated to affect insecticide resistance, the reactive oxygen species (ROS) generation and antioxidant enzyme activities were assessed. Cu exposure caused the accumulation of hydrogen peroxide (H2O2) and enhanced the activities of superoxide dismutase (SOD) and peroxidase (POD) in larval midgut. In addition, two antioxidant response elements (AREs) were identified from the CYP6B50 promoter, indicating that Cu-induced CYP6B50 expression may be related to the ROS burst. Application of ROS scavenger N-acetylcysteine (NAC) effectively suppressed CYP6B50 expression, inhibited P450 activities and impaired larval tolerance to xanthotoxin that had been induced by Cu. These results indicate that the increase in CYP6B50 expression regulated by Cu-induced H2O2 generation contributed to the enhancement of larval tolerance to xanthotoxin in S. litura. Ingestion of heavy metals from their host plants can inadvertently boost the counter-defense system of herbivorous insects to protect themselves against plant defensive toxins.

Cinnamon oil solid self-microemulsion mediates chronic mild stress-induced depression in mice by modulating monoamine neurotransmitters, corticosterone, inflammation cytokines, and intestinal flora.

Cinnamon oil (CO) is a classic Chinese medicine with excellent soothing effects on exhaustion, weakness and depression. Cinnamaldehyde is the main active ingredient of cinnamic oil. Although CO have antidepression-like effects, limited information is available. Furthermore, the disadvantages of CO, such as low oral availability and difficult portability, limit its development. In this study, a Cinnamon Oil Solid Self-Microemulsifying Drug Delivery System (CO-S-SME) was designed, prepared. In addition, we explored the effects and mechanisms of CO-S-SME on chronic unpredictable mild stress (CUMS)-induced depression-like behavior, monoamine neurotransmitters, inflammatory factors, intestinal flora in mice. Mice were subjected CUMS to establish the depression model. The antidepressant effect of CO-S-SME was evaluated by behavioral tests. In addition, the expression levels of neurotransmitters, corticosterone (CORT) and inflammatory factors in CUMS mice were analyzed by enzyme-linked immunosorbent assay. In addition, we explored the effects of CO-S-SME on the diversity and richness of intestinal flora of mice in each group. Behavioral tests showed that CO-S-SME could effectively improve depression-like behaviors in CUMS mice. Specifically, CO-S-SME treatment effectively increased neurotransmitter levels and reduced the expressions of corticosterone and inflammatory factors in CUMS mice. CO-S-SME also changed the intestinal flora composition, decreased the ratio of Firmicutes to Bacteroidetes, reduced relative abundances of Lactobacillus, modulated Alpha diversity and beta diversity. These results suggest that CO-S-SME an act as a good antidepressant, exhibiting effects via monoamine neurotransmitters, CORT, inflammation cytokines, and intestinal flora.

Salvage transoral laser microsurgery for early local recurrence of glottic squamous cell cancer.

BACKGROUND: For recurrent laryngeal cancer, the feasibility of salvage transoral laser microsurgery (TLM) remains controversial. This study compared the efficacy of TLM and open partial laryngectomy (OPL) for treatment of early local recurrence of glottic squamous cell cancer (GSCC) and confirm the effectiveness of salvage TLM as a treatment option. METHODS: This retrospective study involved 55 patients with early local recurrent GSCC treated with TLM, and the oncologic outcomes, functional outcomes, hospitalization time and complications were compared with a group of 40 recurrent GSCC patients matched for clinical variables of TLM group, treated by OPL by the same team of surgeons. RESULTS: The 5-year overall survival and disease-specific survival rates were 65.8% and 91.5%, respectively, for 55 patients with rTis-rT2 stage treated by TLM and 77.1% and 94.7%, respectively, for 40 patients with rTis-rT2 stage treated by OPL (OPL group). In the TLM and OPL groups, the local control rates after 5 years were 77.5% and 79.3%, respectively, and the laryngeal preservation rates were 94.4% and 83.6%, respectively (p > 0.05). Compared with the OPL group, the complication rate (1.82%) and hospitalization duration (5.42 ± 2.26 days) were significantly lower in the TLM group (p < 0.05). Compared with the OPL group, postsurgical health-related quality of life and quality of voice were significantly better in the TLM group (p < 0.001). CONCLUSION: Salvage TLM can be used as an effective treatment option for suitable patients after a full, comprehensive, and careful assessment of the characteristics of early locally recurrent glottic carcinoma.

Analysis of patient medication compliance and quality of life of physician-pharmacist collaborative clinics for T2DM management in primary healthcare in China: A mixed-methods study.

Background: Physician-pharmacist collaboration is a well-established care mode for the management of type 2 diabetes mellitus (T2DM) in developed countries, but no study has been conducted in primary healthcare in China. This study aims to evaluate the effects of physician-pharmacist collaborative clinics to manage T2DM in primary healthcare in China, and to better understand the factors influencing the implementation of physician-pharmacist collaborative clinics. Methods: Two hundred and sixty-seven patients involved in a 12-month randomized controlled trial were assigned to physician-pharmacist collaborative clinics and usual clinics, completing surveys regarding medication compliance, quality of life (QoL) and care-seeking behavior at the baseline, 3rd, 6th, 9th and 12th month respectively, and diabetes knowledge at baseline and 12th month. A sample of twenty-two Patients, nine physicians and twelve pharmacists participated in semi-structured face-to-face interviews. The quantitative and qualitative data was integrated by triangulation. Results: Patients in physician-pharmacist collaborative clinics had significant improvements in medication compliance (p = 0.009), QoL (p = 0.036) and emergency visits (p = 0.003) over the 12-month. Pairwise comparison showed the medication compliance score in the intervention group had been significantly improved at 3rd month (p = 0.001), which is more rapidly than that in the control group at 9th month (p = 0.030). Factors influencing the implementation of physician-pharmacist collaborative clinics were driven by five themes: pharmaceutical service, team-base care, psychological support, acceptability of care and barriers to implementation. Conclusion: Integration of quantitative and qualitative findings showed the effectiveness of physician-pharmacist collaborative clinics in patient medication compliance and QoL in primary healthcare. The qualitative study uncovered barriers in insufficient clinical experience and understaffing of pharmacist. Therefore, the professional training of the primary pharmacist team should be improved in the future. Clinical Trial Registration: clinicaltrials.gov, identifier ChiCTR2000031839.

Allergic Rhinitis and Cancer Risk: A Two-Sample Mendelian Randomization Study.

Background: There is increasing evidence that allergic rhinitis (AR) is associated with cancer. However, these results are inconsistent. Because of common risk factors, there may be reverse causality and confounding factors that affect our understanding of the relationship between AR and cancer. We aimed to explore the role of AR in cancer development using Mendelian randomization (MR) analysis. Materials and Methods: We performed a two-sample MR analysis using summary data from genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) strongly associated with AR (or hay fever) were used as instrumental variables, mainly using the inverse variance weighted analysis method, supplemented by MR Egger, maximum likelihood, weighted media, and penalized weighted media for MR analysis. Sensitivity analyses included heterogeneity and horizontal pleiotropy; and leave-one-out analyses were performed to test the robustness of our results. Results: MR analysis revealed no evidence of a causal relationship between AR and any of the examined cancers (all p > 0.05). The results using five different analytical approaches were similar. Sensitivity analyses showed no evidence of heterogeneity nor horizontal pleiotropy. According to the leave-one-out sensitivity analyses, no individual SNP was significantly influencing the causal effect of AR on cancers. Conclusions: These findings do not provide evidence to support that AR has a large impact on the risk of eight common cancers in the European population. However, we cannot rule out a very minor effect of AR on cancer. Further large-scale studies are necessary to validate our findings.

Structural insights into broadly neutralizing antibodies elicited by hybrid immunity against SARS-CoV-2.

ABSTRACTIncreasing spread by SARS-CoV-2 Omicron variants challenges existing vaccines and broadly reactive neutralizing antibodies (bNAbs) against COVID-19. Here we determine the diversity, potency, breadth and structural insights of bNAbs derived from memory B cells of BNT162b2-vaccinee after homogeneous Omicron BA.1 breakthrough infection. The infection activates diverse memory B cell clonotypes for generating potent class I/II and III bNAbs with new epitopes mapped to the receptor-binding domain (RBD). The top eight bNAbs neutralize wildtype and BA.1 potently but display divergent IgH/IgL sequences and neuralization profiles against other variants of concern (VOCs). Two of them (P2D9 and P3E6) belonging to class III NAbs display comparable potency against BA.4/BA.5, although structural analysis reveals distinct modes of action. P3E6 neutralizes all variants tested through a unique bivalent interaction with two RBDs. Our findings provide new insights into hybrid immunity on BNT162b2-induced diverse memory B cells in response to Omicron breakthrough infection for generating diverse bNAbs with distinct structural basis.

The Landscape of Exosome-Derived Non-Coding RNA in Leukemia.

Leukemia is a group of life-threatening hematological malignancies which is currently incurable and often accompanied by drug resistance or disease relapse. Understanding the pathogenesis of leukemia and finding specific therapeutic targets and biomarkers is of great importance to improve the clinical efficacy of leukemia. Exosome-derived ncRNAs have been demonstrated as critical components of intercellular communication and function as key facilitators in the leukemia biological process. This review outlines the current investigations of exosomal ncRNAs (including miRNA, circRNA, and lncRNA) as important mediators of leukemia and potential therapeutic targets and biomarkers for leukemia treatment. Moreover, we generally analyze the prospects and challenges for exosomal ncRNAs from the aspects of research and clinical application.

Transcriptome analysis and molecular characterization of soluble chemical communication proteins in the parasitoid wasp Anagrus nilaparvatae (Hymenoptera: Mymaridae).

Anagrus nilaparvatae is an important egg parasitoid wasp of pests such as the rice planthopper. Based on the powerful olfactory system of sensing chemical information in nature, A. nilaparvatae shows complicated life activities and behaviors, such as feeding, mating, and hosting. We constructed a full-length transcriptome library and used this to identify the characteristics of soluble chemical communication proteins. Through full-length transcriptome sequencing, splicing, assembly, and data correction by Illumina, we obtained 163.59 Mb of transcriptome data and 501,179 items with annotation information. We then performed Gene Ontology (GO) functional classification of the transcriptome's unigenes. We analyzed the sequence characteristics of soluble chemical communication protein genes and identified eight genes: AnilOBP2, AnilOBP9, AnilOBP23, AnilOBP56, AnilOBP83, AnilCSP5, AnilCSP6, and AnilNPC2. After sequence alignment and conserved domain prediction, the eight proteins encoded by the eight genes above were found to be consistent with the typical characteristics of odorant-binding proteins (OBPs), chemosensory proteins (CSPs), and Niemann-pick type C2 proteins (NPC2s) in other insects. Phylogenetic tree analysis showed that the eight genes share low homology with other species of Hymenoptera. Quantitative real-time polymerase chain reaction (RT-qPCR) was used to analyze the expression responses of the eight genes in different sexes and upon stimulation by volatile organic compounds. The relative expression levels of AnilOBP9, AnilOBP26, AnilOBP83, AnilCSP5, and AnilNPC2 in males were significantly higher than those in females, while the relative expression level of AnilCSP6 was higher in females. The expression levels of AnilOBP9 and AnilCSP6 were significantly altered by the stimulation of ß-caryophyllene, suggesting that these two genes may be related to host detection. This study provides the first data for A. nilaparvatae's transcriptome and the molecular characteristics of soluble chemical communication proteins, as well as an opportunity for understanding how A. nilaparvatae behaviors are mediated via soluble chemical communication proteins.

A broadly neutralizing antibody protects Syrian hamsters against SARS-CoV-2 Omicron challenge.

The strikingly high transmissibility and antibody evasion of SARS-CoV-2 Omicron variants have posed great challenges to the efficacy of current vaccines and antibody immunotherapy. Here, we screen 34 BNT162b2-vaccinees and isolate a public broadly neutralizing antibody ZCB11 derived from the IGHV1-58 family. ZCB11 targets viral receptor-binding domain specifically and neutralizes all SARS-CoV-2 variants of concern, especially with great potency against authentic Omicron and Delta variants. Pseudovirus-based mapping of 57 naturally occurred spike mutations or deletions reveals that S371L results in 11-fold neutralization resistance, but it is rescued by compensating mutations in Omicron variants. Cryo-EM analysis demonstrates that ZCB11 heavy chain predominantly interacts with Omicron spike trimer with receptor-binding domain in up conformation blocking ACE2 binding. In addition, prophylactic or therapeutic ZCB11 administration protects lung infection against Omicron viral challenge in golden Syrian hamsters. These results suggest that vaccine-induced ZCB11 is a promising broadly neutralizing antibody for biomedical interventions against pandemic SARS-CoV-2.

CircRNA Microarray Profiling Reveals hsa_circ_0058493 as a Novel Biomarker for Imatinib-Resistant CML.

Background: CircRNA has appeared as a critical molecular in the development of various cancers. However, the cellular function of circRNAs and exosomal circRNAs has not been well explored in Chronic myeloid leukemia (CML). Methods: Differentially expressed circRNAs were identified by a human circRNA microarray analysis. The expression of hsa_circ_0058493 in peripheral blood mononuclear cells (PBMCs) and exosomes was verified using quantitative real-time PCR. Short hairpin RNAs against hsa_circ_0058493 were constructed to silence the expression of circ_0058493. CCK8, flow cytometry and EdU assay were performed to investigate the biological functions of circ_0058493. Results: Hsa_circ_0058493 was significantly overexpressed in the PBMCs of CML patients and high level of circ_0058493 was associated with the poor clinical efficacy of imatinib. Silencing the expression of circ_0058493 significantly inhibited the development of imatinib-resistant CML cells. miR-548b-3p was overexpressed in circ_0058493-downregulated CML cells. Bioinformatic analysis revealed that circ_0058493 might exert its regulatory function acting as a "sponge" of miR-548b-3p. Moreover, hsa_circ_0058493 was significantly enriched in the exosomes derived from imatinib-resistant CML cells. Conclusion: Hsa_circ_0058493 in PBMCs could be a promising prognostic biomarker and might provide a therapeutic target for CML treatment.

Adipokinetic hormone regulates cytochrome P450-mediated imidacloprid resistance in the brown planthopper, Nilaparvata lugens.

Insect resistance to chemical insecticide is a global problem that presents an ongoing threat to sustainable agriculture. Although the increased production of detoxification enzymes has been frequently implicated in resistance development, the mechanisms employed by insecticide-resistant insects for overexpression of these genes remain elusive. Here we report that neuropeptide adipokinetic hormone (AKH) negatively regulates the expression of CYP6ER1 and CYP6AY1, two important cytochrome P450 monooxygenases (P450s) that confer resistance to neonicotinoid imidacloprid in the brown planthopper (BPH). Imidacloprid exposure suppresses AKH synthesis in the susceptible BPH, and AKH is inhibited in the imidacloprid-resistant strain. RNA interference (RNAi) and AKH peptide injection revealed that imidacloprid exposure inhibits the AKH signaling cascade and then provokes reactive oxygen species (ROS) burst. These in turn activate the transcription factors cap 'n' collar isoform-C (CncC) and muscle aponeurosis fibromatosis (MafK). RNAi and ROS scavenger assays showed that ROS induces CYP6ER1 expression by activating CncC and MafK, while ROS mediates induction of CYP6AY1 through another unidentified pathway in the resistant BPH. Collectively, these results provide new insights into the regulation of insecticide resistance and implicate both the neuropeptide AKH-mediated ROS burst and transcription factors are involved in the overexpression of P450 detoxification genes in insecticide-resistant insects.