Specnuezhenide Ameliorates Hepatic Fibrosis via Regulating SIRT6-Mediated Inflammatory Signaling Cascades.

ETHNOPHARMACOLOGICAL RELEVANCE: Ligustrum lucidum W.T. Aiton is a traditional Chinese medicine that has long been used with high hepatoprotective therapeutic and condition value. Specnuezhenide (SP), the standard prominent secoiridoid compound of Fructus Ligustri Lucidi may ameliorate hepatic inflammation in chronic liver diseases. AIM OF THE STUDY: Regulating inflammation through SIRT6-P2X7R axis has caused the emergence of novel molecular mechanism strategies for reversing hepatic fibrosis. This study focused on the mechanism of SP in modulating the liver inflammatory microenvironment in hepatic fibrosis. MATERIALS AND METHODS: C57BL/6 mice with hepatic fibrosis were stimulated with thioacetamide (TAA) prior to administration of SP. Hepatic stellate cells (HSCs) or normal mouse primary hepatocytes were exposed to transforming growth factor-ß (TGF-ß) treatment. Meanwhile, normal mouse bone marrow-derived macrophages (BMDMs) were treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP), aiming to obtain the conditioned medium. HSCs and hepatocytes were transfected with SIRT6 knockdown vector (siRNA-SIRT6) to estimate the impact of SP on the SIRT6-P2X7R/NLRP3 signaling pathway. RESULTS: SP suppressed the HSCs extracellular matrix (ECM) deposition as well as pro-inflammatory cytokine levels induced by the medium of BMDMs or TGF-ß. In addition, SP also significantly up-regulated SIRT6, inhibited P2X7R-NLRP3 inflammasome in HSCs and hepatocytes, and functioned as MDL-800 (a SIRT6 agonist). SP reduced the hepatocytes pyroptosis and further prevented the occurrence of inflammatory response in the liver. SP could inhibit the activation of BMDMs and impede IL-1ß and IL-18 from entering extracellular regions. Moreover, deficiency of SIRT6 in HSCs or hepatocytes reduced SP's regulation of P2X7R suppression. For TAA-treated mice, SP mitigated histopathological changes, ECM accumulation, EMT process, and NETs formation in hepatic fibrosis. CONCLUSIONS: Therefore, SP decreased inflammatory response via SIRT6-P2X7R/NLRP3 pathway and suppressed fibrillogenesis. These findings supported SP as the novel candidate to treat hepatic fibrosis.

Strategies that regulate Hippo signaling pathway for novel anticancer therapeutics.

As a highly conserved signaling network across different species, the Hippo pathway is involved in various biological processes. Dysregulation of the Hippo pathway could lead to a wide range of diseases, particularly cancers. Extensive researches have demonstrated the close association between dysregulated Hippo signaling and tumorigenesis as well as tumor progression. Consequently, targeting the Hippo pathway has emerged as a promising strategy for cancer treatment. In fact, there has been an increasing number of reports on small molecules that target the Hippo pathway, exhibiting therapeutic potential as anticancer agents. Importantly, some of Hippo signaling pathway inhibitors have been approved for the clinical trials. In this work, we try to provide an overview of the core components and signal transduction mechanisms of the Hippo signaling pathway. Furthermore, we also analyze the relationship between Hippo signaling pathway and cancers, as well as summarize the small molecules with proven anti-tumor effects in clinical trials or reported in literatures. Additionally, we discuss the anti-tumor potency and structure-activity relationship of the small molecule compounds, providing a valuable insight for further development of anticancer agents against this pathway.

Integration of photomagnetic bimodal imaging to monitor an autogenous exosome loaded platform: unveiling strong targeted retention effects for guiding the photothermal and magnetothermal therapy in a mouse prostate cancer model.

BACKGROUND: Prostate cancer (PCa) is the most prevalent cancer among males, emphasizing the critical need for precise diagnosis and treatment to enhance patient prognosis. Recent studies have extensively utilized urine exosomes from patients with cancer for targeted delivery. This study aimed to employ highly sensitive magnetic particle imaging (MPI) and fluorescence molecular imaging (FMI) to monitor the targeted delivery of an exosome-loaded platform at the tumour site, offering insights into a potential combined photothermal and magnetic thermal therapy regime for PCa. RESULTS: MPI and FMI were utilized to monitor the in vivo retention performance of exosomes in a prostate tumour mouse model. The exosome-loaded platform exhibited robust homologous targeting ability during imaging (SPIONs@EXO-Dye:66·48%±3·85%; Dye-SPIONs: 34·57%±7·55%, **P<0·01), as verified by in vitro imaging and in vitro tissue Prussian blue staining. CONCLUSIONS: The experimental data underscore the feasibility of using MPI for in vivo PCa imaging. Furthermore, the exosome-loaded platform may contribute to the precise diagnosis and treatment of PCa.

Calib-RT: an open source python package for peptide retention time calibration in DIA mass spectrometry data.

MOTIVATION: The data independent acquisition (DIA) mass spectrometry (MS) method is increasingly popular in the field of proteomics. But the loss of the correspondence between peptide ions and their spectra in DIA makes the identification challenging. One effective approach to reduce false positive identification is to calculate the deviation between the peptide's estimated retention time (RT) and measured RT. During this process, scaling the spectral library RT into the estimated RT, known as the RT calibration, is a prerequisite for calculating the deviation. Currently, within the DIA algorithm ecosystem, there is a lack of engine-independent and readily usable RT calibration toolkits. RESULTS: In this work, we introduce Calib-RT, a RT calibration method tailored to the characteristics of RT data. This method can achieve the nonlinear calibration across various data scales and tolerate a certain level of noise interference. Calib-RT is expected to enrich the open source DIA algorithm toolchain and assist in the development of DIA identification algorithms. AVAILABILITY AND IMPLEMENTATION: Calib-RT is released as an open source software under the MIT license and can be installed from PyPi as a python module. The source code is available on GitHub at https://github.com/chenghui03/Calib_RT.

Numerical study on the stimulation effect of boundary sealing and hot water injection in marine challenging gas hydrate extraction.

This study proposed a novel development mode combining boundary sealing and hot water injection to address the challenges of gas leakage, limited reservoir sensible heat, boundary water intrusion, and low productivity faced by challenging hydrate extraction, and the stimulation effect was numerically investigated with Shenhu hydrates as the geological background. The results showed that lower boundary permeability facilitated pressure propagation and achieved volumetric dissociation of hydrates, whereas insufficient formation energy resulted in substantial gas retention. Hot water injection was effective for stimulation, but open boundaries could not maintain the high injection pressure, leading to massive hot water losses and gas escapes. However, their combination achieved a synergistic stimulation like "1 + 1 > 2" because a piston water drive similar to secondary recovery in oil and gas development was formed. Relative to three-spot well patterns, the five-spot shortened the extraction cycle by 680 days and enhanced the gas-to-water ratio by 17%. Increasing injection pressure enhanced water yield more significantly while the improvement of gas yield was more significant by increasing hot water temperature. Overall, high-pressure and high-temperature injection was suggested for gas enhancement and water control. These findings provide important guidance for advancing the commercial development of challenging hydrates.

Targeting focal adhesion kinase (FAK) in cancer therapy: A recent update on inhibitors and PROTAC degraders.

Focal adhesion kinase (FAK) is considered as a pivotal intracellular non-receptor tyrosine kinase, and has garnered significant attention as a promising target for anticancer drug development. As of early 2024, a total of 12 drugs targeting FAK have been approved for clinical or preclinical studies worldwide, including three PROTAC degraders. In recent three years (2021-2023), significant progress has been made in designing targeted FAK anticancer agents, including the development of a novel benzenesulfofurazan type NO-releasing FAK inhibitor and the first-in-class dual-target inhibitors simultaneously targeting FAK and HDACs. Given the pivotal role of FAK in the discovery of anticancer drugs, as well as the notable advancements achieved in FAK inhibitors and PROTAC degraders in recent years, this review is underbaked to present a comprehensive overview of the function and structure of FAK. Additionally, the latest findings on the inhibitors and PROTAC degraders of FAK from the past three years, along with their optimization strategies and anticancer activities, were summarized, which might help to provide novel insights for the development of novel targeted FAK agents with promising anticancer potential and favorable pharmacological profiles.

Radium-223 Treatment Produces Prolonged Suppression of Resident Osteoblasts and Decreased Bone Mineral Density in Trabecular Bone in Osteoblast Reporter Mice.

Radium 223 (Ra-223) is an α-emitting bone-homing radiopharmaceutical that targets tumor-induced osteoblasts and is used to reduce bone pain and prolong overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. Both luciferase- or green fluorescence protein (GFP)-labeled osteoblast reporter mice were used to monitor the effect of Ra-223 on resident osteoblasts and normal bone structure. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the osteoblast reduction lasted for at least 18 weeks without detectable recovery, as measured by in vivo bioluminescent imaging. In GFP-labeled osteoblast reporter mice, Ra-223 mainly reduced osteoblasts localized in the trabecular bone areas; the osteoblasts in the growth plates were less affected. Micro-computed tomography analyses showed that Ra-223 significantly reduced bone mineral density and bone microstructure in the trabecular area of femurs but not in the cortical bone. Tumor-induced bone was generated by inoculating osteogenic TRAMP-BMP4 prostate cancer cells into the mouse femurs; Ra-223 treatment significantly reduced tumor-induced osteoblasts. Our study shows that Ra-223 affects bone structures that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223.

Endoplasmic reticulum stress regulates apoptosis and chemotherapeutic via enhancing TNFRSF10B recycling to the cell membrane in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most common malignant tumor in China. The expression and cell surface levels of TNF receptor superfamily member 10B (TNFRSF10B) are associated with apoptosis and chemotherapy. However, the precise molecular mechanisms that govern the regulation of TNFRSF10B remain unclear. MATERIALS AND METHODS: RNA-Seq data related to TNBC chemotherapy resistance were acquired from the GEO database. The mRNA and protein levels of TNFRSF10B were detected using RT-PCR and Western blotting, respectively. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to detect cell proliferation. Annexin V/7-AAD staining was used to evaluate apoptosis. The cell membrane TNFRSF10B was analyzed by Western blotting and immunofluorescence. Inducers and inhibitors of endoplasmic reticulum stress (ERS) were used to assess the effect of ERS on TNFRSF10B localization. RESULTS: TNFRSF10B expression was downregulated in TNBC and was associated with prognosis. TNFRSF10B overexpression inhibits the growth of TNBC both in vivo and in vitro and can partially counteract chemotherapy resistance. ERS activation in TNBC promotes the expression of TNFRSF10B, leading to its enrichment on the cell membrane surface, thereby activating the apoptotic pathways. CONCLUSION: ERS regulates the expression and subcellular localization of TNFRSF10B in TNBC cells. They synergistically affect anti-apoptosis and chemotherapy resistance in TNBC cells.

The potential of Burkholderia gladioli KRS027 in plant growth promotion and biocontrol against Verticillium dahliae revealed by dual transcriptome of pathogen and host.

Verticillium dahliae is a destructive, soil-borne pathogen that causes significant losses on numerous important dicots. Recently, beneficial microbes inhabiting the rhizosphere have been exploited and used to control plant diseases. In the present study, Burkholderia gladioli KRS027 demonstrated excellent inhibitory effects against Verticillium wilt in cotton seedlings. Plant growth and development was promoted by affecting the biosynthesis and signaling pathways of brassinosteroids (BRs), gibberellins (GAs), and auxins, consequently promoting stem elongation, shoot apical meristem, and root apical tissue division in cotton. Furthermore, based on the host transcriptional response to V. dahliae infection, it was found that KRS027 modulates the plants to maintain cell homeostasis and respond to other pathogen stress. Moreover, KRS027 induced disruption of V. dahliae cellular structures, as evidenced by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses. Based on the comparative transcriptomic analysis between KRS027 treated and control group of V. dahliae, KRS027 induced substantial alterations in the transcriptome, particularly affecting genes encoding secreted proteins, small cysteine-rich proteins (SCRPs), and protein kinases. In addition, KRS027 suppressed the growth of different clonal lineages of V. dahliae strains through metabolites, and volatile organic compounds (VOCs) released by KRS027 inhibited melanin biosynthesis and microsclerotia development. These findings provide valuable insights into an alternative biocontrol strategy for Verticillium wilt, demonstrating that the antagonistic bacterium KRS027 holds promise as a biocontrol agent for promoting plant growth and managing disease occurrence.

Synthesis and biological evaluation of 4-phenyl-5-quinolinyl substituted isoxazole analogues as potent cytotoxic and tubulin polymerization inhibitors against ESCC.

The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4), a naturally occurring colchicine-site binder characterized by its structural simplicity and biological activity, has served as a structural blueprint for the development of novel analogues with improved safety and therapeutic efficacy. In this study, a library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole analouges of CA-4, were synthesized and evaluated for their cytotoxicity against Esophageal Squamous Cell Carcinoma (ESCC) cell lines. Compound C11, which features a 2-methyl substitution at the quinoline and carries an isoxazole ring, emerged as the most promising, with 48 h IC50s of less than 20 nmol/L against two ESCC cell lines. The findings from EBI competitive assay, CETA, and in vitro tubulin polymerization assay of C11 are consistent with those of the positive control colchicine, demonstrating the clear affinity of compound C11 to the colchicine binding site. The subsequent cellular-based mechanism studies revealed that C11 significantly inhibited ESCC cell proliferation, arrested cell cycle at the M phase, induced apoptosis, and impeded migration. Experiments conducted in vivo further confirmed that C11 effectively suppressed the growth of ESCC without showing any toxicity towards the selected animal species. Overall, our research suggests that the tubulin polymerization inhibitor incorporating quinoline and the isoxazole ring may deserve consideration for cancer therapy.

Sirtuin-6 knockout causes exacerbated stalled healing of diabetic ulcers in mice.

BACKGROUND: Diabetic ulcers (DUs) are characterized by chronic inflammation and delayed re-epithelialization, with a high incidence and weighty economic burden. The primary therapeutic strategies for refractory wounds include surgery, non-invasive wound therapy, and drugs, while the optimum regimen remains controversial. Sirtuin-6 (SIRT6) is a histone deacetylase and a key epigenetic factor that exerts anti-inflammatory and pro-proliferatory effects in wound healing. However, the exact function of SIRT6 in DUs remains unclear. METHODS: We generated tamoxifen-inducible SIRT6 knockout mice by crossing SIRT6flox/flox homozygous mice with UBC-creERT2+ transgenic mice. Systemic SIRT6 null mice, under either normal or diabetic conditions, were utilized to assess the effects of SIRT6 in DUs treatment. Gene and protein expressions of SIRT6 and inflammatory cytokines were measured by Western blotting and RT-qPCR. Histopathological examination confirmed the altered re-epithelialization (PCNA), inflammation (NF-κB p50 and F4/80), and angiogenesis (CD31) markers during DUs restoration. RESULTS: Knockout of SIRT6 inhibited the healing ability of DUs, presenting attenuated re-epithelialization (PCNA), exacerbated inflammation responses (NF-κB p50, F4/80, Il-1ß, Tnf-α, Il-6, Il-10, and Il-4), and hyperplasia vascular (CD31) compared with control mice. CONCLUSIONS: SIRT6 could boost impaired wound healing through improving epidermal proliferation, inflammation, and angiogenesis. Our study highlighted the therapeutic potential of the SIRT6 agonist for DUs treatment.

BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression.

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.

Radio-Frequency Conductivity Characteristics and Corresponding Mechanism of Graphene/Copper Multilayer Structures.

High-radio-frequency (RF) conductivity is required in advanced electronic materials to reduce the electromagnetic loss and power dissipation of electronic devices. Graphene/copper (Gr/Cu) multilayers possess higher conductivity than silver under direct current conditions. However, their RF conductivity and detailed mechanisms have rarely been evaluated at the micro scale. In this work, the RF conductivity of copper-copper (P-Cu), monolayer-graphene/copper (S-Gr/Cu), and multilayer-graphene/copper (M-Gr/Cu) multilayer structures were evaluated using scanning microwave impedance microscopy (SMIM) and dielectric resonator technique. The results indicated that the order of RF conductivity was M-Gr/Cu < P-Cu < S-Gr/Cu at 3 GHz, contrasting with P-Cu < M-Gr/Cu < S-Gr/Cu at DC condition. Meanwhile, the same trend of M-Gr/Cu < P-Cu < S-Gr/Cu was also observed using the dielectric resonator technique. Based on the conductivity-related Drude model and scattering theory, we believe that the microwave radiation can induce a thermal effect at S-Gr/Cu interfaces, leading to an increasing carrier concentration in S-Gr. In contrast, the intrinsic defects in M-Gr introduce additional carrier scattering, thereby reducing the RF conductivity in M-Gr/Cu. Our research offers a practical foundation for investigating conductive materials under RF conditions.

The changes of intestinal microbiota and metabolomics during the inhibition of bladder cancer by liquiritigenin.

Liquiritigenin is a natural medicine. However, its inhibitory effect and its potential mechanism on bladder cancer (BCa) remain to be explored. It was found that it could be visualized that the transplanted tumours in the low-dose liquiritigenin -treated group and the high-dose liquiritigenin -treated group were smaller than those in the model group. Liquiritigenin treatment led to alterations in Lachnoclostridium, Escherichia-Shigella, Alistipes and Akkermansia. Non-targeted metabolomics analysis showed that a total of multiple differential metabolites were identified between the model group and the high-dose liquiritigenin-treated group. This provides a new direction and rationale for the antitumour effects of liquiritigenin.

Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission.

BACKGROUND: Cartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), is characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead to apoptosis during CEP degeneration and IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis and IVDD. Despite their major success in drug delivery, the full potential of exosomes remains untapped. MATERIALS AND METHODS: In vitro and in vivo models of CEP degeneration were established by using lipopolysaccharide (LPS). We designed genetically engineered exosomes (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on the surface and carrying the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). The affinity between CAP-Nrf2-Exos and CEP was evaluated by in vitro internalization assays and in vivo imaging assays. qRT‒PCR, Western blotting and immunofluorescence assays were performed to examine the expression level of Nrf2 and the subcellular localization of Nrf2 and Drp1. Mitochondrial function was measured by the JC-1 probe and MitoSOX Red. Mitochondrial morphology was visualized by MitoTracker staining and transmission electron microscopy (TEM). After subendplate injection of the engineered exosomes, the degree of CEP degeneration and IVDD was validated radiologically and histologically. RESULTS: We found that the cargo delivery efficiency of exosomes after cargo packaging was increased by surface modification. CAP-Nrf2-Exos facilitated chondrocyte-targeted delivery of Nrf2 and activated the endogenous antioxidant defence system in CEP cells. The engineered exosomes inhibited Drp1 S616 phosphorylation and mitochondrial translocation, thereby preventing mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was alleviated by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, the engineered exosomes successfully attenuated CEP degeneration and IVDD and exhibited better repair capacity than natural exosomes. CONCLUSION: Collectively, our findings showed that exosome-mediated chondrocyte-targeted delivery of Nrf2 was an effective strategy for treating CEP degeneration.

Semisynthesis and biological evaluation of novel honokiol thioethers against colon cancer cells HCT116 via inhibiting the transcription and expression of YAP protein.

Honokiol, derived from Magnolia officinalis (a traditional Chinese medicine), has been reported to have anticancer activity. Here, a series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared and evaluated for their anticancer activities against three types of digestive system tumor cells. Biological evaluation showed that honokiol derivative 3k exhibited the best antiproliferative activity against HCT116 cells with an IC50 value of 6.1 µmol/L, superior to the reference drug 5-fluorouracil (IC50: 9.63 ± 0.27 µmol/L). The structure-activity relationships (SARs) indicated that the introduction of -(4-NO2)Ph, 3-pyridyl, -(2-F)Ph, -(4-F)Ph, -(3-F)Ph, -(4-Cl)Ph, and -(3-Cl)Ph groups was favorable for enhancing the anticancer activity of the title honokiol thioethers. Further study revealed that honokiol thioether 3k can well inhibit the proliferation of colon cancer cells HCT116, arresting the cells in G1 phase and inducing cell death. Moreover, a preliminary mechanism study indicated that 3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway. Thus, honokiol thioether 3k could be deeply developed for the development of honokiol-based anticancer candidates.

Safety and effectiveness of the sutureless integrated stented graft prosthesis in an animal model.

Background: Prolonged circulatory arrest time is an independent risk factor for postoperative adverse events of type A aortic dissection (TAAD) surgery. Further reduction of the circulatory arrest time is essential to improve surgical outcomes. This study aimed to evaluate the safety and effectiveness of the novel Sutureless Integrated Stented (SIS) graft prosthesis in an animal experiment. Materials and methods: Straight type of the SIS graft prosthesis was implanted into the descending aorta of 10 adult male sheep, and the use of the device was scored on a scale of 1-10. Aortic digital subtraction angiography (DSA) was performed at 4, 14, and 26 weeks to investigate the prostheses. After 26 weeks, the animals were sacrificed for histological analysis. Results: The immediate success rate of the surgery was 100 %, and the overall mean score of the use of the device was 9.65 ± 0.99. Three animals died from non-device-related causes during follow-up. Aortic DSA showed filling defects in 5 animals. Histological analysis revealed that all prostheses were intact. Except for 2 early deaths, the other 8 prostheses were endothelialized with mild inflammation, foreign body reactions, and intimal fibrosis. The mean cross-sectional area of the sutureless region was reduced by 26.4 % (range, 1.3-39.1 %). Conclusions: The safety and effectiveness of the novel SIS graft prosthesis were acceptable, and the delivery system exhibited a promising performance. Using the SIS graft prosthesis in TAAD surgery was expected to simplify the procedures and shorten the circulatory arrest time. Further large-scale clinical trials are required to verify these findings.

Circ_0005615 enhances multiple myeloma progression through interaction with EIF4A3 to regulate MAP3K4 m6A modification mediated by ALKBH5.

BACKGROUND: Circular RNAs (circRNAs) are associated with development and progression of multiple myeloma (MM). However, the role and mechanism of circ_0005615 in MM have not been elucidated. METHODS: Circ_0005615 was determined by GEO database. quantitative RT-PCR was performed to confirm the expression of circ_0005615 in peripheral blood of MM patients and MM cells. The roles of circ_0005615 in MM were analyzed using CCK8, transwell invasion, cell apoptosis and tumor xenograft experiments. Bioinformatics tools, RIP and RNA pull down assays were conducted to explore the downstream of circ_0005615. Furthermore, the mechanism was investigated by quantitative RT-PCR, western blot, dot blot and meRIP-PCR assays. RESULTS: Circ_0005615 was upregulated in MM. Overexpression of circ_0005615 promoted cell viability and invasion, and suppressed apoptosis in vitro, which were opposite when circ_0005615 was knockdowned. Mechanistically, EIF4A3, a RNA-binding protein (RBP), could directly bind to circ_0005615 and ALKBH5, where ALKBH5 could directly combine with MAP3K4, forming a circ_0005615- EIF4A3-ALKBH5-MAP3K4 module. Furthermore, circ_0005615 overexpression increased m6A methylation of MAP3K4 by inhibiting ALKBH5, leading to decreased MAP3K4. Further functional experiments indicated that ALKBH5 overexpression weakened the promoting roles of circ_0005615 overexpression in MAP3K4 m6A methylation and tumor progression in MM. The above functions and mechanism were also verified in vivo. CONCLUSIONS: Elevated circ_0005615 decreased MAP3K4 mediated by ALKBH5 through interacting with EIF4A3, thereby accelerating MM progression. Circ_0005615 might be a promising biomarker and target of MM.

Nomogram based on multimodal magnetic resonance combined with B7-H3mRNA for preoperative lymph node prediction in esophagus cancer.

BACKGROUND: Accurate preoperative prediction of lymph node metastasis (LNM) in esophageal cancer (EC) patients is of crucial clinical significance for treatment planning and prognosis. AIM: To develop a clinical radiomics nomogram that can predict the preoperative lymph node (LN) status in EC patients. METHODS: A total of 32 EC patients confirmed by clinical pathology (who underwent surgical treatment) were included. Real-time fluorescent quantitative reverse transcription-polymerase chain reaction was used to detect the expression of B7-H3 mRNA in EC tissue obtained during preoperative gastroscopy, and its correlation with LNM was analyzed. Radiomics features were extracted from multi-modal magnetic resonance imaging of EC using Pyradiomics in Python. Feature extraction, data dimensionality reduction, and feature selection were performed using XGBoost model and leave-one-out cross-validation. Multivariable logistic regression analysis was used to establish the prediction model, which included radiomics features, LN status from computed tomography (CT) reports, and B7-H3 mRNA expression, represented by a radiomics nomogram. Receiver operating characteristic area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the predictive performance and clinical application value of the model. RESULTS: The relative expression of B7-H3 mRNA in EC patients with LNM was higher than in those without metastasis, and the difference was statistically significant (P < 0.05). The AUC value in the receiver operating characteristic (ROC) curve was 0.718 (95%CI: 0.528-0.907), with a sensitivity of 0.733 and specificity of 0.706, indicating good diagnostic performance. The individualized clinical prediction nomogram included radiomics features, LN status from CT reports, and B7-H3 mRNA expression. The ROC curve demonstrated good diagnostic value, with an AUC value of 0.765 (95%CI: 0.598-0.931), sensitivity of 0.800, and specificity of 0.706. DCA indicated the practical value of the radiomics nomogram in clinical practice. CONCLUSION: This study developed a radiomics nomogram that includes radiomics features, LN status from CT reports, and B7-H3 mRNA expression, enabling convenient preoperative individualized prediction of LNM in EC patients.